agenda - 1 - ohp preferred drug list

Drug Use Research & Management Program

OHA Division of Medical Assistance Programs

500 Summer Street NE, E35; Salem, OR 97301-1079

Phone 503-947-5220 | Fax 503-947-1119

Agenda items with an asterisk will be discussed by Committee members for the purpose of making recommendations to the Oregon Health Plan for adoption into Oregon Administrative Rules 410-121-0030 & 410-121-0040 as required by 414.325(9)

Oregon Drug Use Review / Pharmacy & Therapeutics Committee

Thursday, January 26, 2012 1:00-4:00 PM Clackamas Community Training Center

29353 SW Town Center Loop East Wilsonville, OR 97070

Meeting Agenda I. CALL TO ORDER 1:00 pm – 1:05 pm

a. Roll Call & Introductions B. Origer (Chair) b. Conflict of Interest Declaration R. Citron (OSU) c. Approval of Agenda and Minutes B. Origer (Chair)

II. PROCESS 1:05 pm – 1:15 pm a. Review Procedure Document M. Herink (OSU) b. EBM Review D. Haxby (OSU) c. Approval

III. OLD BUSINESS 1:15 pm – 1:30 pm

a. Methadone / LAO Drug Use Evaluation K.Ketchum (OSU) 1. Proposed PA Criteria 2. Public comment 3. Discussion of clinical recommendations to OHA

IV. NEW BUSINESS 1:30 pm – 2:00 pm

a. Dose Consolidation concept R. Citron (OSU) b. Approval Pathway for New Drugs not in PDL classes* R. Magrish (DMAP)

1. Proposed policy 2. Public Comment 3. Discussion of Clinical recommendations to OHA

BREAK 2:00 pm – 2:10 pm

IV. NEW BUSINESS (continued) 2:10 pm – 3:30 pm

c. Oral Anticoagulants Abbreviated Class Review* K. Sentena (OSU) 1. Pradaxa (dabigatran) 2. Xarelto (rivaroxaban) 3. Public comment 4. Discussion of clinical recommendations to OHA

d. Hepatitis C New Drug Reviews* S. Willard (OSU) 1. Incivek (telaprevir) 2. Victrelis (boceprevir) 3. Public comment 4. Discussion of clinical recommendations to OHA

e. ACE-Is/ARBs/DRIs Class Update* M. Herink (OSU) 1. Edarbi (azilsartan) 2. Public comment 3. Discussion of clinical recommendations to OHA

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*

Agenda items with an asterisk will be discussed by Committee members for the purpose of making recommendations to the Oregon Health Plan for adoption into Oregon Administrative Rules 410-121-0030 & 410-121-0040 as required by 414.325(9)

f. Drug Class Scans* M. Herink (OSU) 1. HSV Antivirals 2. Influenza Antivirals 3. Beta Blockers 4. Calcium Channel Blockers 5. Public Comment

V. EXECUTIVE SESSION 3:30 PM VI. RECONVENE for PUBLIC RECOMMENDATIONS* VII. FUTURE BUSINESS

Tentative Review Schedule and Prioritization

VIII. ADJOURN

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OHA Division of Medical Assistance Programs

500 Summer Street NE, E35; Salem, OR 97301-1079

Phone 503-947-5220 | Fax 503-947-1119

Oregon Pharmacy & Therapeutics Committee

Thursday, November 17, 2011 2:00-5:00 PM Barbara Roberts Human Resources Building Rm#137

500 Summer Street NE, Salem, OR DRAFT Meeting Minutes

Members Present: Andris Antoniskis, MD; Joshua Bishop, PharmD; Zahia Esber, MD; Tracy Klein, PhD, FNP; Phillip Levine, PhD; Meena Mital, MD; William Origer, MD; David Pass, MD; Stacy Ramirez, PharmD; James Slater, PharmD; Cathy Zehrung, RPh Staff Present: Dean Haxby, PharmD; Roger Citron, RPh; Megan Herink, PharmD, BCPS; Ann Hamer, PharmD, BCPP; Kathy Sentena, PharmD; Ted Williams, PharmD, BCPS; Valerie Smith; Trevor Douglass, DC, MPH; Richard Holsapple, RPh; Ralph Magrish, MPA Audience Present: Shannon Beatty (Med Immune); Linda Krueger (Eli Lilly); Venus Holder (Eli Lilly); Deron Grothe (Teva); Jim Graves (BMS); Bob Viadorx (BMS); John Stockton (Astellas); Amy Burus (OSU/OHSU Cop); David Barba (Forest); Barry Benson (Merck); Anne Marie Licos (Med Immune); Jeana Colabianchi (Sunovion); Lori Howarth (Bayer); Kate Ryan (Astra Zeneca); Dave Barrows (Merck); Tom Barrows (Merck); Cheryl Fletcher (Abbott); Bruce Smith (GSK); Jim Hoover (Bayer); Kathy Kirk (OPMC); Kathy Hahn (OPMC); Don Stoches (Novartis); Trish McDaid-O’Neill (Astra Zeneca); Darlene Halverson (Astra Zeneca); James Mattencci (MSD); Paul Nielsen (Med Immune); Shane Hall (Purdue); Mike Willett (Pfizer)

I. CALL TO ORDER

a. The meeting was called to order at 2:10 pm and introductions were made b. Presentation by Dr. Bruce Goldberg, Director OHA c. Presentation by Linda Grimms, Legal Counsel to OHA d. Conflict of interest declaration; no new conflicts were disclosed

II. ELECTION of CHAIR and VICE CHAIR a. Dr. William Origer was nominated to chair the committee

ACTION: Committee voted unanimously to appoint Dr. Origer as chair b. Dr. Tracy Klein was nominated as vice-chair of the committee

ACTION: Committee voted unanimously to appoint Dr. Klein as vice-chair

SUSPEND P&T MEETING

III. RULES ADVISORY COMMITTEE for TEMP RULES a. Minutes from this meeting were recorded separately

CONTINUE P&T MEETING

IV. PROCESS

a. Members were asked to review a draft document and provide feedback at the next meeting

ACTION: No action at this time

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V. PLANNING b. Future meeting dates, times and locations were discussed

ACTION: Future meetings will be held on the last Thursday of each month beginning in January 2012 from approximately 1-4 pm in the SW Portland Metro area VI. NEW BUSINESS

a. Dr. Sentena presented a new drug evaluation on Prasugrel. Public comment was offered by Linda Krueger from Eli Lilly.

b. Dr. Sentena presented new drug evaluation on Ticagrelor. Public comment was offered by Kate Ryan from Astra Zeneca.

ACTION: Committee approved prior authorization criteria after adding the following: • Diagnosis codes for the approved drug indications • Length of treatment allowed for up to 12 months • Allow for continuation of therapy for 30 days after hospitalization • Grandfather patients currently taking medications for 12 months • Make Prasugrel 2nd line and Prasugrel 3rd line therapy

VII. REPORTS/ DUR ACTIVITIES

a. The committee did not review the Methadone / LAO Drug Use Evaluation (DUE); however public comment was offered by Kathy Kirk and Kathy Hahn from Oregon Pain Management Commission

The meeting adjourned at approximately 5:25 pm

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Methadone – New starts @ doses >20 mg

Goals: Promote safe use of methadone upon initiation

Prescribing Recommendations • Opioid naïve or patients receiving codeine preparations: start at low dose and increase slowly:

• 2.5 mg BID-TID; upward titration by 2.5 mg q8h no sooner than weekly • Conversion from other opioids

• Starting dose 2.5mg-5mg q8h; upward titration by 2.5 mg q8h no sooner than weekly • Use short-acting opioid for breakthrough pain until optimum dose reached.

See Oregon DUR Board newsletter at: http://pharmacy.oregonstate.edu/drug_policy/pages/dur_board/newsletter/articles/volume11/DURV11I2.pdf http://pharmacy.oregonstate.edu/drug_policy/pages/dur_board/newsletter/articles/volume5/5_5.html Length of Authorization: Up to 1 year Requires PA: Patients initiated on methadone (i.e. no previous claim within 90 days) on a daily dose of > 20mg

Approval Criteria 1. What is the patient’s diagnosis?

Record ICD9 code.

2. Has patient been continuously on opioids other than codeine over the past 90 days?

Yes: Go to #3 No: Pass to RPH; Deny (Medical Appropriateness) Opioid naïve or patients receiving codeine preparations should start methadone @ 2.5 mg BID-TID; upward titration by 2.5 mg q8h no sooner than weekly

3. Is the total Morphine Equivalent Dose per Day < 200mg? Dose Calculator at: http://pharmacy.oregonstate.edu/drug_policy/prescriber_tools/Opioid_Conversion_Suggestions.pdf

Yes: Pass to RPH; Deny (Medical Appropriateness) Recomment initiat methadone @ 2.5mg - 5 mg q8h; upward titration by 2.5 mg q8h no sooner than weekly and use short-acting opioids for break-through pain

No: Go to #4

4. Is this patient terminal (< 6 months) or admitted to hospice?

Yes: Approve for up to 6 months.

No: Go to #5.

5. Is patient being treated for oncology pain?


No: Pass to RPH; Deny (Medical Appropriateness)

DUR Board Action: 11/17/11 (KK), 5/19/11KK), 3/17/11(KK) Revision(s) Initiated: 1/1/12

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DHS Division of Medical Assistance Programs, 500 Summer Street NE, E35; Salem, OR 97301-1079

Phone 503-947-5220 | Fax 503-947-1119

Drug Use Evaluation: Long-Acting Opioids (LAO) Summary

The LAO prior authorization policy was successful in lowering both utilization and cost of LAOs

The LAO prior authorization policy reduced LAO excessive dose and duplication rates

The methadone dose limit reduced the number of patients on more than 100mg per day

Approximately 50% of patients on any LAO exceed 120mg morphine equivalent dose per day.

About 30% of patients on any LAO concurrently take a benzodiazepine

5% of all methadone patients are started without any previous LAO therapy.

46% of patients newly started on methadone, without previous LAO therapy, exceed 120mg morphine equivalents per day.

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Drug Use Evaluation: Long-Acting Opioids (LAO)

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The use of long-acting opioids (LAO) has been steadily increasing despite concerns over efficacy and safety. Medicaid prescriptions for opioids doubled between 1998 and 2003, accounting for approximately 4% of all Medicaid prescriptions by 2003.1 With increasing use of LAO there has been a corresponding increase in morbidity, as illustrated by an increasing amount of emergency department (ED) visits. The Drug Abuse Warning Network (DAWN) studied ED visits from 2004-2008 and saw a 111% increase in visits related to nonmedical use of opioid analgesics. Methadone, oxycodone and hydrocodone use were associated with the highest number of visits. The non-medical use of benzodiazepines accounted for an 89% increase in ED visits for the same study period.2 The consequences of escalating opioid use was reflected in a report from the 2010 Oregon Prescription Opioid Poisoning Workgroup. In 2007 opioid related poisonings accounted for 22.3% of all medication and drug-related hospitalizations in Oregon. Deaths due to prescription opioids in 2008 represented 53% of all deaths due to poisonings by medications and drugs. Methadone poisonings increased 70-fold since 1997 and deaths due to methadone accounted for 33% of the deaths due to poisonings in Oregon in 2008. In 75% of the deaths due to methadone, patients had a history of substance abuse listed in their charts.3 Other studies have demonstrated that 18-41% of patients using opioids for chronic pain, showed drug abuse behavior.4 Deaths associated with LAO have also been increasing. Some states have reported proportional increases in deaths with the number of opioids prescribed, however, this phenomenon is not consistent in other states with rising mortality rates. It is unknown if increasing LAO deaths are due to an increased distribution of opioids, higher doses, specific LAO or other factors.5 Adverse Effects and Safety Issues The most common adverse effects with LAO treatment are gastrointestinal, headache, fatigue and urinary complications. More severe, but less common, consequences of LAO therapy include sedation, hypoventilation, hallucinations, and abdominal pain. Methadone has been associated with additional serious warnings, outlined in the methadone section. Chronic opioid use has also been shown to effect hormone levels, cause abuse and addiction, tolerance and hyperalgesia.6 LAO products include black box warnings for respiratory depression, inappropriate use and drug/alcohol interactions. Methadone prescribing information specifically warns against rapid-titration of methadone with consequential drug accumulation leading to respiratory and cardiac effects. Additionally, warnings of QTc prolongation and arrhythmias in patients on high doses of methadone, and less commonly on maintenance doses, are described.7 Fentanyl prescribing also contains additional warnings of life-threatening hypoventilation, even in opioid-tolerant patients, due to peak fentanyl concentrations occurring between 20-72 hours of treatment and because of its high potency.8

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Although rare, serious consequences of LAO therapy include death due to drug abuse and misuse issues. Opioid treatment guidelines identify personal or family history of alcohol or drug abuse as one of the strongest predictors of aberrant drug use.6 Additionally, patients with comorbid psychiatric conditions and younger age have also been shown to be at increased risk of opioid abuse in some studies.9 Drug Interactions Many LAO are prone to drug interactions due to metabolism via CYP enzyme metabolic pathways. Commonly LAO are used in combination with benzodiazepines, which also utilize the CYP3A4 enzyme system. Studies have shown that patients on LAO therapy, taking benzodiazepines, routinely show more harms than non-benzodiazepine users. Newly published guidelines from the Canadian Guideline for the Safe and Effective Use of Opioids recommend that patients on benzodiazepines, starting opioid therapy, undergo a tapering trial or proceed with opioids with a slow titration and at lower doses if the combination is necessary.10 A pharmacodynamic study of a single dose of diazepam in patients taking methadone resulted in greater subjective effects, or drug “high”, but no acute physiological effects were seen.11 Other studies have noted increased sedation and deterioration of reaction time when methadone and diazepam were given together. A study using “abuse” conditions – 0 and 40 mg diazepam in addition to 100% and 150% normal opioid-assisted therapy doses in four methadone and seven buprenorphine patients, demonstrated evidence of respiratory depression in some patients. Patients on LAO therapy requesting benzodiazepines should be assessed for appropriate use, other substance abuse, and source of benzodiazepines and likelihood of high-risk behaviors. LAO prescribing information warns against combining benzodiazepines, and other sedatives, and that these combinations may result in respiratory depression, profound sedation, hypotension and coma. Alcohol has been shown to further decrease respiration resulting in fatal overdoses in patients taking LAO, benzodiazepines and alcohol together.11 Methadone As outline above, specific attention has been focused on the adverse effect profile of methadone, with an increased number of poisonings and death in Oregon and nation-wide. A 2004 Substance Abuse and Mental Health Services Administration (SAMHSA) report concluded that methadone related deaths were often a result of combining the drug with other central nervous system depressants, such as benzodiazepines, alcohol and other opioids.12 Methadone is known to cause QTc prolongation and cardiac arrhythmias at higher doses or when give with interacting drugs. A small case series found episodes of torsades de pointes in high dose methadone uses (>400mg/day). Another case series in patients taking lower doses of methadone (median 110 mg/day) found that 32% had QTc prolongation but no incidences of torsades de pointes.13 A recent study of QTc effects in advanced cancer patients taking methadone, found clinically significant increases in the QTc interval in only 1.6% of patients at week 2 and no changes at weeks 4 or 8.14 However, there has been criticism of how this study

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measured the QTc changes in addition to other design flaws. 15 To minimize this risk methadone should not be given to patients at increased risk of cardiac disease, arrhythmias or presentation of a prolonged QT interval prior to starting methadone therapy.13 Methadone pharmacokinetics and pharmacodynamics further complicate its use, as it has an unpredictable half-life, ranging from 15-60 hours and up to 120 hours in some patients.6 Additionally, it is generally accepted that the analgesic efficacy wanes before its corresponding half-life, lending itself to be re-dosed leading to drug accumulation.16 Guidelines recommend starting opioid naïve patients on 2.5mg every 8 hours, titrating the dose no more than weekly. It is also recommended that when switching patients to methadone from other LAO, doses above 40mg not be used even in patients taking high doses of LAO. Patients taking other LAO may be incompletely tolerant to the effects of methadone and deaths have resulted when converting patients from other chronic, high-dose opioid treatment regimens.7

Drug use criteria for appropriate methadone use has been suggested in the literature.17 Recommendations include:

- Naïve patients should be initiated at a low dose and increased slowly. - Patients converting from other opioids should be initiated on no more than

40mg/day and titrated no sooner than weekly. - Patients should be assessed for QTc risk especially at high methadone doses.

Doses of 60-150mg/day are recommended thresholds.

Guideline Recommendations Using LAO for cancer or end of life pain is widely accepted but treating chronic noncancer pain with opioid therapy is more controversial. Many pain guidelines advocate the use of LAO for chronic noncancer pain despite limitations in evidence, escalating use, abuse and potential for life-threatening adverse effects.6,18 The Veterans Affairs/Department of Defense Guidelines state that there is good evidence that LAO are effective for continuous pain.19 The Cochrane report concluded that there is data to support that there is clinically important long-term pain relief for patients taking opioids for more than 6 months.20 Guidelines and systematic reviews on using LAO for non-cancer pain cite that there is no clear evidence that a specific opioid has demonstrated superior efficacy or safety over another.6,10,21 There is limited evidence on the safest and most effective way to initiate, titrate, transition and select LAO therapy. Guidelines recommend initiating opioids at a low dose and titrating the drug slowly, taking into account the specific pharmacokinetics of the drugs, in order to minimize adverse effects. No LAO has specifically been shown to be safer of more effective as initial therapy.6 Although opioids are viewed as having no maximum dose, guidelines recommend not exceeding

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200mg/day of oral morphine, or equivalent, in patients with chronic noncancer pain (table 1).6,10 Table 1. Morphine Equivalents

Morphine 120mg

Fentanyl 50mcg/day

Morphine 200mg

Fentanyl 83mcg/day

Hydromorphone 30mg/day

Hydromorphone 50mg/day

Oxycodone 80mg/day Oxycodone 133mg/day

Oxymorphone 40mg/day Oxymorphone 67mg/day

Methadone 40mg/day Methadone 67mg/day

Literature Review A recent retrospective claim analysis of chronic opioid therapy in patients with non-cancer pain in commercial insured and Arkansas Medicaid populations was preformed. Regression analysis was used to determine risk factors for emergency department visits (EDV) and alcohol- or drug-related encounters (ADEs). ED visits were more commonly associated with younger age, females, more medical comorbidities, presence of headaches and greater number of nontracer pain conditions (less common pain conditions not specifically tracked). Opioid doses >120mg/day ME was associated with more ADEs but only statistically significant in the commercial insured population. In the Medicaid population the use of Schedule II long-acting drugs, alone or with non-Schedule II drugs, was significantly associated with more ADEs. Statistically significant RR increases in ADEs were seen with alcohol and/or nonopioid drug abuse or dependence in the Medicaid population. Combining sedative and/or hypnotic drugs with prescription opioids were also associated with ADEs and ED visits.22 In an additional analysis of the same populations, risk of possible and probable opioid misuse was performed. Twenty percent of the Medicaid population using chronic opioids were estimated to be misusing the drugs and 3% were probably misusing. The most common factors associated with misuse was younger age, back pain, multiple pain complaints, and substance abuse disorders. High dose opioids (>120 mg MED) and short-acting Schedule II opioids were also associated with misuse. There were also correlations between misuse and increasing numbers of prescribers and pharmacies.9 Additional studies of health plans have showed increased utilization of LAO for chronic noncancer pain. A study by Boudreau et al found that along with increased utilization there were also 28.6%-30.2% of plan members also using sedative hypnotics concomitantly with opioids.22 Another study looking at opioid prescribing from 1991 to 2007 found an 850% increase in the number of oxycodone prescriptions, in which 28% were for long-acting oxycodone. There was a 5-fold increase in the number of oxycodone related deaths over the same period.23

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Drug Use Evaluations

In response to LAO safety concerns, Oregon FFS Medicaid LAO drug use was evaluated from January 2000 through December 2004. A retrospective observational study of 5684 patients with prescriptions for at least 28 days were analyzed. First reported adverse outcome among patients with new prescriptions for methadone, extended-release (ER) oxycodone, morphine ER, or transdermal fentanyl were documented. Patients in the oxycodone ER cohort were 35% less likely to have an event compared to the morphine ER cohort. Patients taking fentanyl for non-cancer pain had a higher risk of emergency department (ED) encounters compared to morphine ER. Patients with non-cancer pain taking methadone had a 57% increased risk of having symptoms of overdose compared to the morphine ER cohort. However, subjects taking methadone were less likely to be hospitalized than those taking morphine ER.24

More recently, methadone use in the Oregon FFS Medicaid population was analyzed. Drug claims from December 2007 through November 2008 in 1,045 patients showed 10% of the population taking methadone doses associated with QTc prolongation. Doses >120/day are known to cause QTc changes, putting patients at increased risk of sudden death. In 39% of new methadone users there was no record of prior claims for opioid medications and average daily doses were 47mg, exceeding recommendations for new starts and conversion from other opioid therapies. 17

New policies were adopted to address these concerns regarding the safety risks associated with methadone and LAO use:

1. A prior authorization for Methadone doses > 100mg/day was implemented 1/1/10. 2. RetroDUR letters were sent to prescribers of methadone > 40mg/day, starting early 2010. 3. A prior authorization for non-preferred LAO was initiated, focusing on dose and duplication issues, for patients with OHP coverage on 7/1/2009.

The effectiveness of these policies were evaluated. Methods Trend analysis A LAO was defined as an opioid drug that can be dosed one or two times daily. LAOs include fentanyl patches, levorphanol and methadone as well as long acting formulations of morphine, oxycodone, oxymorphone and morphine combined with naltrexone. See Appendix A for complete list of Generic Sequence Numbers used to identify these drugs. Paid, clean, fee-for-service pharmacy claims from January 1, 2009 thru December 31, 2010 were queried for trends in LAO costs and utilization and quantified as a monthly per member per month (PMPM) value. Costs were defined as ingredient cost (paid

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amount + copay amount + other insurance paid – dispensing fee) and utilization was defined as the claim count. Rebates were not included in the reported costs. Total eligibility figures for BMH (OHP Plus) and KIT (OHP standard) benefit packages were used for the denominator. Finally, total and average costs for 30 days were quantified during the pre-intervention period (1/1/09 - 6/30/09) and post intervention period (7/1/10-12/31/10). LAO User Analysis For pre-intervention period (1/1/09 – 6/30/2010) and the post-intervention period (7/1/10-12/31/10), LAO users were identified if a single claim was paid for a LAO. Each LAO user with at least 90 continuous days of therapy was included in the chronic use cohort. Continuous therapy is defined as sequential claims where the beginning of the next claim is no greater than 14 days after the end of the previous claim. The “end” of a claim is defined as claim date + day supply. Demographic information such as age, sex, and race were quantified in all LAO users as well as the chronic use cohort. The prevalence of patients on more than one LAO was characterized pre- and post- intervention. The average dose and number of subjects exceeding 120mg of morphine equivalent per day (MED) was also described pre- and post intervention. Finally the number of patients exceeding 100mg per day of methadone was quantified pre- and post interventions. Dose calculations are included in Appendix A. Duplicate LAO use was defined claims for two unique LAO with a continuous overlap of at least 60 days. This analysis was done in chronic users pre- and post- intervention. Additionally, those chronic LAO users on 60 days concurrently with drugs of concern (benzodiazepine, skeletal muscle relaxants and drugs affecting the QTc interval) were quantified. The complete lists of drugs of concern is in Appendix B. The number of opioid naïve patients initiating methadone was quantified in the post period. This included any patient starting on methadone with no LAO in the previous 90-days. Patients in this analysis were restricted to those with >75% eligibility for the period. Among the chronic users the prevalence of diagnoses thought to be common for LAO users was characterized. Specifically, ICD9CM codes from paid, clean, FFS or FCHP medical claims within 6 months prior of an index LAO claim were used to quantify the number of patients with conditions known to be treated with LAOs. A patient may have more than one condition of interest. Results Trend Analyses From January 1, 2009 to December 31, 2010 utilization of LAO trended steadily downward (Figure 1). When the trend is examined for the three independent segments of pre-intervention, post LAO prior authorization (PA) and post methadone dose limit there is a discernable reduction in use temporal to the policies. The LAO PA affected all LAOs except generic long-acting morphine, methadone and levophanol and was

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started July 1, 2009. It requires a covered OHP diagnosis and limits duplication and excessive dose. The LAO PA reduced use by 32% annually. Methadone doses exceeding 100mg required PA starting January 1, 2010. A RetroDUR intervention targeted doses greater than 40mg for education began in Q1-2010. There does not appear to be an additional reduction in response to the methadone policies. The trend is downward in all drugs with no apparent increases from drugs requiring PA to those that do not. One confounding factor is the increase in denominator overall during the same time period due to increasing enrollment which may account for the general downward trend in use PMPM. Figure 1 - LAO Utilization PMPM (x10,000) 2009-2010

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Figure 2 – LAO Utilization PMPM (x 10,000) 2009-2010

There is a similar downward trend in LAO PMPM costs with the total cost curve primarily following the oxycodone long-acting curve (Figure 3). Table 1 confirms that long-acting oxycodone is the primary cost driver. It captures 52.5% of the total gross drug costs while ranked 3rd by utilization (Figure 2). Figure 3 - LAO Ingredient Cost PMPM (x100) 2009-2010

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14

16

18

Jan-0

9

Feb-0

9

Mar-0

9

Apr-0

9

May-0

9

Jun-0

9

Jul-0

9

Aug-0

9

Sep-0

9

Oct-0

9

Nov-0

9

Dec-0

9

Jan-1

0

Feb-1

0

Mar-1

0

Apr-1

0

May-1

0

Jun-1

0

Jul-1

0

Aug-1

0

Sep-1

0

Oct-1

0

Nov-1

0

Dec-1

0

Rx P

MP

M (

x10

,00

0)

MORPHINE (ALL LONG ACTING FORMS)

METHADONE ORAL

OXYCODONE LONG-ACTING

FENTANYL PATCHES

LEVORPHANOL ORAL

MORPHINE / NALTREXONE

OXYMORPHONE LONG-ACTING

$0

$10

$20

$30

$40

$50

$60

$70

$80

$90

$100

$0

$5

$10

$15

$20

$25

$30

$35

$40

$45

$50

Jan-0

9

Fe

b-0

9

Mar-0

9

Apr-0

9

May-0

9

Jun-0

9

Jul-0

9

Aug-0

9

Sep-0

9

Oct-0

9

Nov-0

9

Dec-0

9

Jan-1

0

Fe

b-1

0

Mar-1

0

Apr-1

0

May-1

0

Jun-1

0

Jul-1

0

Aug-1

0

Sep-1

0

Oct-1

0

Nov-1

0

Dec-1

0

Ing

red

ien

t C

ost

PM

PM

(x100)

Total Cost

OXYCODONE LONG-ACTING

MORPHINE (ALL LONG-ACTING FORMS)

FENTANYL PATCHES

METHADONE ORAL

LEVORPHANOL ORAL

MORPHINE / NALTREXONE

OXYMORPHONE LONG-ACTING

15 of 187


10

Table 1: Oregon FFS LAO Cost Summary

% Change Pre-period to Post-Period Post Period Costs

PMPM Utilization (x10,000)

PMPM Cost (x100) Total Cost

(%) Total LAO Costs

Avg Cost / 30 Days

FENTANYL PATCHES -52.4% -60.1% $255,723 18.4% $325

LEVORPHANOL ORAL -88.9% -95.1% $46 0.0% $195

METHADONE ORAL -36.7% -43.7% $33,138 2.4% $16

MORPHINE (ALL LONG-ACTING FORMS) -27.7% -25.1% $356,573 25.7% $122

MORPHINE / NALTREXONE $7,084 0.5% $646

OXYCODONE LONG-ACTING -51.6% -39.0% $727,972 52.5% $473

OXYMORPHONE LONG-ACTING -73.2% -84.3% $6,772 0.5% $339

$1,387,308 $189

LAO User Analysis A total of 2273 unique patients had at least one claim for an LAO in the pre-intervention period of which 1437 (63%) were considered a chronic user of an LAO. During the post intervention period there were 1690 unique LAO patients identified and 941 (56%) were considered a chronic user. The demographics, shown in table 2, suggest that chronic users were similar to all users in terms of measurable patient characteristics. The mean age was ~48 years, however the range was from the very young (<1) to the very old (91). Most LAO users are in the 19-65 age group. There is perhaps a more prevalent LAO use among American Indians than the overall OHP population which is reported at just 1.8%.

Table 2: Demographics of all LAO users and chronic users

Pre - Period Post - Period

All Users Chronic Users All Users Chronic Users

Total 2,273 (%) 1,437 (%) 1,690 (%) 941 (%)

Mean Age 47 48 48 49

Range 1-91 4-91 0-77 12-67

<6 5 0.2% 1 0.1% 4 0.2% 0.0%

6-12 4 0.2% 1 0.1% 1 0.1% 1 0.1%

13-18 9 0.4% 5 0.3% 7 0.4% 3 0.3%

19-65 2,244 98.7% 1,424 99.1% 1,672 98.9% 933 99.1%

>65 11 0.5% 6 0.4% 6 0.4% 4 0.4%

Female 1,421 62.5% 904 62.9% 1,045 61.8% 591 62.8%

Race

White 1,943 85.5% 1,227 85.4% 1,414 83.7% 805 85.5%

Am.Indian 153 6.7% 117 8.1% 157 9.3% 85 9.0%

Black 45 2.0% 20 1.4% 27 1.6% 13 1.4%

Asian 5 0.2% 3 0.2% 6 0.4% 3 0.3%

Other 127 5.6% 70 4.9% 86 5.1% 35 3.7%

16 of 187


11

Most chronic LAO users were taking long-acting forms of morphine followed by methadone. A market share shifted from both oxycodone long-acting and fentanyl patches toward morphine can be detected in this table. There was a 1% increase in the number of patients on methadone. Table 3 summarizes the distribution of specific LAO use. Table 3: Distribution of LAO users pre- and post- interventions

Drug Pre-Period% All Users Post-Period % All Users

MORPHINE (ALL LONG-ACTING FORMS) 33% 41%

METHADONE ORAL 34% 35%

OXYCODONE LONG-ACTING 28% 19%

FENTANYL PATCHES 14% 10%

OXYMORPHONE LONG-ACTING 1% 0%

MORPHINE / NALTREXONE 0% 0%

LEVORPHANOL ORAL 0% 0%

Total 100% 100%

Table 4 depicts the average dose per day for each drug. With the exception of oxycodone and the naltrexone combination product the average dose declined or remained constant in the post-intervention period. The table also identifies the number of patients exceeding 120 mg MED before and after the interventions. The absolute numbers declined across the entire class but percentages remain concerning with 50% or more of patients on LAO exceeding the 120mg MED per day. Finally, the number of patients exceeding 100mg per day of methadone declined both in absolute numbers and percentage of patients on methadone.

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12

Table 4: Dose Analysis of Chronic LAO users

Pre - Period Post - Period

Drug

Avg Daily Dose (mg)

Patients >120mg ME/ day

(%) of patients on drug

Patients >100mg

/ day


Avg Daily Dose (mg)

Patients >120mg ME/day


Patients >100mg

/ day


FENTANYL PATCH TD72

2 37 16% 2 15 15%

LEVORPHANOL TABLET

9 -

METHADONE ORAL CONC

73 3 75% 1 25% 10

METHADONE SOLUTION

58 1 50% 1 50% 30

METHADONE TABLET

62 309 60% 110 21% 56 184 57% 29 9%

MORPHINE CAP ER PEL

139 14 50% 142 8 53%

MORPHINE CPMP 24HR

134 5 33% 120 1 50%

MORPHINE TABLET ER

142 212 42% 140 134 38%

MORPHINE / NALTREXONE CAP ER PEL

40 120 1 50%

OXYCODONE TAB ER 12H

90 202 47% 101 107 50%

OXYMORPHONE TAB ER 12H

62 14 88% 37 2 67%

Tables 5a and 5b compare 60 day duplication of LAO therapy pre- and post intervention. Prior to the intervention 6.7% of fentanyl patch users also used methadone concurrently, 5.1% used long-acting oxycodone concurrently and 2.8% used long-acting morphine concurrently. No other combinations exceeded 2%. Fentanyl patch users remain the only group that duplicated LAO by more than 2% in the post period but rates reduced to 3.3% with methadone, 2.2% with long-acting oxycodone and 3.3% with long-acting morphine. Absolute numbers were <3 for each combination in the post period.

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13

Table 5a: Prevalence of concurrent LAO drugs among chronic users in the PRE period (n=1437)

FE

NT

AN

YL

PA

TC

HE

S

(%)

LE

VO

RP

HA

NO

L

OR

AL

(%)

ME

TH

AD

ON

E

OR

AL

(%)

MO

RP

HIN

E (A

LL

LO

NG

-AC

TIN

G

FO

RM

S)

(%)

MO

RP

HIN

E /

NA

LT

RE

XO

NE

(%)

OX

YC

OD

ON

E

LO

NG

-AC

TIN

G

(%)

OX

YM

OR

PH

ON

E

LO

NG

-AC

TIN

G

(%)

n 178 1 446 416 0 372 10

FENTANYL

PATCHES 0 0.0% 12 2.7% 5 1.2% 9 2.4% 0 0.0%

LEVORPHANOL 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

METHADONE 12 6.7% 0 0.0% 7 1.7% 5 1.3% 0 0.0%

MORPHINE (ALL

LONG-ACTING

FORMS) 5 2.8% 0 0.0% 7 1.6% 2 0.5% 0 0.0%

MORPHINE /

NALTREXONE 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

OXYCODONE

LONG-ACTING 9 5.1% 0 0.0% 5 1.1% 2 0.5% 0 0.0%

OXYMORPHONE

LONG-ACTING 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

Table 5b: Prevalence of concurrent LAO drugs among chronic users in the POST period (n=941)

FE

NT

AN

YL

PA

TC

HE

S

(%)

LE

VO

RP

HA

NO

L

OR

AL

(%)

ME

TH

AD

ON

E

OR

AL

(%)

MO

RP

HIN

E (A

LL

LO

NG

-AC

TIN

G

FO

RM

S)

(%)

MO

RP

HIN

E /

NA

LT

RE

XO

NE

(%)

OX

YC

OD

ON

E

LO

NG

-AC

TIN

G

(%)

OX

YM

OR

PH

ON

E

LO

NG

-AC

TIN

G

(%)

n 92 0 312 340 2 204 3

FENTANYL

PATCHES 3 1.0% 3 0.9% 0 0.0% 2 1.0% 0 0.0%

LEVORPHANOL 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

METHADONE 3 3.3% 2 0.6% 0 0.0% 2 1.0% 0 0.0%

MORPHINE (ALL

LONG-ACTING

FORMS) 3 3.3% 2 0.6% 0 0.0% 0 0.0% 0 0.0%

MORPHINE /

NALTREXONE 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

OXYCODONE

LONG-ACTING 2 2.2% 2 0.6% 0 0.0% 0 0.0% 0 0.0%

OXYMORPHONE

LONG-ACTING 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

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14

Table 6 indicates that there is a 29-34% incidence of 60-day concurrent use of LAOs with benzodiazepines, a 16-24% incidence of 60-day concurrent use of LAOs with skeletal muscle relaxants and 11-21% incidence of 60-day concurrent use of LAOs with drugs affecting the QTc interval. Table 6: Chronic users with concurrent medications of concern in Post period

Concurrent with:

Skeletal Muscle

Relaxant

QTc Interval

Drug Chronic Users Benzodiazepine

Drug n= 941 n= (%) n= (%) n= (%)

FENTANYL PATCHES 102 32 31% 24 24% 20 20%

METHADONE ORAL 324 109 34% 64 20% 67 21%

MORPHINE (ALL LONG-ACTING FORMS) 371 107 29% 61 16% 67 18%

OXYCODONE LONG-ACTING 214 68 32% 40 19% 24 11%

OXYMORPHONE LONG-ACTING 3 1 33% 0%

Table 7 quantifies the number patients initiated on methadone with no prior LAO claim in the previous 90 days. There were 26 new patients that were LAO naïve. This represented 5% of all methadone users in the post-period. Of these, the average dose was 44mg per day. Sixteen patients exceeded 120mg MED and 1 exceed 100mg of methadone per day. Table 7: New Methadone Starts in Post Period with no history of other LAOs in prior 90 Days

Total N=26 5% (all

methadone users)

Age

Mean 45

Range 19-62

<6

6-12

13-18

19-65 26 100%

>65

Female 21 81%

Race

White 21 81%

American Indian 4 15%

Black

Asian

Other 1 4%

Average Daily Methadone Dose 44mg

Patients exceeding 120mg MED 12 46% Patients exceeding 100mg methadone / day 1 4%

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15

Diagnoses within the previous 6 months of an index claim for an LAO among chronic users in the post period are represented in Table 8. The most prevalent diagnosis present was dorsopathies. Table 8: Presence of Pain Diagnosis in Prior 6 months, Chronic Users in Post Period only

Chronic Users

Post Period

Pain Diagnoses ICD9 n= 941 (%)

Cancer: 140x-239x 115 12.2%

Dorsopathy: 720x-724x 221 23.5%

Fibromyalgia: 7291 71 7.5%

Neuropathy: 350x-359x 66 7.0%

Osteoarthritis: 715x 96 10.2%

Discussion: There has been a significant decrease in both the utilization and cost of LAOs since a prior authorization policy for the class was initiated on July 1, 2009 and a methadone dose limit and educational intervention was initiated on January 1, 2010. While the trend line is temporal to the PA policy, it is confounded by significant increases in OHP enrollment overall during the time period. However, absolute numbers have decreased in addition to PMPM trends and thus the policy likely had a significant effect on both use and cost. Long-acting oxycodone remains the drug associated with the most cost despite losing 8% of patients between the pre- and post- intervention periods. Fentanyl patches also lost 4% market share by patient. Long-acting morphine gained 8% market share by patient and methadone gained 1%. This likely reflects the PA policy that exempted both long-acting morphine and methadone. Several utilization markers of concern improved in the post- intervention period. Excessive doses remain with over 50% of users of most LAOs exceeding 120mg MED. However, absolute numbers have diminished. Methadone doses exceeding 100mg per day has declined from 110 patients (21%) to just 29 patients (9%). There was also a reduction the concurrent use of LAOs. Patients on fentanyl patches remain the only patients that require duplicate LAO used in excess of 2% but absolute numbers are very low (<3). Finally, there appears to be a significant concurrent use (10-30%) of LAOs with drugs of concern for interaction. Benzodiazepines are the most prevalent.

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Twenty-six patients (5%) were LAO naïve when initiated on methadone and the average dose exceeded 40mg per day. These clients are at the most risk for adverse outcome from methadone use. Conclusions: The LAO PA policy was successful in lowering both utilization and cost of LAOs. It has also improved LAO dosing and duplication. The methadone dose limit has improved methadone dosing. However, approximately 50% of patients on any LAO exceed 120mg MED. And, there is a significant incidence of concurrent use with drugs of concern, particularly benzodiazepines. Finally, over half of new methadone patients were started on doses exceeding 120 MED. Recommendation:

Consider adding LAO patients with concurrent use criteria for benzodiazepines or skeletal muscle relaxants to Pharmacy Lock-in Program (add current Lock-in Program screening criteria).

Consider adding any patient the methadone dose limit to >40mg to Pharmacy Lock-in Program (add to current Lock-in Program screening criteria)

Consider requiring a prior authorization for new methadone starts with no prior LAO use in last 90 days.

References:

1. Brixner D, Oderda G, Roland C, et al. Opioid expenditures and Utilization in the Medicaid System. J

Pain Palliat Care Pharmacother 2006;20:5-13. 2. Centers for Disease Control and Prevention. Emergency Department Visits Involving Nonmedical Use

of Selected Prescription Drugs – United States, 2004-2008. Morbidity and Mortality Weekly 2010; 59(23):705-709.

3. Oregon Prescription Opioid Poisoning Workgroup. Methadone Poisoning in Oregon. Oregon Public Health Division Injury Prevention and Epidemiology Program. October 6, 2010.

4. Manchikanti, L, Fellows B, Ailinani H, et al. Therapeutic Use, Abuse, and Nonmedical Use of Opioids:

A Ten-Year Perspective. Pain Physicians 2010; 13:401-435. 5. The American Pain Society/American Academy of Pain Medicine. Guideline for the Use of Chronic

Opioid Therapy in Chronic Noncancer Pain. www.ampainsoc.org/pub/pdf/LBPEvidRev.pdf. Accessed February 28, 2011.

6. Chou R, Fanciullo G, Fine P, et al. Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic

Noncancer Pain. The Journal of Pain 2009;10(2):113-130. 7. Dolophine [product information]. Columbus, OH; Roxane Laboratories, Inc., 2006.

8. Duragesic [package insert]. Raritan, NJ; Ortho-McNeil-Janssen Pharmaceutical, Inc., 2009. 9. Sullivan M, Edlund M, Fan M, et al. Risks for Possible and Probable Opioid Misuse Among Recipients

of Chronic Opioid Therapy in Commercial and Medicaid Insurance Plans: The TROUP Study. Pain 2010;150:332-339.

10. National Opioid Use Guideline Group. Canadian Guideline for Safe and Effective Use of Opioids for

Chronic Non-Cancer Pain. 2010, version 5.6. http://nationalpaincentre.mcmaster.ca/documents/opioid_guideline_part_b_v5_6.pdf. Accessed February

27, 2011. 11. Lintzeris N, Nielsen S. Benzodiazepines, Methadone and Buprenorphine: Interactions and Clinical

Management. Am J Addict 2009;19:59-72.

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http://www.ampainsoc.org/pub/pdf/LBPEvidRev.pdf

http://nationalpaincentre.mcmaster.ca/documents/opioid_guideline_part_b_v5_6.pdf


17

12. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Drug Abuse

Warning Network 2007: National Estimates of Drug-related Emergency Department Visits. Rockville, MD, 2010.

13. McCance-Katz E, Sullivan L, Nallani S. Drug Interactions of Clinical Importance among the Opioids, Methadone, and Buprenorphine, and Other Frequently Prescribed Medications: A Review. Am J Addict

2009;19:4-16.

14. Reddy S, Hui D, Osta B, et al. The Effect of Oral Methadone on the QTc Interval in Advanced Cancer

Patients: A Prospective Pilot Study. J of Palliative Med 2010;13(1):33-39. 15. Heppe D, Haigney M, Krantz M. The Effect of Oral Methadone on the QTc Interval in Advanced

Cancer Patients: A Prospective Pilot Study, Letter to the Editor. J of Palliative Med 2010;13(6):638-639. 16. Trescot A, Boswell M, Atluri S, et al. Opioid Guideline in the Management of Chronic Non-Cancer

Pain. Pain Physician 2006;9:1-40.

17. Drug Use Research and Management Program. Drug Use Evaluation: Methadone. Oregon State College of Pharmacy 2009.

18. Jost L, Roila F. Management of Cancer Pain: ESMO Clinical Practice Guidelines. Annals of Oncology 2010;21(S5):v257-v260.

19. The Management of Opioid Therapy for Chronic Pain Working Group. Va/DoD Clinical Practice

Guidelines for the Management of Opioid Therapy for Chronic Pain. Contract Number: V101 (93) P-1633 (version 1.0) 2003.

20. Noble M, Treadwell J, Tregear S, et al. Long Term Opioid Management for Chronic Non-cancer Pain. Cochrane Database for Systematic Reviews 2010, Issue 1. Art. No.: CD006605. DOI:

10.1002/14651858.CD006605.pub2. 21. Chou R, Clark E, Helfand M. Comparative Efficacy and Safety of Long-Acting Oral Opioids for Chronic

Non-Cancer Pain: A Systematic Review. J Pain Symptom Manage 2003;26:1026-1048.

22. Braden J, Russo J, Fan M, et al. Emergency Department Visits Among Recipients of Chronic Opioid Therapy. Arch Intern Med 2010;170(16):1425-1432.

22. Boudreau D, Von Korff M, Rutter C, et al. Trends in long-term opioid therapy for chronic non-cancer pain. Pharmacoepidemiol Drug Saf 2009;18:1166-1175.

23. Caudill-Slosberg M, Schwartz L, Woloshin S. Office Visits and Analgesic Prescriptions for

Musculoskeletal Pain in US: 1980 versus 2000. Pain 2004;109:514-519. 24. Hartung D., Middleton L, Haxby D, et al. Rates of Adverse Events of Long-Acting Opioids in a State

Medicaid Program. Ann Pharmacother 2007;41:921-8.

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Appendix A

GSN Generic Name Strength

120mg Morphine

Equivalent (ME)

Approx 120mg ME Disp

Quantity / Day =

Max Dose /

Day

Max Quantity /

Day

15883 FENTANYL 100 mcg/ho 50 mcg / hr 0

59102 FENTANYL 12 mcg/hou 50 mcg / hr 1.33333333



15882 FENTANYL 75 mcg/hou 50 mcg / hr 0

4228 LEVORPHANOL TARTRATE 2 mg 24 mg / day 12

4240 METHADONE HCL 10 mg 40mg / day 4 100mg 10

4237 METHADONE HCL 10 mg/5 mL 40mg / day 20 100mg 50

4239 METHADONE HCL 10 mg/mL 40mg / day 4 100mg 10

23767 METHADONE HCL 40 mg 40mg / day 1 100mg 2.5

4242 METHADONE HCL 5 mg 40mg / day 8 100mg 20

4238 METHADONE HCL 5 mg/5 mL 40mg / day 40 100mg 100

60355 MORPHINE SULFATE 10 mg 120mg / day 12











64739 MORPHINE SULFATE 45 mg 120mg / day 2.5








65549 MORPHINE SULFATE/NALTREXONE 100 mg-4 m 120mg / day 1

65544 MORPHINE SULFATE/NALTREXONE 20 mg-0.8 120mg / day 6


65546 MORPHINE SULFATE/NALTREXONE 50 mg-2 mg 120mg / day 2.5

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19


65548 MORPHINE SULFATE/NALTREXONE 80 mg-3.2 120mg / day 1.5

24504 OXYCODONE HCL 10 mg 70mg / day 7







61092 OXYMORPHONE HCL 10 mg 35mg / day 3.5

63783 OXYMORPHONE HCL 15 mg 35mg / day 2

61093 OXYMORPHONE HCL 20 mg 35mg / day 1.5




63782 OXYMORPHONE HCL 7.5 mg 35mg / day 5 Appendix B

Benzodiazepine List GenName HSN RtCode

ESTAZOLAM 6036 PO

FLURAZEPAM HCL 1593 PO

MIDAZOLAM HCL 1619 PO

QUAZEPAM 1595 PO

TEMAZEPAM 1592 PO

TRIAZOLAM 1594 PO

ALPRAZOLAM 1617 PO

CLORAZEPATE DIPOTASSIUM 1612 PO

DIAZEPAM 1615 PO

LORAZEPAM 4846 PO

OXAZEPAM 1616 PO

CLONAZEPAM 1894 PO

TEMAZEPAM/DIET8 33614 PO

ALPRAZOLAM/DIETARY SUPPL NO.17 34747 PO

Skelatal Muscle Relaxants; any drug in STC = 08

Qtc Intx Drugs GenName HSN RtCode

CLARITHROMYCIN 6228 PO

25 of 187


20

ERYTHROMYCIN BASE 4022 PO

ERYTHROMYCIN ESTOLATE 4017 PO

ERYTHROMYCIN ETHYLSUCCINATE 4018 PO

ERYTHROMYCIN STEARATE 4021 PO

TELITHROMYCIN 23095 PO

ITRACONAZOLE 6503 PO

KETOCONAZOLE 4132 PO

POSACONAZOLE 33461 PO

VORICONAZOLE 23720 PO

AMIODARONE HCL 83 PO

QUINIDINE GLUCONATE 73 PO

QUINIDINE SULFATE 75 PO

ISONIAZID 4080 PO

ATAZANAVIR SULFATE 25390 PO

FOSAMPRENAVIR CALCIUM 25662 PO

INDINAVIR SULFATE 10683 PO

NELFINAVIR MESYLATE 10858 PO

RITONAVIR 10412 PO

SAQUINAVIR MESYLATE 10232 PO

ABACAVIR SULFATE/LAMIVUDINE 26524 PO

ABACAVIR/LAMIVUDINE/ZIDOVUDINE 21800 PO

DELAVIRDINE MESYLATE 12954 PO

EFAVIRENZ 18748 PO

ETRAVIRINE 35342 PO

LAMIVUDINE/ZIDOVUDINE 14014 PO

NEVIRAPINE 11592 PO

GATIFLOXACIN 20788 PO

LEVOFLOXACIN 12384 PO

MOXIFLOXACIN HCL 20690 PO

NORFLOXACIN 4123 PO

OFLOXACIN 6035 PO

CLOZAPINE 4834 PO

ILOPERIDONE 36778 PO

OLANZAPINE 11814 PO

PALIPERIDONE 34343 PO

QUETIAPINE FUMARATE 14015 PO

RISPERIDONE 8721 PO

ZIPRASIDONE HCL 21974 PO

ARIPIPRAZOLE 24551 PO

CHLORPROMAZINE HCL 1621 PO

FLUPHENAZINE HCL 1626 PO

PERPHENAZINE 1627 PO

THIORIDAZINE HCL 1631 PO

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21

TRIFLUOPERAZINE HCL 1630 PO

DRONEDARONE HYDROCHLORIDE 36444 PO

PROCHLORPERAZINE EDISYLATE 1628 PO

PROCHLORPERAZINE MALEATE 1629 PO

PROMETHAZINE HCL 12014 PO

CIPROFLOXACIN 13446 PO

CIPROFLOXACIN HCL 4124 PO

CIPROFLOXACIN/CIPROFLOXA HCL 32882 PO

AMITRIPTYLINE HCL 1643 PO

AMOXAPINE 1648 PO

CLOMIPRAMINE HCL 4744 PO

DESIPRAMINE HCL 1645 PO

DOXEPIN HCL 1650 PO

IMIPRAMINE HCL 1641 PO

IMIPRAMINE PAMOATE 1642 PO

MAPROTILINE HCL 1651 PO

NORTRIPTYLINE HCL 1644 PO

PROTRIPTYLINE HCL 1646 PO

TRIMIPRAMINE MALEATE 1649 PO

27 of 187

71

Opioids, Long-Acting – High Dose Limit Goal(s):

Ensure safe use of long-acting opiods. o Opioids have been associated with an increasing proportion of deaths in Oregon and the US. o Opioid deaths in Oregon are often associated with concurrent use of other drugs (e.g. other opioids,

benzodiazepines, skeletal muscle relaxants) o Opioid deaths in Oregon are often associated with patients with a history of drug abuse.

Buprenorphine, Fentanyl and Methadone carry FDA Black Box Warnings and have been associated with adverse cardiac effects associated with QTc prolongation and/or life-threatening hypoventalation.

o This risk is increased with concurrent use of other drugs prolonging the QTc interval or other drugs affecting metablolism of methadone or fentanyl.

See Oregon DUR Board newsletter at: http://pharmacy.oregonstate.edu/drug_policy/pages/dur_board/newsletter/articles/volume11/DURV11I2.pdf http://pharmacy.oregonstate.edu/drug_policy/pages/dur_board/newsletter/articles/volume5/5_5.html Initiative: Long-Acting Opioid High Dose Limit - Prior authorization is required for daily doses above the Dose Threshold in the table below. Patients with metastatic neoplasms (ICD9 = 190xx – 199xx) are exempt for the PA requirement. Length of Authorization: up to 6 months

Dosing Threshold adapted from Washington State Agency Medical Directors Interagency Guideline on Opioid Dosing for Chronic Non-cancer Pain 2010 (www.agencymeddirectors.wa.gov )

Opioid Dose threshold

Recommended starting dose for

opioid-naïve patients

Considerations

Buprenorphine Transdermal

20mcg/hour (q 7 days)

5mcg/hr patch q 7 days

May increase dose q72 hours patients up to a max of 20mcg/hr q 7 days. Doses >20mcg/hr q7days increase risk of QTc prolongation.

Fentanyl Transdermal

50mcg/hour (q 72 hr) Use only in opioid-tolerantpatients who have been taking ≥ 60mg MED daily for a week or longer

Hydromorphone 30mg per 24 hours 2mg q 4–6 hours

Methadone 80mg per 24 hours 2.5-5mg BID – TID

Methadone is difficult to titrate due to its half-life variability. It may take a long time to reach a stable level in the body. Methadone dose should not be increased more frequently than every 7 days. Do not use as PRN or combine with other long-acting (LA) opioids.

Immediate-release: 10mg q 4 hours Morphine 120mg per 24 hours Sustained-release: 15mg q 12 hours

Adjust dose for renal impairment.

Immediate-release: 5mg q 4–6 hours

Oxycodone 80mg per 24 hours Sustained Release: 10mg q 12 hours

See individual product labeling for maximum dosing of combination products. Avoid concurrent use of any OTC products containing acetaminophen (maximum dose = 4000mg/day x <10day or 2500mg/day for 10 days or more)

Immediate-release: 5–10mg q 4–6 hours Oxymorphone 40mg per 24 hours Sustained Release: 10mg q 12 hours

Use with extreme caution due to potential fatal interaction with alcohol or medications containing alcohol.

Approval Criteria

1. What is the patient’s diagnosis? 2. Is this patient terminal (< 6 months) or admitted to hospice?


No: Go to #3

3. Is patient being treated for oncology pain?

Yes: Approve for up to 6 months. No: Go to #4 Comment [KLK1]: DUR Board recommended that any patient with claim with a “metastatic CA” diagnosis be excluded from PA altogether.

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4. Is the diagnosis chronic back pain? (ICD-9 = 721.0, 721.2-721.3, 721.7-721.8, 721.90, 722.0 -722.6, 722.8-722.9, 723.1, 723.5-723.9, 724.1 -724.2, 724.5-724.9, 739, 839.2, or 847)

Yes: Pass to RPh, Go to #5. No: Go to #6

5. Is there neurologic impairment defined as objective evidence of at least 1 of the following:

a. Reflex loss b. Dermatomal muscle weakness c. Dermatomal sensory loss d. EMG or NCV evidence of

nerve root impingement e. Cauda equina syndrome f. Neurogenic bowel or bladder

Yes: Document objective evidence with chart notes; Go to #8

No: Deny. (Not Covered by the OHP)

6. Is the diagnosis fibromyalgia (ICD-9 = 729.0 -729.2, 729.31-729.39,729.4-729.9 or V53.02)?

Yes: Pass to RPh, Deny (Not Covered by the OHP)

No: Go to #7

7. Is the diagnosis covered by the OHP?

Yes: Go to #8 No: Pass to RPh, Deny (Not Covered by the OHP)

8. Is this new therapy (i.e. no previous prescription for the same dose last month)?

Yes: Pass to RPH; Deny (Medical Appropriateness)

In general, the total daily dose of opioid should not exceed 120 mg oral MED. Risks substantially increase at doses at or above 100mg.1

Alternatives: Preferred NSAIDs or LAOs @ doses < 120mg MED.

No: Go to #9

9. Is the patient seeing a single prescribing practice & pharmacy for pain treatment?

Yes: Pass to RPh, Go to #10

No: Pass to RPh, Approve 30-90 days to allow for case review. Refer to Rx Lock-In program for evaluation, monitoring & potential taper. Further approvals pending RetroDUR/Medical Director review of case.

10. Can the prescriber provide documentation of sustained improvement in both function and pain AND is prescriber is aware of additional risk factors (e.g. concurrent benzodiazepines, skeletal muscle relaxants, other LAOs or history of drug abuse)?

Yes: Approve up to 6 months.

Quantity Limits Apply: Avinza: 1 dose / day Butrans: 1 patch / week Embeda: 2 doses / day Exalgo: 1 dose / day Fentanyl: 1 patch / 72 hours Kadian: 2 doses / day Opana XR: 2 doses / day Oxycodone ER: 2 doses / day

No: Pass to RPh, Approve 30-90 days to allow for potential tapering of dose. Refer to Rx Lock-In program for evaluation, monitoring & potential taper. Further approvals pending RetroDUR/Medical Director review of case.

1 Dunn KM, Saunders KW, Rutter CM, Banta‐Green CJ, Merrill JO, Sullivan MD, Weisner CM, Silverberg MJ, Campbell CI, Psaty BM, Von Korff M. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med 2010;152(2):85‐92

P&T or DUR Board Action: 11/17/11(KK), 3/17/11(KK), 5/19/11KK), 9/24/09(DO/KK), 5//21/09(KK) Revision(s) 1/1/12 Initiated: 1/1/10 (Methadone only)

Comment [KLK2]: DUR Board recommended that upon implementation all current patients be “grandfathered”. This criteria will only apply to new patients to the OHP or new therapy.

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Opioids - Long-Acting

Initiative: Long Acting Opioids for PDL Length of Authorization: Up to 1 year

Approve use of non-preferred long-acting opioids only for covered diagnosis.

OHP does not cover:

Includes ICD9:

Includes ICD9:

Disorders of soft tissue

729.0-729.2,

729.31-729.39, 729.4-729.9, V53.02

OR

Acute and chronic disorders of spine without neurologic impairment

721.0 721.2-721.3 721.7-721.8 721.90 722.0-722.6 722.8-722.9 723.1 723.5-723.9 724.1-724.2 724.5-724.9 739 839.2 847

Preferred Alternatives at doses below 120 Morphine Equivalent per day: Listed at: http://www.oregon.gov/DHS/healthplan/tools_prov/pdl.shtml Non-Preferred LAOs require PA at any dose.

Approval Criteria 1. What is the patient’s diagnosis?

Record ICD9 code.

2. Will the prescriber consider a change to a preferred product? Message:

• Preferred products do not require PA at doses below 120mg Morphine Equivalent per days.

Yes: Inform provider of covered alternatives in class. http://www.dhs.state.or.us/policy/healthplan/guides/pharmacy/main.html

No: Go to #3.

3. Is patient being treated for oncology pain? Yes: Approve for up to 6 months No: Go to #4

4. Is this patient terminal (< 6 months) or admitted to hospice?


No: Go to #5.

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5. Is the diagnosis chronic back pain

721.0

723.1

721.2-721.3 723.5-723.9 721.7-721.8 724.1-724.2 721.90 724.5-724.9 722.0-722.6 739 722.8-722.9 839.2 847

Yes: Pass to RPH, Go to #5.

No: Go to #7.

6. Is there neurologic impairment defined as objective evidence of at least 1 of the following:

a. Reflex loss b. Dermatomal muscle weakness c. Dermatomal sensory loss d. EMG or NCV evidence of nerve

root impingement e. Cauda equina syndrome f. Neurogenic bowel or bladder

Yes: Document objective evidence with chart notes; Go to #8.

No: Deny (Not Covered by the OHP)

7. Is the diagnosis fibromyalgia (ICD-9 = 729.0 -729.2, 729.31-729.39,729.4-729.9 or V53.02)?

Yes: Pass to RPh, Deny (Not Covered by the OHP)

No: Go to #8

8. Is the diagnosis covered by the OHP? Yes: Go to #9 No: Pass to RPh, Deny (Not Covered by the OHP)

9. Is this new therapy (i.e. no previous prescription for the same drug last month)?

Yes: Go to #9

No: Go to #10.

9. Does dose exceed 120mg Morphine Equivalents per day?

a. Fentanyl 50mcg/day b. Hydromorphone 30mg/day c. Oxycodone 80mg/day d. Oxymorphone 40mg/day e. Methadone 40mg/day

Yes: Pass to RPh, Deny (Medical Appropriateness) In general, the total daily dose of opioid should not exceed 120 mg oral MED. Risks substantially increase at doses at or above 100mg.i Alternatives: Preferred NSAIDs or LAOs @ doses < 120mg MED.

No: Go to #10.

10. Is the patient seeing a single prescribing practice & pharmacy for pain treatment?

Yes: Go to #11

No: Approve 30-90 days; Refer to Rx Lock-In program for evaluation, monitoring & potential taper. Further approvals pending RetroDUR/Medical Director review of case.

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11. Is the patient concurrently on other long-acting opioids (e.g. fentanyl patches, methadone, or long-acting morphine, long-acting oxycodone, long-acting oxymorphone)?

Yes: Pass to RPH. Go to #12.

No: Approve up to 6 months.

Quantity Limits Apply: Avinza: 1 dose / day Butrans: 1 patch / week Embeda: 2 doses / day Exalgo: 1 dose / day Fentanyl: 1 patch / 72 hoursKadian: 2 doses / day Opana XR: 2 doses / day Oxycodone ER: 2 doses / day

12. Is the duplication due to tapering or switching products? The concurrent use of multiple long-acting narcotics is not recommended unless tapering and switching products. Consider a higher daily dose of a single long-acting opioid combined with an immediate release product for breakthrough pain. http://www.ohsu.edu/ahec/pain/home.html

Yes: Approve for 30-90 days at which time duplication LAO therapy will no longer be approved.

No: Deny, Appropriateness. May approve for taper only. If necessary, inform prescriber of provider reconsideration process and refer to RetroDUR for review.

P&T or DUR Board Action: 11/17/11(KK); 12/3/09 (KS), 9/9/09(klk),12/4/08klk, 3/19/09 Revision(s): 1/1/12; 1/1/10 Initiated: 7/1/09

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ADDICTIONS AND MENTAL HEALTH DIVISION

PUBLIC HEALTH DIVISION

Prescription Opioid Overdose Prevention Workgroup (POP) Interim Report

May 3, 2011

Executive Summary

OHA staff formed the POP in 2010 to determine how to reduce prescription opioid analgesic overdose deaths in Oregon. This report is an interim summary of information and recommendations from the Prescription Opioid Overdose Prevention Workgroup (POP). The POP formed four subcommittees to focus on data, education, policy, and clinical practice. The subcommittees considered three questions: 1. What is the current state of knowledge for each specific POP areas of

focus: data, policy, education, and clinical practice? What is known about the frequency and risk factors for opioid overdose (data group)? What policies might contribute to the current state of affairs (policy group)? What education strategies have been employed (education group)? What do we know about the pharmacology of methadone and pain management practices (clinical practice group)?

2. What questions do we still have unanswered? What patient factors are likely to contribute to fatal overdose? To what extent have insurance reimbursement policies contributed to this problem?

3. What are the next steps for each specific subject area (data, education, policy, and clinical practice)?

Summary of Next Step Findings

• Need to reduce methadone overdose deaths - the cause of the majority of overdose mortalities occurring among Oregonians aged 25-54.

• Conduct a study to identify risk factors and circumstances among decedents. • Identify healthcare provider education needs. • Increase healthcare provider awareness of the efficacy of pharmacological

and non-pharmacological pain treatment to relieve acute and chronic pain.

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• Promote and disseminate standards for the use of opioids to relieve acute and chronic pain

• Encourage healthcare providers to use the Prescription Drug Monitoring Program beginning in September 2011.

• Assure that providers: o understand the side effects and risks of opioid use, o are knowledgeable about the use of medications used to treat opioid

dependence, o Are able to recognize and screen for behaviors indicating potential

substance abuse, and make appropriate referrals to addiction treatment providers.

• Develop and implement statewide public education and awareness focused on methadone misuse and overdose.

• Determine what best practice prescription opioid policies are needed to provide adequate patient management when using opioids to treat acute and chronic pain.

• Develop a policy recommendation that removes barriers and increases the availability and payment of Buprenorphine to treat chronic pain, opioid dependence and addiction.

• Develop a pilot project and test the usefulness of notifying primary care providers when a patients is referred to addiction treatment

• Develop a pilot project and test the usefulness of notifying the primary care provider when a patient dies of drug overdose.

• Develop a pilot project and test the usefulness of hospitals notifying the primary care provider when a patient is hospitalized for overdose.

• Develop a pilot project and test the usefulness of police notifying the primary care provider when a patient is cited or arrested on a drug charge.

• Develop survey questions for the Behavioral Risk Factor Surveillance Survey to determine what factors influence drug sharing and what factors might decrease this practice among Oregonians.

The POP will continue to meet monthly to coordinate OHA efforts.

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Introduction

The Oregon Health Authority’s (OHA) Addictions and Mental Health Division (AMH) and Public Health Division (PHD) formed the POP in 2010 to address prescription opioid analgesic overdose deaths in Oregon. A sharp increase in deaths related to opioid medications began in the late 1990’s and continues to rise.

The POPP has two co-chairs, one from AMH, and one from PHD. The group consists of members from the OHA Division of Medical Assistance Programs (DMAP), OHA Addictions and Mental Health Division (AMH), Criminal Justice Commission (CJC), OHA Public Health Division (PHD), local health department representatives, Oregon Board of Pharmacy (OBP), Oregon Pain Commission (OPC), Advisory Commission for the Oregon Prescription Drug Monitoring Program, Kaiser Permanente, and the OHA Directors Office.

Methods

The POPP meets monthly to define and understand the scope of the problem (i.e. what is the magnitude and trend in overdose deaths, and what factors are associated with the increase in prescription opioid deaths). The POPP chartered four subcommittees to define the problem, explore current resources and practice, and examine evidence to formulate recommendations for the state. The subcommittee subject areas include: 1) data analysis, 2) clinical practice, 3) education; and 4) policy

Subcommittee Findings

I. Data

1. Deaths due to opioid analgesics have increased in Oregon. • Since 1999, prescription opioid overdose/poisoning deaths increased over

900%. • Between 1999 and 2009, there were over 1,250 prescription opioid;

unintentional overdose/poisoning deaths in the state. Overall, this was a rate of 4.8 deaths per 100,000 persons in 2009.

• Increases in hospitalizations also occurred. In 1997, opioid-related overdose/poisonings represented 5.6% of all medication and drug-related overdose/poisoning hospitalizations. In 2007, opioid-related

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overdose/poisonings represented 22.3% of all medication and drug-related hospitalizations in Oregon.

• In 1999, prescription opioids represented 11% of all deaths due to overdose/poisoning by medications and drugs; in 2008, prescription opioids represented 53% of all deaths due to overdose/ poisoning by medications and drugs in Oregon.

2. The increase in opioid overdose deaths is primarily driven by methadone.

• Methadone is commonly used to treat chronic pain, which accounts for much of its current use.

• Methadone is more frequently mentioned on overdose death certificates than any other licit or illicit drug including heroin.

• In 1999, methadone represented 3% of all deaths due to overdose/poisoning by medications and drugs; in 2008, methadone represented 33% of all deaths due to overdose/ poisoning by medications and drugs (both licit and illicit) in Oregon.

• Methadone has unique pharmacological properties that increase the risk of adverse outcomes compared to other drugs used to treat chronic pain such as Percocet, OxyContin, Oxycodone, Hydromorphone and others. Methadone has a longer “half life” meaning that it takes longer for the medication to be eliminated from the bloodstream.

• Individuals may accidentally or intentionally take more than the prescribed dose of methadone or take the medication more often than prescribed for a variety of reasons including confusion, forgetting the time of the last dose, inability to experience pain relief, or seeking a euphoric high from medications known to produce these effects.

• Methadone is inexpensive compared to other opioid pain treatment options (an approximate 30 day cost of $8.10 compared to $360 for equianalgesic equivalent treatment with OxyContin).

• Most deaths occur among Oregonians aged 35-54 age group. • Medical examiner records indicate that about 75% of methadone

overdose decedents have a history of substance use disorder; about 50% had a history of mental illness.

• Many deaths are occurring among persons prescribed methadone for pain treatment. Preliminary analysis of medical examiner data shows that about 40% of methadone overdose/poisoning decedents had evidence of being prescribed methadone. About an equal number had no evidence for a methadone prescription or authorized treatment.

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3. Use of prescription opioid analgesics has increased in Oregon.

• In 2007 Oregon was the 3rd largest per capita consumer of retail methadone (distributed from pharmacies) in the US (US DOJ, Automation of Reports& Consolidated Orders System (ARCOS), 2007).

• Distribution of methadone (per capita) in Oregon increased over 2,000% between 1997 and 2006.

• The increase in methadone distribution for retail (i.e. pharmacies) closely parallels the death rate associated with methadone overdose.

• Oregon is among the states with the highest proportion of prescription painkiller misuse (National Survey on Drug Use and Health).

Unanswered questions:

1. What proportion of opioid deaths in Oregon is among Medicaid enrollees? Washington State found that 45% of opioid poisoning decedents were Medicaid enrollees, and that Medicaid enrollees were about six times more likely to die of opioid overdose compared to the non-Medicaid population. Research in Oregon should focus on determining whether a similar level of risk is present among the Medicaid population here.

2. Are Medicaid enrollees in Oregon disproportionately prescribed methadone? Methadone is inexpensive when compared to other prescription opioids. The low cost of methadone may increase incentives to prescribe the drug, possibly putting vulnerable populations at increased risk for opioid overdose/poisoning.

3. What proportion of deaths occurs among persons prescribed methadone (versus those using methadone, who don’t have a prescription, i.e. diverted)? About 40% of methadone poisoning decedents were prescribed methadone, but do not know about decedents poisoned by other drugs.

4. What factors are associated with mortality among those under medical care for pain treatment (through pain specialty clinics, general practice, or other)?

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History of substance use disorders among methadone poisoning decedents is high (among those prescribed methadone). Standard screening practices might reduce risk of death among those being treated for pain with prescription opioids.

5. What factors contribute to diversion of prescription painkillers? Data show that 60% of those who report misuse or nonmedical use of prescription pain relievers got those medicines from friends or family.

Next steps

Collect data on decedent risk factors by carrying out a study of opioid overdose decedents through the OHA Public Health Division. Develop survey questions for the Behavioral Risk Factor Surveillance Survey to determine what factors influence drug sharing and what factors might decrease this practice among Oregonians.

II. Policy

Current state of knowledge:

• Policies might contribute to overdoses. • Prescription benefit limits on chronic pain treatment may limit

medications available (promotes use of methadone), may limit non-pharmacological options.

• Lack of adequate addiction and mental health treatment.

1. Policies already in place may help improve the situation. • Prescription Monitoring Program slated to start September 1, 2011 will

provide prescribers access to information about patient drug use. • All prescribers of opiates are required to take continuing education in

pain management (OR). • Federal Drug Administration (FDA) Risk Evaluation and Mitigation

Strategies (REM) program will provide education and training to ensure

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physicians prescribe opioids appropriately, and counsel their patients on safe use and disposal.

Unanswered questions:

1. How do policies affect:

• Prescribing opioids for pain relief? • Counseling and monitoring? • Patients’ misuse or abuse of drugs? • Sharing of pain pills with relatives or friends? • Doctor shopping to obtain multiple prescriptions? • Diversion of opioids leading to illicit sales, abuse and unintended deaths?

2. What are effective policies in place in other states? Next steps: 1. Look at the policies created in Washington and Utah (and elsewhere). 2. Determine what balanced policy in Oregon would look like; consider what is

already in place and what is in development. III. Clinical Practice

Current knowledge:

1. What might contribute to opiate overdose?

• Standardized prescribing guidelines for chronic pain are not widely adopted by prescribers.

• Patients using opioids to manage chronic pain are not consistently screened for risk factors associated with substance use disorders using standardized risk assessment tools. Policy directives governing practice in this regard are generally applied at the individual clinic or provider network level, not a statewide policy level.

• Healthcare providers lack understanding of addiction and therefore overlook signs of addiction.

• When substance use disorders are recognized by healthcare providers or even patients, appropriate treatment for opioid addiction is hindered by

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the stigma associated with using medication assisted treatments (methadone, Buprenorphine, Naltrexone) and the general lack of understanding of the benefits associated with medication assisted treatment. Medications other than methadone are fairly new and not widely understood by the medical community or even the addiction treatment community. However, there is a growing body of research about the substantial benefits related to using medications to treat addictions, particularly as related to opioid addiction.

• Clinicians are not informed when their patients enroll in a chemical dependency treatment programs.

• Clinicians are not informed when their patient overdoses. • Cost limits treatment options for chronic pain patients. ▪ Reliance upon methadone because it’s inexpensive and preferred on

drug formularies; and ▪ Inability to provide Complementary Alternative Medicine (CAM)

because it’s not a covered benefit or due to cost if uninsured. • Clinicians are not allowed to prescribe Buprenorphine without prior

authorization. • While many clinicians will treat their existing patients using

Buprenorphine, they are reluctant to accept new patients with serious addiction histories.

• Patients expect and demand clinicians to prescribe opioids even if an opioid is not indicated.

• Patients and the public do not understand the risk of opioid misuse. • Drug interactions increase risk of overdose and death. At highest risk are

those prescribed methadone due to the cardiac and respiratory depression that occurs with methadone and the long half life of methadone.

2. What policies already in place may help improve the situation?

• The Oregon Prescription Drug Monitoring Program. • Professional Board statements and recommendations. • Oregon Pain Commission policies. • Professional guidelines.

3. What questions do we still have unanswered? • What evidence is there for multidisciplinary treatments for chronic pain? • What populations are at risk for dying from opioids?

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• What can prescribers do to reduce the risk of overdose and death?

4. What are our next steps? Prescriber education: • Improve prescriber continuing education about the use of opioids to treat

acute pain, chronic pain, and addiction in every clinical discipline; • Improve professional addiction and pain treatment education; • Expand the capacity for physicians to receive continuing medical

education hours related to this topic; • Include a minimum number of questions on certification examinations

that relate to the topic of chronic pain management: ▪ Include a minimum number of questions on certification

examinations on addressing substance use disorders and use of medication assisted treatments particularly where opioids are concerned; and

▪ Require specific information on prescription of methadone and patient medication management of methadone.

• Disseminate standards of care for managing chronic pain; • Create and disseminate standards for prescribing opioids safely and

effectively; • Standardize evaluation of safety and effectiveness of opioid therapy: ▪ Track and document functional improvement and pain relief; and ▪ Consider specialty consultation if there is evidence of adverse effects

or lack of response. • When prescribing opioid therapy: ▪ Assess patient to determine current or past alcohol or other substance

abuse, including nicotine (Opioid Risk Tool, AUDIT, DAST, CAGE-AID);

▪ Augment pharmacological care with behavioral therapies; ▪ Assess depression severity and treat; ▪ Document a baseline urine drug test with each patient; ▪ Document a baseline assessment of function and pain; ▪ Conduct a risk/benefit discussion with each patient; ▪ Provide mandatory patient education that teaches self-management of

chronic pain when initiating chronic opioid therapy; and ▪ Document treatment goals that include improvements in function and

pain and track and document patient progress or lack thereof. • After prescribing:

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▪ Routinely monitor patients for adverse effects and document treatment strategies and patient progress or lack thereof using standard measurements;

▪ Routinely administer and document patient urine testing; ▪ Conduct and document pill counts; and ▪ Patient follow-up in treatment plan should include specify time

intervals to monitor treatment. • Safety: ▪ Each patient should use a single prescriber or clinical practice; ▪ Each patient should use a single pharmacy; ▪ Prescribers should use the lowest effective dose; ▪ Prescribers and patients should continuously assess for conditions that

can potentiate opioid adverse effects, document those conditions and follow up on those conditions on a routine basis;

▪ Prescribers should avoid prescribing opiates at the same time a patient is taking sedative-hypnotics, benzodiazepines, or barbiturates; and

▪ Prescribers must monitor for medication misuse. • Barriers: ▪ There are a limited number of pain specialists and addictions medicine

specialists; ▪ Limited access to addiction treatment, behavioral therapy and mental

health treatment. Roughly 25-40% of those individuals in need of these services access services annually according to estimates from national survey data and treatment episode data; and

▪ Improve communication about opiate use and misuse between all care providers including primary care, emergency departments, alcohol and drug treatment providers, case workers, emergency medical services (EMS).

• Advocate for the increased availability of Buprenorphine: ▪ Incentivize physicians to become Buprenorphine prescribers. ▪ Encourage managed care companies to pay for Buprenorphine

treatment. ▪ Encourage managed care companies to remove prior authorizations

requirements for Buprenorphine and other medications that demonstrate efficacy in treating opioid addiction.

• Create a feedback loop for prescribers so they can learn about their patients who experience negative consequences related to prescription drug misuse (legal issues, use of crisis or other emergency services);

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• The medical examiner should notify the primary care provider of deceased when the death is caused by drug overdose;

• Chemical dependency treatment programs should notify patient primary care providers of their patient’s entry into treatment for chemical dependency;

• Create patient education materials/website; • Promote clinician use of the prescription drug monitoring program

beginning in September 2011; • Increase healthcare provider awareness of the efficacy of non-

pharmacological treatments for pain; • Educate the public about safe use and storage of opioids.

IV. Education

Current knowledge:

1. There are gaps in clinical education among prescribers:

• Insufficient addiction and pain management education for health care payers, prescribers and medical students, patients, pharmacists, law makers, policy developers, and the general public.

• Education for clinicians on the use of prescription methadone is not standardized nor is it evaluated.

2. Education policies already in place:

• Mandatory continuing education in pain management (OR). • Screening, Brief Intervention and Referral to Treatment (SBIRT) for

alcohol misuse and addition is incorporated into physician residency program at Oregon Health and Science University.

3. There is low public awareness of the dangers of opioid misuse and overdose. Unanswered questions: 1. How do current clinical education policies and practices effect:

• Clinician prescribing by specialty; • Counseling and monitoring patients using prescribed methadone for pain; • Patients’ misuse or abuse of prescribed methadone for pain;

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• Sharing of methadone with relatives or friends; • Doctor shopping to obtain multiple prescriptions; and • Diversion of opioids leading to illicit sales, abuse and unintended deaths.

Next steps for education: 1. Review the curriculum content, requirements, policies, and outcomes of

clinical education in Washington and Utah (and elsewhere). 2. Assess the gaps in clinical education and determine appropriate standards

and requirements needed to establish improved clinical education in Oregon for prescribers in each discipline that prescribe opiates for the relief of acute pain, the relief of chronic pain, and addiction.

3. Study the needs and messaging content that would contribute to increased

awareness and behavior change among Oregonians.

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General Page 2

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410-121-0040 Page 1

410-121-0040 Prior Authorization Required for Drugs and Products

(1) Prescribing practitioners are responsible for obtaining prior authorization (PA) for the drugs and categories of drugs requiring PA in this rule, using the procedures required in OAR 410-121-0060.

(2) All drugs and categories of drugs, including but not limited to those drugs and categories of drugs that require PA as described in this rule, are subject to the following requirements for coverage:

(a) Each drug must be prescribed for conditions funded by Oregon Health Plan (OHP) in a manner consistent with the Oregon Health Services Commission’s Prioritized List of Health Services (OAR 410-141-0480 through 410-141-0520). If the medication is for a non-covered diagnosis, the medication shall not be covered unless there is a co-morbid condition for which coverage would be extended. The use of the medication must meet corresponding treatment guidelines, be included within the client’s benefit package of covered services, and not otherwise excluded or limited;

(b) Each drug must also meet other criteria applicable to the drug or category of drug in these pharmacy provider rules, including PA requirements imposed in this rule.

(3) The Oregon Health Authority (Authority) may require PA for individual drugs and categories of drugs to ensure that the drugs prescribed are indicated for conditions funded by OHP and consistent with the Prioritized List of Health Services and its corresponding treatment guidelines (see OAR 410-141-0480). The drugs and categories of drugs that the Authority requires PA for this purpose are found in the OHP Fee-For-Service Pharmacy PA Criteria Guide (PA Criteria Guide) dated Jan. 1, 2011, incorporated in rule by reference and found on our Web page at:http://www.dhs.state.or.us/policy/healthplan/guides/pharmacy/clinical.html

(4) The Authority may require PA for individual drugs and categories of drugs to ensure medically appropriate use or to address potential client safety risk associated with the particular drug or category of drug, as recommended by the Pharmacy & Therapeutics Committee

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410-121-0040 Page 2

(P&T) and adopted by the Authority in this rule (see OAR 410-121-0100 for a description of the DUR program). The drugs and categories of drugs for which the Authority requires PA for this purpose are found in the Pharmacy PA Criteria Guide.

(5) PA is required for all new drugs added to the National Drug Data File (NDDF):

(a) The new drug will be prioritized to be presented to the P & T Committee after the drug’s NDDF add date. The P & T Committee will make additional drug specific recommendations to the Authority regarding PA criteria, if any, that should be adopted for the new drug:

(i) If the new drug is in a class where current PA criteria apply, all PA criteria associated with that class shall be required at the time the new drug is added to the NDDF;

(ii) If the new drug is indicated for a condition below the funding line on the Prioritized List of Health Services, PA shall be required to ensure that the drug is prescribed for a condition funded by OHP;

(b) PA for the new drug under section (5) of this rule remains in effect until such time as the Authority makes a determination regarding the applicability of PA criteria for the new drug or six months elapse from the drug’s NDDF add date without a decision regarding PA criteria for that drug, whichever occurs first;

(c) Oral oncology medications, anti-retrovirals, and family planning drugs are excluded from the PA requirements in section (5) of this rule.

(6) PA is required for brand name drugs that have two or more generically equivalent products available and that are NOT determined Narrow Therapeutic Index drugs by the Oregon P&T Committee:

(a) Immunosuppressant drugs used in connection with an organ transplant must be evaluated for narrow therapeutic index within 180 days after United States patent expiration;

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(b) Manufacturers of immunosuppressant drugs used in connection with an organ transplant must notify the department of patent expiration within 30 days of patent expiration for (5)(a) to apply;

(c) Criteria for approval are:

(A) If criteria established in subsection (3) or (4) of this rule applies, follow that criteria;

(B) If (6)(A) does not apply, the prescribing practitioner must document that the use of the generically equivalent drug is medically contraindicated, and provide evidence that either the drug has been used and has failed or that its use is contraindicated based on evidence-based peer reviewed literature that is appropriate to the client’s medical condition.

(7) PA is required for non-preferred Preferred Drug List (PDL) products in a class evaluated for the PDL except in the following cases:

(a) The drug is a mental health drug as defined in OAR 410-121-0000;

(b) The original prescription is written prior to 1/1/10;

(c) The prescription is a refill for the treatment of seizures, cancer, HIV or AIDS; or

(d) The prescription is a refill of an immunosuppressant.

(8) PA may not be required:

(a) When the prescription ingredient cost plus the dispensing fee is less than the PA processing fees as determined by the Authority;

(b) For over-the-counter (OTC) covered drugs when prescribed for conditions covered under OHP or;

51 of 187

410-121-0040 Page 4

(c) If a drug is in a class not evaluated from the Practitioner-Managed Prescription Drug Plan under ORS 414.334.

Stat. Auth.: ORS Chap. 409.110, 413.042, 414.065, and 414.334

Stats. Implemented: 414.065

1-1-12

52 of 187

D

rug

Use

Res

earc

h &

Man

agem

ent P

rogr

am

Ore

gon

Stat

e U

nive

rsity

, 500

Sum

mer

Stre

et N

E, E

35, S

alem

, Ore

gon

9730

1-10

79

Phon

e 50

3-94

5-52

20 |

Fax

503-

947-

1119

1 O

ral A

ntic

oagu

lant

s Cl

ass

Revi

ew –

Add

itio

n of

War

fari

n M

onth

/Yea

r of

Rev

iew

: Ja

nuar

y 20

12

PDL

Clas

s: N

o cu

rren

t PD

L cl

ass

Su

gges

ted

Revi

sion

: A

dd w

arfa

rin to

PD

L

Curr

ent

Stat

us o

f Ant

icoa

gula

nts:

No

PDL-

stat

us/n

o re

stri

ctio

ns: w

arfa

rin

Non

-pre

ferr

ed O

ral A

ntic

oagu

lant

s: ri

varo

xaba

n (p

endi

ng) a

nd d

abig

atra

n (p

endi

ng)

FDA

App

rove

d In

dica

tion

s:

War

fari

n is

app

rove

d fo

r pro

phyl

axis

and

trea

tmen

t of v

enou

s th

rom

bosi

s an

d its

ext

ensi

on, p

ulm

onar

y em

bolis

m;

prop

hyla

xis

and

trea

tmen

t of t

hrom

boem

bolic

com

plic

atio

ns a

ssoc

iate

d w

ith a

tria

l fib

rilla

tion

and/

or c

ardi

ac v

alve

rep

lace

men

t; a

nd re

duct

ion

in

the

risk

of d

eath

, rec

urre

nt m

yoca

rdia

l inf

arct

ion,

and

thro

mbo

embo

lic e

vent

s su

ch a

s st

roke

or

syst

emic

em

boliz

atio

n af

ter

myo

card

ial i

nfar

ctio

n.1

Su

mm

ary:

Th

e vi

tam

in K

ant

agon

ist

(VKA

), w

arfa

rin,

has

ser

ved

as t

he g

old

stan

dard

for

oral

ant

icoa

gula

tion

and

is a

cov

ered

the

rapy

for

Ore

gon

Hea

lth P

lan

(OH

P) p

atie

nts.

A

ppro

xim

atel

y 35

0 pa

tient

s ut

ilize

d lo

ng t

erm

ant

icoa

gula

tion

(>45

day

s), r

epre

sent

ing

over

2,0

00 p

resc

ript

ion

clai

ms

with

in t

he

last

six

mon

ths

with

in th

e O

HP

popu

latio

n.

A m

eta-

anal

ysis

for

str

oke

prev

entio

n in

pat

ient

s w

ith n

on-v

alvu

lar

AF

foun

d w

arfa

rin t

hera

py t

o re

duce

str

oke

by 6

0%,

whi

ch w

as 4

0% m

ore

effic

acio

us th

an a

nti-p

late

let t

hera

py.2 T

he C

ochr

ane

Dat

abas

e fo

r Sy

stem

atic

Rev

iew

s es

timat

es th

at a

ppro

xim

atel

y 25

str

okes

and

12

disa

blin

g or

fa

tal s

trok

es w

ould

be

prev

ente

d pe

r yea

r, fo

r eve

ry 1

000

prim

ary

prev

entio

n pa

tient

s w

ith A

F tr

eate

d w

ith w

arfa

rin.3

Acu

te D

VT tr

eatm

ent i

s an

add

ition

al in

dica

tion

for

antic

oagu

latio

n. D

VT is

a s

erio

us m

edic

al c

ondi

tion

that

aff

ects

1 in

100

0 pe

ople

and

can

lead

to

PE

and

rela

ted

risk

of m

orbi

dity

and

mor

talit

y.4 C

HES

T gu

idel

ines

reco

mm

end

initi

al tr

eatm

ent w

ith L

MW

H, u

nfra

ctio

nate

d he

pari

n (U

FH) o

r fo

ndap

arin

ux fo

r at l

east

5 d

ays

and

initi

atio

n of

war

fari

n on

the

first

trea

tmen

t day

.5 Dis

cont

inua

tion

of h

epar

in p

repa

ratio

ns s

houl

d oc

cur w

hen

the

INR

reac

hes

2.0

or m

ore

for

at le

ast 2

4 ho

urs.

For

pat

ient

s w

ith D

VT o

r PE

sec

onda

ry to

a re

vers

ible

ris

k fa

ctor

, the

gui

delin

es re

com

men

d tr

eatm

ent w

ith w

arfa

rin

for 3

mon

ths.

Tre

atm

ent r

ecom

men

datio

ns fo

r pa

tient

s w

ith u

npro

voke

d D

VT o

r PE

incl

ude

war

farin

for

at le

ast 3

mon

ths

and

up to

a y

ear

or lo

nger

bas

ed o

n cl

inic

al ju

dgm

ent.

53 of 187

2 A

utho

r: K

athy

Sen

tena

For

patie

nts

unde

rgoi

ng T

HR

or T

KR p

roph

ylac

tic a

ntic

oagu

lant

s ar

e co

nsid

ered

sta

ndar

d pr

actic

e. A

rec

ent g

uide

line

by th

e A

mer

ican

Aca

dem

y of

O

rtho

paed

ic S

urge

ons

give

s a

mod

erat

e re

com

men

datio

n fo

r the

use

of p

roph

ylac

tic p

harm

acol

ogic

al a

gent

s fo

r VT

E pr

even

tion

in th

ose

patie

nts

that

are

not

at e

leva

ted

risk.

Due

to in

suff

icie

nt e

vide

nce

they

are

una

ble

to re

com

men

d an

y pa

rtic

ular

pre

vent

ativ

e st

rate

gy o

r tr

eatm

ent

dura

tion.

6 Th

e A

mer

ican

Col

lege

of C

hest

Phy

sici

ans

(ACC

P) E

vide

nce-

Base

d Cl

inic

al P

ract

ice

Gui

delin

es (C

HES

T) o

n an

tithr

ombo

tic a

nd

thro

mbo

lytic

ther

apy

reco

mm

ends

trea

tmen

t with

war

farin

, LM

WH

, or f

onda

pari

nux

for

7 to

10

days

for T

KR a

nd 1

0 to

35

days

for T

HR.

7 Ore

gon

Hea

lth P

lan

(OH

P) fe

e-fo

r-se

rvic

e FF

S c

urre

ntly

list

s LM

WH

s, e

noxa

pari

n an

d da

ltepa

rin,

as p

refe

rred

, and

fond

apar

inux

(Ari

xtra

®) a

nd ti

nzap

arin

(In

nohe

p®) a

s no

t pre

ferr

ed. D

esir

udin

(Ipr

ivas

k®) i

s no

t man

aged

via

PD

L an

d cu

rren

tly h

as n

o ut

iliza

tion

rest

rict

ions

. In

the

prev

ious

six

mon

ths

appr

oxim

atel

y 20

0 pa

tient

s re

ceiv

ed s

hort

term

ant

icoa

gula

tion

(<45

day

s) a

ccou

ntin

g fo

r al

mos

t 200

pre

scri

ptio

n cl

aim

s.

PDL

Plac

emen

t Re

com

men

dati

on:

Reco

mm

end

mai

ntai

ning

war

fari

n as

a p

refe

rred

and

firs

t-lin

e ag

ent i

n th

e or

al a

ntic

oagu

lant

cla

ss fo

r pro

phyl

axis

and

trea

tmen

t of

thro

mbo

embo

lic d

isor

ders

.

54 of 187

3 A

utho

r: K

athy

Sen

tena

Refe

renc

es:

1.

Cou

mad

in®

Pres

crib

ing

Info

rmat

ion.

Bri

stol

-Mye

rs S

quib

b, In

c. P

rinc

eton

, NJ.

Janu

ary

2010

. 2.

H

art R

, Pea

rce

L, A

guila

r M

. M

eta-

anal

ysis

: Ant

ithro

mbo

tic

Ther

apy

to P

reve

nt S

trok

e in

Pat

ient

s W

ho H

ave

Non

valv

ular

Atr

ial F

ibri

llatio

n. A

nn In

tern

Med

. 20

07;1

46:8

57-8

67.

3.

Agu

ilar,

M, H

art R

. O

ral a

ntic

oagu

lant

s fo

r pr

even

ting

stro

ke in

pat

ient

s w

ith n

on-v

alvu

lar

atri

al fi

brill

atio

n an

d no

pre

viou

s hi

stor

y of

str

oke

or tr

ansi

ent i

sche

mic

at

tack

s. T

he C

ochr

ane

Dat

abas

e of

Sys

t Rev

. 20

09 (1

): CD

0019

27.

4.

Am

eric

an A

cade

my

of O

rtho

paed

ic S

urge

ons.

Pre

vent

ing

Ven

ous

Thro

mbo

embo

lic D

isea

se in

Pat

ient

s U

nder

goin

g El

ectiv

e H

ip a

nd K

nee

Art

hrop

last

y Ev

iden

ce-B

ased

G

uide

line

and

Evid

ence

Rep

ort,

201

1. (

Acc

esse

d O

ctob

er 2

7, 2

011,

at h

ttp:

//w

ww

.aao

s.or

g/re

sear

ch/g

uide

lines

/VTE

/VTE

_ful

l_gu

idel

ine.

pdf.)

5.

H

irsh

J, G

uyat

t G, A

lber

s G

, et

al.

Exec

utiv

e Su

mm

ary:

Am

eric

an C

olle

ge o

f Che

st P

hysi

cian

s Ev

iden

ce-B

ased

Clin

ical

Pra

ctic

e G

uide

lines

(8th

Edi

tion)

. Ch

est

2008

;133

;71S

-109

S.

6.

Am

eric

an A

cade

my

of O

rtho

paed

ic S

urge

ons.

Pre

vent

ing

Ven

ous

Thro

mbo

embo

lic D

isea

se in

Pat

ient

s U

nder

goin

g El

ectiv

e H

ip a

nd K

nee

Art

hrop

last

y Ev

iden

ce-B

ased

G

uide

line

and

Evid

ence

Rep

ort,

201

1. (

Acc

esse

d O

ctob

er 2

7, 2

011,

at h

ttp:

//w

ww

.aao

s.or

g/re

sear

ch/g

uide

lines

/VTE

/VTE

_ful

l_gu

idel

ine.

pdf.)

7.

H

irsh

J, G

uyat

t G, A

lber

s G

, et

al.

Exec

utiv

e Su

mm

ary:

Am

eric

an C

olle

ge o

f Che

st P

hysi

cian

s Ev

iden

ce-B

ased

Clin

ical

Pra

ctic

e G

uide

lines

(8th

Edi

tion)

. Ch

est

2008

;133

;71S

-109

S.

55 of 187

D

rug

Use

Res

earc

h &

Man

agem

ent P

rogr

am

Ore

gon

Stat

e U

nive

rsity

, 500

Sum

mer

Stre

et N

E, E

35, S

alem

, Ore

gon

9730

1-10

79

Phon

e 50

3-94

5-52

20 |

Fax

503-

947-

1119

1 M

onth

/Yea

r of

Rev

iew

: Ja

nuar

y 2

011

En

d da

te o

f lit

erat

ure

sear

ch:

Dec

embe

r 201

1 G

ener

ic N

ame:

Dab

igat

ran

Br

and

Nam

e (M

anuf

actu

rer)

: Pr

adax

a (B

oehr

inge

r In

gelh

eim

)

Dos

sier

rec

eive

d:

Yes

PDL

Clas

s: N

o cu

rren

t PD

L cl

ass

Co

mpa

rato

r Th

erap

ies:

Eno

xapa

rin a

nd w

arfa

rin

Pref

erre

d A

ntic

oagu

lant

s: e

noxa

parin

and

dal

tepa

rin

Non

-pre

ferr

ed A

ntic

oagu

lant

s: fo

ndip

arin

ux, t

inza

pari

n, r

ivar

oxab

an (p

endi

ng) a

nd d

abig

atra

n (p

endi

ng)

No

PDL-

stat

us/n

o re

stri

ctio

ns: w

arfa

rin

FD

A A

ppro

ved

Indi

cati

ons:

To

red

uce

the

risk

of s

trok

e an

d sy

stem

ic e

mbo

lism

in p

atie

nts

with

non

-val

vula

r at

rial

fibr

illat

ion

(AF)

. Su

mm

ary:

-

Dab

igat

ran

is a

dir

ect t

hrom

bin

inhi

bito

r use

d fo

r ora

l str

oke

prop

hyla

xis

in p

atie

nts

with

AF,

as

an a

ltern

ativ

e to

vita

min

K a

ntag

onis

ts (V

KA)

such

as

war

fari

n. D

abig

atra

n ha

s fe

w d

rug/

food

inte

ract

ions

and

is n

ot a

sub

stra

te, i

nhib

itor o

r in

duce

r of

CYP

450

enzy

mes

.1 -

The

reco

mm

ende

d da

biga

tran

dos

e is

150

mg

twic

e da

ily fo

r AF.

Dos

e ad

just

men

t to

75m

g tw

ice

daily

if C

rCl 1

5-30

mL/

min

. N

o ad

just

men

ts r

equi

red

with

mod

erat

e he

patic

dys

func

tion.

Ef

ficac

y an

d Sa

fety

Sum

mar

y fo

r FD

A A

ppro

ved

Indi

cati

ons

Atr

ial F

ribr

illat

ion

- D

abig

atra

n ap

prov

al w

as b

ased

on

a la

rge,

pro

spec

tive,

non

-blin

ded,

ran

dom

ized

tria

l, th

e Ra

ndom

ized

Eva

luat

ion

of L

ong-

term

A

ntic

oagu

latio

n Th

erap

y (R

E-LY

).2 RE-

LY w

as a

mul

ti-ce

nter

, mul

ti-na

tiona

l, pa

ralle

l gro

up, n

on-in

ferio

rity

tria

l com

parin

g tw

o bl

inde

d do

ses

of d

abig

atra

n (1

10m

g tw

ice

daily

or

150

mg

twic

e da

ily) w

ith o

pen-

labe

l war

fari

n w

ith a

targ

et in

tern

atio

nal n

orm

aliz

ed r

atio

(IN

R) r

ange

of

2-3.

Mea

n tim

e in

ther

apeu

tic r

ange

(TTR

) was

64%

.2 -

A h

igh

degr

ee o

f bia

s is

ass

ocia

ted

with

an

open

-labe

l stu

dy d

esig

n. T

he F

DA

cite

d th

is c

once

rn in

thei

r re

view

but

felt

that

bec

ause

ther

e w

ere

sign

ifica

nt d

iffer

ence

s sh

own

in th

e do

uble

-blin

d co

mpa

riso

n be

twee

n th

e da

biga

tran

dos

es, t

his

help

ed to

sub

stan

tiate

the

resu

lts.3

The

rate

s of

intr

acra

nial

ble

eds

was

the

prim

ary

fact

or c

ontr

ibut

ing

to th

e co

mpo

site

out

com

es.

- Tw

o do

ses

wer

e st

udie

d in

RE-

LY, a

110

mg

dose

and

a 1

50 m

g do

se.

The

110m

g do

se w

as n

ot a

ppro

ved

and

did

not d

emon

stra

te

supe

rior

ity o

ver

war

fari

n. T

here

was

mod

erat

e-st

reng

th o

f evi

denc

e th

at d

abig

atra

n 15

0mg

was

sup

erio

r to

war

fari

n fo

r the

pri

mar

y co

mpo

site

end

poin

t of s

trok

e or

sys

tem

ic e

mbo

lism

(RR

0.65

; 95%

CI,

0.52

to 0

.81;

p<0

.001

, NN

T 16

7).

Ther

e w

as lo

w-s

tren

gth

of e

vide

nce

56 of 187

Gen

eric

Nam

e: D

abig

atra

n

R

evie

w D

ate:

Janu

ary

2011

2 A

utho

r: K

athy

Sen

tena

that

dab

igat

ran

150m

g ha

d si

mila

r rat

es o

f all-

caus

e m

orta

lity

com

pare

d to

war

farin

. FD

A a

naly

sis

of R

E-LY

sta

tes

that

in p

atie

nts

who

m

INRs

are

wel

l con

trol

led,

war

fari

n an

d da

biga

tran

150

mg

twic

e da

ily c

arry

the

sam

e ri

sk o

f str

oke

or fa

tal e

vent

s.3

- Th

ere

was

low

-str

engt

h of

evi

denc

e of

sim

ilar r

ates

of m

ajor

ble

edin

g w

ith d

abig

atra

n 15

0mg,

com

pare

d to

war

farin

, whi

ch w

as in

fluen

ced

by th

e TT

R. T

here

wer

e si

gnifi

cant

ly m

ore

gast

roin

test

inal

ble

eds

in th

e da

biga

tran

150

mg

grou

p co

mpa

red

to w

arfa

rin.

Dab

igat

ran

was

as

soci

ated

with

less

intr

acra

nial

ble

edin

g, w

hich

was

sta

tistic

ally

sig

nific

ant a

nd in

depe

nden

t of T

TR.4

Oth

er C

onsi

dera

tion

s:

- D

abig

atra

n is

ass

ocia

ted

with

dys

peps

ia, w

hich

is th

e m

ost c

omm

only

cite

d re

ason

for d

rug

disc

ontin

uatio

n. I

n th

e da

biga

tran

150

mg

grou

p an

nual

dis

cont

inua

tion

rate

s w

ere

2% c

ompa

red

to 0

.6%

of w

arfa

rin p

atie

nts.

2

- A

n in

crea

sed

rate

of m

yoca

rdia

l inf

arct

ions

(MI)

wer

e se

en w

ith b

oth

dose

s of

dab

igat

ran

but n

eith

er w

ere

stat

istic

ally

sig

nific

ant a

fter

ne

wly

iden

tifie

d ev

ents

wer

e in

clud

ed in

the

revi

sed

data

.5 -

Ther

e is

no

antid

ote

to re

vers

e bl

eedi

ng in

a b

leed

ing

emer

genc

y. U

nlik

e w

arfa

rin,

vita

min

K a

dmin

istr

atio

n w

ill n

ot re

duce

the

antic

oagu

lant

eff

ects

of d

abig

atra

n in

the

even

t of a

maj

or b

leed

.1 -

The

FDA

has

rece

ntly

ann

ounc

ed th

at th

ey w

ill b

e co

nduc

ting

a sa

fety

rev

iew

of p

ost-

mar

ketin

g re

port

s of

ser

ious

ble

edin

g as

soci

ated

with

da

biga

tran

. A

t thi

s tim

e th

e FD

A be

lieve

s th

e be

nefit

s of

dab

igat

ran

still

exc

eed

the

risk

. Ef

ficac

y an

d Sa

fety

Sum

mar

y on

off

-labe

l Use

s Su

rger

y Pr

ophy

laxi

s -

Thre

e st

udie

s ev

alua

ted

the

use

of d

abig

atra

n fo

r pre

vent

ion

of V

TE a

fter

TKR

and

TH

R. I

n TK

R, th

e ev

iden

ce fo

und

that

dab

igat

ran

was

no

ninf

erio

r to

enox

apar

in (E

urop

ean

dosi

ng r

egim

en o

f 40m

g da

ily w

as u

sed

com

pare

d to

Nor

th A

mer

ican

regi

men

of 3

0 m

g tw

ice

daily

) ho

wev

er, i

t was

dee

med

infe

rior t

o en

oxap

arin

whe

n th

e N

orth

Am

eric

an d

osin

g re

gim

en w

as u

sed.

One

fair

qual

ity s

tudy

in T

HR

show

ed

dabi

gatr

an to

be

non-

infe

rior

to e

noxa

pari

n. A

ll su

rger

y pr

ophy

laxi

s st

udie

s in

clud

ed a

sym

ptom

atic

and

sym

ptom

atic

DVT

s, in

whi

ch th

e cl

inic

al u

tility

of a

sym

ptom

atic

DVT

s is

unk

now

n. O

vera

ll, th

e us

e of

dab

igat

ran

for

prop

hyla

xis

of D

VT in

pat

ient

s un

derg

oing

TH

R an

d TK

R ha

s lo

w le

vel e

vide

nce

to s

uppo

rt it

s us

e.

A

cute

DVT

Tre

atm

ent

- Th

ere

is o

ne fa

ir qu

ality

stu

dy o

f dab

igat

ran

use

in th

e ac

ute

trea

tmen

t of V

TE (R

ECO

VER)

, whi

ch d

emon

stra

ted

that

dab

igat

ran

was

no

ninf

erio

r to

war

fari

n w

ith s

imila

r rat

es o

f ble

edin

g.

Cost

Con

side

rati

ons:

Co

sts

will

be

disc

usse

d in

the

exec

utiv

e se

ssio

n.

57 of 187

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eric

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e: D

abig

atra

n

R

evie

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ate:

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ary

2011

3 A

utho

r: K

athy

Sen

tena

PDL

Plac

emen

t Re

com

men

dati

on:

Ther

e is

low

-mod

erat

e le

vel o

f evi

denc

e to

sup

port

the

use

of d

abig

atra

n in

AF.

The

rel

ativ

e ef

ficac

y of

dab

iaga

tran

com

pare

d to

war

fari

n is

stil

l un

cert

ain

due

to p

oten

tial b

ias

tow

ard

dabi

gatr

an a

s a

resu

lt of

an

open

-labe

l stu

dy d

esig

n. S

ub-o

ptim

al IN

R co

ntro

l in

the

war

fari

n gr

oup

in R

E-LY

su

gges

ts p

atie

nts

with

wel

l con

trol

led

INRs

may

not

ben

efit

from

dab

igat

ran

trea

tmen

t. I

t is

reco

mm

ende

d da

biga

tran

be

adde

d to

the

PDL

as a

se

cond

line

age

nt re

quir

ing

prio

r au

thor

izat

ion.

D

ata

on u

sing

dab

igat

ran

for a

cute

VTE

is li

mite

d, h

owev

er, d

ue to

lim

ited

oral

ant

icoa

gula

nt o

ptio

ns, d

abig

atra

n sh

ould

be

adde

d to

the

PDL

with

a

PA r

estr

ictio

n fo

r thi

s in

dica

tion

as a

sec

ond

line

optio

n.

BACK

GRO

UN

D/C

URR

ENT

LAN

DSC

APE

Th

e vi

tam

in K

ant

agon

ist

(VKA

), w

arfa

rin,

has

ser

ved

as t

he g

old

stan

dard

for

oral

ant

icoa

gula

tion

and

is a

cov

ered

the

rapy

for

Ore

gon

Hea

lth P

lan

(OH

P) p

atie

nts.

A

ppro

xim

atel

y 35

0 pa

tient

s ut

ilize

d lo

ng t

erm

ant

icoa

gula

tion

(>45

day

s), r

epre

sent

ing

over

2,0

00 p

resc

ript

ion

clai

ms

with

in t

he

last

six

mon

ths

with

in t

he O

HP

popu

latio

n.

A m

eta-

anal

ysis

for

str

oke

prev

entio

n in

pat

ient

s w

ith n

on-v

alvu

lar

AF

foun

d w

arfa

rin

ther

apy

to

redu

ce s

trok

e by

60%

, whi

ch w

as 4

0% m

ore

effic

acio

us th

an a

nti-p

late

let t

hera

py.12

The

Coc

hran

e D

atab

ase

for

Syst

emat

ic R

evie

ws

estim

ates

that

ap

prox

imat

ely

25 s

trok

es a

nd 1

2 di

sabl

ing

or f

atal

str

okes

wou

ld b

e pr

even

ted

per

year

, fo

r ev

ery

1000

pri

mar

y pr

even

tion

patie

nts

with

AF

trea

ted

with

war

fari

n.13

H

owev

er,

ther

e is

a s

igni

fican

t cl

inic

al n

eed

for

an a

ltern

ativ

e to

war

fari

n fo

r tr

eatm

ent

and

prop

hyla

xis

of n

umer

ous

cond

ition

s th

at r

equi

re a

ntic

oagu

latio

n.

War

farin

has

a n

arro

w t

hera

peut

ic in

dex,

dru

g an

d di

etar

y in

tera

ctio

ns, v

aria

ble

phar

mac

okin

etic

s, a

nd

unpr

edic

tabl

e ph

arm

acod

ynam

ic r

espo

nses

, re

sulti

ng i

n re

duce

d pr

otec

tion

agai

nst

thro

mbo

embo

lic e

vent

s an

d po

tent

ially

cau

sing

se

riou

s bl

eeds

.14 C

onse

quen

tly,

war

fari

n is

oft

en u

nder

utili

zed,

with

onl

y 64

% o

f el

igib

le p

atie

nts

taki

ng w

arfa

rin

ther

apy.

15

Even

with

opt

imal

m

anag

emen

t, s

ome

patie

nts

do n

ot a

chie

ve a

dequ

ate

INR

cont

rol.

Pa

tient

s w

ith A

F ar

e at

a fo

ur t

o fiv

e-fo

ld in

crea

sed

risk

of s

trok

e an

d sy

stem

ic e

mbo

lism

com

pare

d to

tho

se w

ithou

t A

F. A

nnua

l rat

es o

f str

oke

in

patie

nts

with

AF

are

estim

ated

to

be b

etw

een

3-8%

, de

pend

ing

on a

dditi

onal

ris

k fa

ctor

s.16

An

ticoa

gula

nts

are

a ke

y co

mpo

nent

to

man

agin

g pa

tient

s w

ith A

F th

at a

re a

t an

incr

ease

d ri

sk o

f str

oke

from

car

dioe

mbo

lic e

vent

s. S

trok

e ri

sk in

AF

patie

nts

is m

ost c

omm

only

est

imat

ed u

sing

the

CHA

DS 2

ris

k st

ratif

icat

ion

sche

me.

Thi

s sc

hem

e es

timat

es s

trok

e ri

sk b

ased

on:

pre

senc

e of

hea

rt fa

ilure

, pre

senc

e of

hyp

erte

nsio

n, a

ge ≥

75 y

ears

, pr

esen

ce o

f di

abet

es m

ellit

us,

and

a hi

stor

y of

pre

viou

s st

roke

or

tran

sien

t is

chem

ic a

ttac

k (Tab

le 1

).17

The

grea

ter

the

num

ber

of r

isk

fact

ors

pres

ent,

the

gre

ater

the

ris

k of

str

oke.

Cu

rren

t CH

EST

guid

elin

es r

ecom

men

d an

ticoa

gula

tion

for

patie

nts

with

AF

and

sugg

est

aspi

rin t

hera

py f

or

patie

nts

with

up

to o

ne r

isk

fact

or a

nd t

reat

men

t w

ith a

VKA

for

patie

nts

with

one

or

mor

e ri

sk fa

ctor

s or

in s

econ

dary

pre

vent

ion

patie

nts.

18

The

guid

elin

es a

lso

reco

mm

end

VKA

ther

apy

for p

atie

nts

with

a C

HA

DS 2

sco

re o

f ≥2.

58 of 187

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eric

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abig

atra

n

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evie

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Janu

ary

2011

4 A

utho

r: K

athy

Sen

tena

Tabl

e 1. C

HADS

2 Clas

sifica

tion

Sche

me f

or S

troke

Risk

17

Ri

sk F

acto

r Po

ints

C

Cong

estiv

e Hea

rt Fa

ilure

1

H Hy

perte

nsion

1

A Ag

e ≥75

year

s 1

D Di

abete

s 1

S 2

Histo

ry of

strok

e or T

IA

2 O

bser

ved

rate

s of

ven

ous

thro

mbo

embo

lism

(VTE

) aft

er to

tal h

ip a

nd k

nee

repl

acem

ent s

urge

ry o

ccur

s in

app

roxi

mat

ely

5% o

f pat

ient

s w

ithou

t re

com

men

ded

prop

hyla

ctic

ant

icoa

gula

tion.

A r

ecen

t gui

delin

e by

the

Am

eric

an A

cade

my

of O

rtho

paed

ic S

urge

ons

give

s a

mod

erat

e re

com

men

datio

n fo

r the

use

of p

roph

ylac

tic p

harm

acol

ogic

al a

gent

s fo

r VTE

pre

vent

ion

in th

ose

patie

nts

that

are

not

at e

leva

ted

risk

. D

ue to

in

suff

icie

nt e

vide

nce

they

are

una

ble

to re

com

men

d an

y pa

rtic

ular

pre

vent

ativ

e st

rate

gy o

r tre

atm

ent d

urat

ion.

19 T

he C

HES

T gu

idel

ines

re

com

men

d at

leas

t 10

days

of t

hera

py a

nd u

p to

35

days

with

eith

er w

arfa

rin,

low

mol

ecul

ar w

eigh

t hep

arin

(LM

WH

), or

fond

apar

inux

for

knee

an

d hi

p re

plac

emen

t.18

OH

P co

vers

all

LMW

H p

rodu

cts,

fond

apar

inux

(Arix

tra®

) and

des

irud

in (I

priv

ask®

). I

n th

e pr

evio

us s

ix m

onth

s ap

prox

imat

ely

200

patie

nts

rece

ived

sho

rt te

rm a

ntic

oagu

latio

n (<

45 d

ays)

acc

ount

ing

for

alm

ost 2

00 p

resc

ript

ion

clai

ms.

VT

E is

a s

erio

us m

edic

al c

ondi

tion

that

can

lead

to p

ulm

onar

y em

bolis

m a

nd re

late

d ri

sk o

f mor

bidi

ty a

nd m

orta

lity.

20 C

HES

T gu

idel

ines

rec

omm

end

initi

al tr

eatm

ent w

ith L

MW

H, u

nfra

ctio

nate

d he

pari

n (U

FH) o

r fon

dapa

rinu

x fo

r at l

east

5 d

ays

and

initi

atio

n of

war

fari

n on

the

first

trea

tmen

t da

y.18

Dis

cont

inua

tion

of h

epar

in p

repa

ratio

ns s

houl

d oc

cur w

hen

the

INR

reac

hes

2.0

or m

ore

for

at le

ast 2

4 ho

urs.

For

pat

ient

s w

ith D

VT o

r PE

seco

ndar

y to

a r

ever

sibl

e ri

sk fa

ctor

, the

gui

delin

es r

ecom

men

d tr

eatm

ent w

ith w

arfa

rin fo

r 3 m

onth

s. T

reat

men

t rec

omm

enda

tions

for p

atie

nts

with

unp

rovo

ked

DVT

or P

E in

clud

e w

arfa

rin fo

r at

leas

t 3 m

onth

s an

d up

to a

yea

r or l

onge

r ba

sed

on c

linic

al ju

dgm

ent.

CL

INIC

AL

PHA

RMA

COLO

GY

D

abig

atra

n is

a c

ompe

titiv

e, d

irec

t thr

ombi

n in

hibi

tor

with

act

ive

met

abol

ites

(acy

l glu

curo

nide

s).

Dab

igat

ran

inhi

bits

free

and

clo

t-bo

und

thro

mbi

n, a

s w

ell a

s th

rom

bin-

indu

ced

plat

elet

agg

rega

tion.

Dur

ing

the

com

mon

pat

hway

of t

he c

oagu

latio

n ca

scad

e, th

rom

bin

is r

equi

red

for t

he

conv

ersi

on o

f fib

rino

gen

to fi

brin

whi

ch is

then

cro

ss-li

nked

to fo

rm a

thro

mbu

s. I

nhib

ition

of t

his

tran

sfor

mat

ion

prev

ents

the

deve

lopm

ent o

f th

rom

bi.1

59 of 187

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n

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evie

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2011

5 A

utho

r: K

athy

Sen

tena

COM

PARA

TIV

E CL

INIC

AL

EFFI

CACY

Re

leva

nt E

ndpo

ints

St

udy

Endp

oint

s:

All

Stud

ies:

A

ll-ca

use

Mor

talit

y

RE

-LY:

Str

oke

or S

yste

mic

Em

bolis

m

Maj

or b

leed

ing

RECO

VER:

VTE

and

Rel

ated

dea

th

D

VT:

Sy

mpt

omat

ic D

VT

REM

OBI

LIZE

, REM

OD

EL, R

ENO

VATE

: Tot

al V

TE a

nd A

ll-ca

use

D

VT P

roph

ylax

is:

PE

m

orta

lity

Sym

ptom

atic

DVT

A

F:

St

roke

Ev

iden

ce T

able

Ref.

/ St

udy

Des

ign1

Dru

g Re

gim

ens

Pati

ent

Popu

lati

on

N

Dur

atio

n Ef

ficac

y Re

sult

s2

(CI,

p-va

lues

)

ARR

/

NN

T3 Sa

fety

Re

sult

s^

(CI,

p-va

lues

)

ARR

/ N

NH

3 Q

ualit

y Ra

ting

4 ; Com

men

ts

RE-L

Y2,5

Conn

olly

SJ

, et a

l Ph

ase

III,

RCT,

PG

1. D

abig

atra

n 11

0mg

bid

2.

Dab

igat

ran

150m

g bi

d 3.

War

fari

n ad

just

ed to

IN

R of

2-3

Age:

71

yrs

Mal

e: 6

4%

Prio

r st

roke

/TIA

: 20

%

CHAD

S 2: 2

Av

g. T

TR

(war

fari

n):

64%

1. 6

015

2. 6

076

3. 6

022

Med

ian

F/U

24

mon

ths

Stro

ke o

r Sy

stem

ic E

mbo

lism

: D

110

mg:

182

(1.

54%

) W

: 199

(1.7

1%)

RR 0

.90

95%

CI 0

.74

to 1

.10,

p<0

.001

for

noni

nfer

iori

ty

P= 0

.30

for

supe

rior

ity

D 1

50m

g: 1

34 (1

.11%

) W

: 199

(1.7

1%)

RR 0

.65

95%

CI 0

.52-

0.81

, p<

0.00

1 fo

r su

peri

ority

St

roke

: D

110

mg:

171

(1.4

4%)

W: 1

85 (1

.57%

) RR

.92

95%

CI 0

.74

to 1

.13

P=0.

41

D 1

50m

g: 1

22 (1

.01%

)

NS

ARR

0.6

0%

NN

T 16

7 N

S

ARR

0.56

%

Maj

or B

leed

s:

D 1

10m

g: 2

.87%

RR

0.8

0 9

5% C

I 0.7

0 to

0.9

3

p=0.

003

D

150

mg:

3.3

2%

RR 0

.93

95%

CI 0

.81

to 1

.07

p=0.

32

W:

3.57

%

ARR

0.7%

N

NH

142

N

S

• Fa

ir

• O

pen-

labe

l des

ign

may

bia

s re

sult

s in

favo

r of

dab

igat

ran

•

TTR

for

war

fari

n pa

tient

s w

as

64%

sug

gest

ing

subo

ptim

al

war

fari

n us

e.

• M

ajor

ble

eds

wer

e le

ss i

n da

biga

tran

gro

ups

only

in

cent

ers

whe

re T

TRs

wer

e w

orse

than

med

ian.

•

INR

test

ing

prot

ocol

was

not

cl

earl

y ou

tline

d. T

TR h

as a

di

rect

eff

ect o

n sa

fety

and

ef

ficac

y.

• U

se in

a b

road

er p

atie

nt

popu

latio

n is

nee

ded

to

defin

e M

I ris

k, G

I ble

edin

g an

d ef

fect

of n

o an

tidot

e.

60 of 187

Gen

eric

Nam

e: D

abig

atra

n

R

evie

w D

ate:

Janu

ary

2011

6 A

utho

r: K

athy

Sen

tena

W: 1

85 (1

.57%

) RR

0.6

4 95

% C

I 0.5

1 to

0.8

1 P<

0.00

1 Al

l Cau

se M

orta

lity:

D

110

mg:

446

(3.7

5%)

W: 4

87 (4

.13%

) RR

0.9

1 95

% C

I 0.8

0 to

1.0

3 P=

0.13

D

150

mg:

438

(3.6

4%)

W: 4

87 (4

.13%

) RR

0.8

8 95

% C

I 0.7

7 to

1.0

0 P=

0.05

1

NN

T 17

9 N

S N

S

RE-C

OV

ER11

Schu

lman

S,

et a

l Ph

ase

III,

RCT,

DB,

PG

1. D

abig

atra

n 15

0mg

bid

2. W

arfa

rin

adju

sted

to

INR

of 2

-3

.

Age:

54

yrs

Mal

e: 5

8%

Avg.

TTR

(w

arfa

rin)

: 60%

In

clus

ion:

Pa

tient

s 18

or

olde

r w

ith a

cute

, sy

mpt

omat

ic,

obje

ctiv

ely

veri

fied

prox

imal

DV

T of

th

e le

gs o

r pu

lmon

ary

embo

lism

who

m

6 m

o. o

f ant

i- co

agul

atio

n w

as

deem

ed

appr

opri

ate.

Ex

clus

ion:

Sy

mpt

oms

>14

days

, PE

with

1. 1

273

2. 1

266

Med

ian

F/U

5.

5 m

onth

s tx

with

1

mon

th F

/U

VTE

or R

elat

ed d

eath

: D

150

mg:

30

(2.4

%)

W: 2

7 (2

.1%

) H

R 1.

10

95%

CI -

0.65

to 1

.84

p<0.

001

Sy

mpt

omat

ic D

VT:

D 1

50m

g: 1

6 (1

.3%

) W

: 18

(1.4

%)

HR

0.87

95

% C

I 0.4

4 to

1.7

1 Al

l Cau

se M

orta

lity:

D

150

mg:

21

(1.6

%)

W:

21 (1

.7%

) H

R 0.

98

95%

CI 0

.53

to 1

.79

ARR

0.4%

N

NT

250

Maj

or B

leed

ing:

D

150

mg:

20

(1.6

%)

W:

24 (1

.9%

) H

R 0.

82

95%

CI 0

.45

to

1.48

p=

0.38

NS

• Fa

ir

• N

o pr

otoc

ol w

as g

iven

for

INR

test

ing.

TTR

for

war

fari

n pa

tient

s co

uld

influ

ence

ef

ficac

y an

d sa

fety

res

ults

•

TTR

for

war

fari

n pa

tient

s w

as

60%

.

61 of 187

Gen

eric

Nam

e: D

abig

atra

n

R

evie

w D

ate:

Janu

ary

2011

7 A

utho

r: K

athy

Sen

tena

hem

odyn

amic

in

stab

ility

or

requ

irin

g

thro

mbo

lytic

s,

addi

tiona

l war

fari

n in

dica

tion,

hig

h ri

sk o

f ble

edin

g,

unst

able

CV

di

seas

e, a

nd r

enal

an

d liv

er

abno

rmal

ities

RE

-MO

BILI

ZE6

Gin

sber

g JS

, et

al

Phas

e III

, RC

T, D

B, P

G

1. D

abig

atra

n 22

0mg

QD

2.

D

abig

atra

n 15

0mg

QD

3.

En

oxap

arin

30

mg

BID

(N

orth

Am

eric

an

sugg

este

d do

sing

)

Age

: 66

yrs

M

ale:

43%

Ti

me

to fi

rst d

ose:

9.

5 hr

s Fi

rst d

ose

of

dabi

gatr

an.

was

½ a

ssig

ned

dose

In

clus

ion:

Pa

tient

s 18

and

ov

er u

nder

goin

g pr

imar

y el

ectiv

e un

ilate

ral k

nee

arth

ropl

asty

Ex

clus

ion:

Bl

eedi

ng d

isor

der,

un

cont

rolle

d ht

n,

surg

ery,

con

ditio

n or

med

icat

ion

pred

ispo

sing

pt.

to

ble

edin

g,

abno

rmal

live

r fx

n

rena

l ins

uffic

ienc

y

1. 6

04

2. 6

49

3. 6

43

Med

ian

tx

dura

tion

: 14

day

s F/

U:

3 m

o

Tota

l VTE

+ a

ll-ca

use

mor

talit

y:

D 2

20m

g: 1

88 (3

1.1%

) E:

163

(25.

3%)

RR 1

.2

95%

CI 1

.0 to

1.5

D

150

mg:

219

(33.

7%)

E: 1

63 (2

5.3%

) RR

1.3

3 95

% C

I 1.1

to 1

.6

Non

fata

l PE:

D

220

mg:

6 (1

.0%

) E:

5 (0

.8%

) RR

1.3

95

% C

I 0.4

0 to

4.2

D

150

mg:

0 (0

%)

E: 5

(0.8

%)

NA

N

A

NA

Maj

or B

leed

ing:

D

220

mg:

5 (0

.6%

) E:

12

(1.4

%)

RR 0

.42

95%

CI 0

.15

to 1

.2

D 1

50m

g: 5

(0.6

%)

E: 1

2 (1

.4%

) RR

0.4

2 95

% C

I 0.1

5 to

1.2

•

Fair

•

Dab

igat

ran

deem

ed in

feri

or

due

to e

xcee

ding

non

-in

feri

ority

mar

gin

• H

igh

num

ber

of p

atie

nts

(26

30%

) exc

lude

d fr

om a

naly

sis

• Pr

imar

y ou

tcom

e w

as a

co

mpo

site

end

poin

t in

clud

ing

sym

ptom

atic

and

as

ympt

omat

ic (v

enog

raph

y).

The

impo

rtan

ce a

nd c

linic

al

rele

vanc

e of

asy

mpt

omat

ic

DVT

is

unkn

own

• N

o pr

otoc

ol g

iven

for

VTE

diag

nosi

s •

Conc

omita

nt u

se o

f ASA

and

se

lect

ive

cox-

2 in

hibi

tors

al

low

ed

• Co

mpr

essi

on s

tock

ings

al

low

ed

• Bi

late

ral v

enog

raph

y

RE-M

OD

EL 7

Erik

sson

Bl,

et a

l

1. D

abig

atra

n 22

0mg

QD

Age:

68

yrs

Mal

e: 4

5%

Tim

e to

firs

t

1. 5

03

Med

ian

Tx

dura

tion:

8

days

Tota

l VTE

+ a

ll-ca

use

mor

talit

y:

D 2

20m

g: 1

83 (3

6.4%

)

Maj

or B

leed

ing:

D

220

mg:

9 (1

.5%

) E:

9 (1

.3%

)

• Fa

ir

• Pr

imar

y en

dpoi

nt in

clud

ing

62 of 187

Gen

eric

Nam

e: D

abig

atra

n

R

evie

w D

ate:

Janu

ary

2011

8 A

utho

r: K

athy

Sen

tena

Phas

e III

, RC

T, D

B, P

G

2. D

abig

atra

n 15

0mg

QD

3.

Eno

xapa

rin

40m

g Q

D

(Eur

opea

n su

gges

ted

dosi

ng fo

r TK

R)

dose

: 3.5

hrs

Fi

rst

dose

of

dabi

gatr

an

was

½ a

ssig

ned

dose

In

clus

ion:

Pat

ient

s 18

and

old

er

unde

rgoi

ng

unila

tera

l TKR

Ex

clus

ion:

Sam

e

as a

bove

2. 5

26

3. 5

12

E: 1

93 (3

7.7%

) RR

0.9

7

95%

CI 0

.82

to 1

.1

D

150

mg:

213

(40.

5%)

E: 1

93 (3

7.7%

) RR

1.1

95

% C

I -0.

23 to

0.1

N

onfa

tal P

E:

D 2

20m

g: 0

(0%

) E:

1 (0

.1%

) D

150

mg:

1 (0

.1%

) E:

1 (0

.1%

) RR

0.9

8 95

% C

I 0.0

6 to

15.

7 Sy

mpt

omat

ic D

VT:

D

220

mg:

1 (0

.1%

)

E: 8

(1.2

%)

RR

1.0

95%

CI 0

.06

to 1

6

D 1

50m

g: 1

(0.1

%)

E:

8 (1

.2%

)

RR 0

.37

95

% C

I 0.1

to 1

.4

RR 1

.1

95%

CI 0

.46

to 2

.8

D 1

50m

g: 9

(1.3

%)

E: 9

(1.3

%)

RR 0

.99

95%

CI 0

.40

to 2

.5

sym

ptom

atic

and

as

ympt

omat

ic (v

enog

raph

y).

The

impo

rtan

ce a

nd c

linic

al

rele

vanc

e of

asy

mpt

omat

ic

DVT

s is

unk

now

n •

Excl

uded

25%

of p

atie

nts

in

prim

ary

outc

ome

anal

ysis

•

No

prot

ocol

giv

en fo

r VT

E di

agno

sis

• U

ncle

ar if

cen

tral

ad

judi

cato

rs w

ere

blin

ded

• D

osin

g re

gim

en fo

r en

oxap

arin

is c

omm

on in

Eu

rope

for

join

t rep

lace

men

t bu

t not

in N

orth

Am

eric

a.

RE-N

OV

ATE

8 Er

ikss

on B

l,

et a

l Ph

ase

III,

RCT,

DB,

PG

1. D

abig

atra

n 22

0mg

QD

2.

Dab

igat

ran

150m

g Q

D

3. E

noxa

pari

n 40

mg

QD

Age:

64

yrs

Mal

e: 4

4%

Incl

usio

n: P

atie

nts

18 a

nd o

lder

un

derg

oing

un

ilate

ral T

HR

Excl

usio

n: S

ame

as

abo

ve

1. 8

80

2. 8

74

3. 8

97

Med

ian

Tx

dura

tion:

33

day

s M

edia

n f/

u:

94

days

Tota

l VTE

+ a

ll-ca

use

mor

talit

y :

D 2

20m

g: 5

3 (6

.0%

) E:

60

(6.7

%)

RR 0

.90

95%

CI 0

.63

to 1

.3

D15

0mg:

75

(8.6

%)

E: 6

0 (6

.7%

) RR

1.3

95

% C

I 0.9

3 to

1.8

NA

Maj

or B

leed

ing:

D

220

mg:

23

(2.0

%)

E: 1

8 (1

.6%

) RR

1.3

95

% C

I 0.7

4 to

2.4

D

150

mg:

15

(1.3

%)

E: 1

8 (1

.6%

) RR

0.8

3 95

% C

I 0.4

2 to

1.6

•

Fair

•

Prim

ary

endp

oint

incl

udin

g sy

mpt

omat

ic a

nd

asym

ptom

atic

(ven

ogra

phy)

. Th

e im

port

ance

and

clin

ical

re

leva

nce

of a

sym

ptom

atic

D

VTs

is u

nkno

wn

• Ex

clud

ed 2

3% o

f pat

ient

s in

pr

imar

y ou

tcom

e an

alys

is

(mIT

T)

• N

o pr

otoc

ol g

iven

for

VTE

diag

nosi

s

63 of 187

Gen

eric

Nam

e: D

abig

atra

n

R

evie

w D

ate:

Janu

ary

2011

9 A

utho

r: K

athy

Sen

tena

PE:

D 2

20m

g: 5

(0.4

%)

E: 3

(0.3

%)

RR 1

.7

95%

CI 0

.40

to 7

.0

D 1

50m

g: 1

(0.1

%)

E: 3

(0.3

%)

RR 0

.33

95%

CI 0

.03

to 3

.2

Sym

ptom

atic

DVT

: D

220

mg:

6 (0

.5%

) E

: 1 (0

.1%

) R

R 6.

0 9

5% C

I 0.7

3 to

50

D 1

50m

g: 9

(0.8

%)

E:

1 (0

.1%

) R

R 8.

90

95%

CI 1

.1 to

70

• D

osin

g re

gim

en fo

r en

oxap

arin

is c

omm

on in

Eu

rope

for

join

t rep

lace

men

t

1 Stud

y de

sign

abb

revi

atio

ns: D

B =

doub

le-b

lind,

RCT

= r

ando

miz

ed tr

ial,

PC =

pla

cebo

-con

trol

led,

PG

= p

aral

lel -

grou

p, X

O =

cro

ssov

er.

2 Resu

lts

abbr

evia

tion

s: R

RR =

rel

ativ

e ri

sk r

educ

tion

, RR

=rel

ativ

e ri

sk, O

R= O

dds

Ratio

, HR

= H

azar

d Ra

tio,

ARR

= ab

solu

te r

isk

redu

ctio

n,

NN

T =

num

ber

need

ed to

trea

t, N

NH

= n

umbe

r ne

eded

to h

arm

, CI =

con

fiden

ce in

terv

al

3 NN

T/N

NH

are

rep

orte

d on

ly fo

r st

atis

tical

ly s

igni

fican

t res

ults

4 Q

ualit

y Ra

ting

: (G

ood-

like

ly v

alid

, Fai

r- li

kely

val

id/p

ossi

bly

valid

, Poo

r- fa

tal f

law

-not

val

id)

Clin

ical

Abb

revi

atio

ns:

TTR=

tim

e in

ther

apeu

tic r

ange

64 of 187

Gen

eric

Nam

e: D

abig

atra

n

R

evie

w D

ate:

Janu

ary

2011

10

Aut

hor:

Kat

hy S

ente

na

Stud

y D

etai

ls –

FDA

app

rova

l of d

abig

atra

n w

as b

ased

on

a ph

ase

III tr

ial i

n 18

,113

pat

ient

s w

ith A

F, th

e Ra

ndom

ized

Eva

luat

ion

of L

ong-

term

Ant

icoa

gula

tion

Ther

apy

(RE-

LY).2,

5 RE

-LY

was

a m

ulti-

cent

er, m

ulti-

natio

nal,

pros

pect

ive,

rand

omiz

ed, p

aral

lel g

roup

, non

-infe

riori

ty tr

ial c

ompa

ring

two

blin

ded

dose

s of

dab

igat

ran

(110

mg

twic

e da

ily o

r 150

mg

twic

e da

ily) w

ith o

pen-

labe

l war

fari

n w

ith a

targ

et IN

R ra

nge

of 2

-3.

Pat

ient

s ha

d at

leas

t one

CH

AD

S 2 r

isk

fact

or.

Med

ian

follo

w-u

p w

as tw

o ye

ars

and

the

prim

ary

endp

oint

of t

he tr

ial w

as ti

me

to fi

rst o

ccur

renc

e of

str

oke

(isch

emic

or

hem

orrh

agic

) or

syst

emic

em

bolic

eve

nt (S

EE).

The

pri

mar

y sa

fety

out

com

e m

easu

re w

as m

ajor

ble

edin

g. P

atie

nts

had

sim

ilar

base

line

char

acte

rist

ics,

with

a m

ean

age

of 7

1, a

n av

erag

e CH

AD

S 2 s

core

of 2

.1 a

nd 6

4% w

ere

mal

e. O

ver h

alf o

f the

enr

olle

d pa

tient

s ha

d be

en o

n pr

evio

us lo

ng-t

erm

VKA

ther

apy

and

the

othe

r hal

f wer

e tr

eatm

ent n

aïve

to V

KA.

Ther

e w

as lo

w-s

tren

gth

of e

vide

nce

from

the

RELY

tria

l tha

t dab

igat

ran

110m

g w

as n

on-in

feri

or to

war

fari

n fo

r the

pri

mar

y en

dpoi

nt o

f str

oke

or

syst

emic

em

bolis

m.

The

re w

as a

lso

low

-str

engt

h of

evi

denc

e fo

r da

biga

tran

110

mg

that

inci

denc

e of

str

oke

and

all-c

ause

mor

talit

y ra

tes

wer

e si

mila

r to

war

farin

(RR

0.91

; 95%

CI,

0.80

to 1

.03;

p=0

.13)

with

low

-str

engt

h of

evi

denc

e of

red

uced

rat

es o

f maj

or b

leed

ing.

The

re w

as lo

w-

stre

ngth

of e

vide

nce

that

dab

igat

ran

150m

g w

as s

uper

ior t

o w

arfa

rin

for t

he p

rim

ary

endp

oint

of s

trok

e or

sys

tem

ic e

mbo

lism

(RR

0.65

; 95%

CI,

0.52

to 0

.81;

p<0

.001

) and

for t

he c

ompo

nent

out

com

e of

str

oke,

with

a N

NT

of 1

67 a

nd 1

79, r

espe

ctiv

ely.

The

re w

as lo

w-s

tren

gth

of e

vide

nce

that

dab

igat

ran

150m

g ha

d si

mila

r rat

es o

f all-

caus

e m

orta

lity

com

pare

d to

war

farin

and

no

diff

eren

ce in

maj

or b

leed

ing

rate

s.

RELY

was

sub

ject

to a

hig

h ri

sk o

f bia

s ba

sed

on o

pen-

labe

l war

farin

arm

as

a co

mpa

rato

r. T

he F

DA

cite

d th

is c

once

rn in

thei

r re

view

but

felt

that

be

caus

e th

ere

was

sig

nific

ant d

iffer

ence

s sh

own

in th

e do

uble

-blin

d co

mpa

riso

n be

twee

n th

e da

biga

tran

dos

es th

at th

is h

elpe

d to

sub

stan

tiate

the

resu

lts.3

FDA

ana

lysi

s of

RE-

LY s

tate

s th

at in

pat

ient

s w

hom

IN

Rs a

re w

ell c

ontr

olle

d, w

arfa

rin

and

dabi

gatr

an 1

50 m

g tw

ice

daily

car

ry t

he s

ame

risk

of

stro

ke o

r fa

tal e

vent

s.3

Addi

tiona

lly, t

he F

DA

ass

ocia

ted

the

bene

fits

in a

ll-ca

use

mor

talit

y ra

tes

in fa

vor

of d

abig

atra

n w

as d

rive

n by

cen

ters

whe

re

TTR

was

wor

se t

han

the

med

ian.

The

inci

denc

e of

maj

or b

leed

s an

d ga

stro

inte

stin

al b

leed

ing

decr

ease

d in

the

war

fari

n gr

oups

as

TTR

impr

oved

an

d m

ajor

ble

eds

wer

e le

ss in

dab

igat

ran

grou

ps o

nly

at c

ente

rs in

whi

ch T

TR w

as w

orse

tha

n th

e m

edia

n.

How

ever

, rat

es o

f in

trac

rani

al b

leed

s w

ere

not a

ffec

ted

by T

TR, w

ith c

onsi

sten

tly lo

wer

inci

denc

es in

bot

h da

biga

tran

gro

ups.

4 I

ntra

cran

ial b

leed

s w

ere

also

the

maj

or c

ontr

ibut

or o

f the

pr

imar

y co

mpo

site

out

com

e.

Off

-labe

l Ind

icat

ions

A

cute

VTE

Tre

atm

ent

In R

ECO

VER

a no

n-in

feri

ority

stu

dy o

f da

biga

tran

com

pare

d to

war

fari

n fo

r th

e ac

ute

trea

tmen

t of

VTE

was

don

e in

ove

r 25

00 p

atie

nts.

Pa

rtic

ipan

ts w

ere

rand

omly

ass

igne

d in

a b

linde

d m

anne

r to

dab

igat

ran

150m

g tw

ice

daily

or

war

fari

n, d

ose-

adju

sted

to

an IN

R of

2.0

-3.0

, aft

er

65 of 187

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eric

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abig

atra

n

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ate:

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ary

2011

11

Aut

hor:

Kat

hy S

ente

na

initi

al t

reat

men

t w

ith p

aren

tera

l ant

icoa

gula

tion

(med

ian

dura

tion

of 9

day

s).11

T

he p

rim

ary

outc

ome

mea

sure

was

the

6-m

onth

inci

denc

e of

re

curr

ent

sym

ptom

atic

, ob

ject

ivel

y co

nfirm

ed V

TE a

nd r

elat

ed d

eath

s.

Non

infe

rior

ity w

as d

eter

min

ed f

or t

he h

azar

d ra

tio w

ith t

he p

rede

fined

m

argi

n of

2.7

5 an

d th

e di

ffer

ence

in r

isk

with

the

pred

efin

ed m

argi

n of

3.6

per

cent

age

poin

ts.

RE

COVE

R ha

d m

oder

ate-

stre

ngth

of

evid

ence

tha

t da

biga

tran

is

noni

nfer

ior

to w

arfa

rin

for

the

prim

ary

endp

oint

of

VTE

or r

elat

ed d

eath

. A

dditi

onal

ly, t

here

was

mod

erat

e-st

reng

th o

f evi

denc

e th

at m

ajor

ble

edin

g ra

tes

wer

e si

mila

r for

dab

igat

ran

and

war

fari

n.

The

RE-C

OVE

R st

udy

show

ed d

abig

atra

n to

be

as e

ffec

tive

as w

arfa

rin

over

a s

ix m

onth

tim

e pe

riod

for

acut

e tr

eatm

ent

of V

TE.

War

fari

n tr

eate

d pa

tient

s w

ere

note

d to

be

in t

he t

hera

peut

ic r

ange

onl

y 60

% o

f the

tim

e, w

hich

cou

ld o

vere

stim

ate

the

effe

ctiv

enes

s of

dab

igat

ran

in c

ompa

riso

n.

A s

tatis

tical

ly s

igni

fican

t nu

mbe

r of

pat

ient

s di

scon

tinue

d tr

eatm

ent

in t

he d

abig

atra

n gr

oup

com

pare

d to

war

fari

n, s

ugge

stin

g cl

inic

ally

rel

evan

t is

sues

with

tole

rabi

lity

with

long

term

use

. V

TE P

reve

ntio

n D

abig

atra

n w

as s

tudi

ed fo

r pr

even

tion

of V

TE a

fter

TKR

in 5

,266

pat

ient

s in

the

RE-M

OBI

LIZE

and

REM

OD

EL s

tudi

es.6,

7 In

the

RE-M

OBI

LIZE

stu

dy

patie

nts

rece

ived

eith

er d

abig

atra

n 22

0mg

or d

abig

atra

n 15

0mg

once

dai

ly o

r en

oxap

arin

30m

g tw

ice

daily

(Nor

th A

mer

ican

dos

ing

regi

men

) in

a ra

ndom

ized

, dou

ble

blin

d fa

shio

n fo

r a

mea

n tr

eatm

ent d

urat

ion

of 1

4 da

ys.

In th

e RE

MO

DEL

stu

dy p

atie

nts

rece

ived

dab

igat

ran

150m

g,

dabi

gatr

an 2

20m

g on

ce d

aily

or e

noxa

pari

n 40

mg

subc

utan

eous

onc

e da

ily (E

urop

ean

dosi

ng r

egim

en) i

n a

rand

omiz

ed, d

oubl

e bl

ind

desi

gn fo

r a

med

ian

trea

tmen

t of 8

day

s. T

he p

rim

ary

effic

acy

outc

ome

was

the

com

posi

te o

f tot

al V

TE e

vent

s (s

ympt

omat

ic o

r ve

nogr

aphi

c) a

nd a

ll-ca

use

mor

talit

y.

The

two

stud

ies

had

conf

lictin

g pr

imar

y en

dpoi

nt re

sults

, with

RE-

MO

BILI

ZE h

avin

g lo

w-s

tren

gth

of e

vide

nce

that

dab

igat

ran

220m

g an

d 15

0mg

dose

s w

ere

infe

rior

to e

noxa

pari

n in

the

prev

entio

n of

VTE

aft

er T

KR.

In th

e RE

MO

DEL

stu

dy th

ere

was

low

-str

engt

h of

evi

denc

e th

at s

how

ed b

oth

dose

s of

dab

igat

ran

wer

e no

n-in

feri

or to

eno

xapa

rin.

In

resp

ect t

o co

mpo

nent

end

poin

ts, t

here

was

low

-str

engt

h of

evi

denc

e th

at e

noxa

parin

had

le

ss d

ista

l DVT

s. M

ajor

ble

edin

g ra

tes

wer

e lo

w in

bot

h st

udie

s, w

ith s

light

ly h

ighe

r rat

es w

ith e

noxa

pari

n in

REM

OBI

LIZE

and

equ

al o

r le

ss m

ajor

bl

eedi

ng w

ith e

noxa

parin

than

dab

igat

ran

in th

e RE

MO

DEL

stu

dy.

RE

-NO

VATE

eva

luat

ed th

e ef

ficac

y of

dab

igat

ran

for

the

prev

entio

n of

VTE

in p

atie

nts

unde

rgoi

ng T

HR

com

pare

d to

eno

xapa

rin.

8 Pat

ient

s re

ceiv

ed

dabi

gatr

an 1

50m

g, d

abig

atra

n 22

0mg

once

dai

ly o

r en

oxap

arin

40m

g su

bcut

aneo

us o

nce

daily

in a

ran

dom

ized

, dou

ble

blin

d de

sign

for

a m

edia

n du

ratio

n of

33

days

.

The

prim

ary

effic

acy

outc

omes

was

the

com

posi

te o

f to

tal

veno

us t

hrom

boem

bolis

m (

veno

grap

hic

or s

ympt

omat

ic)

and

mor

talit

y fr

om a

ll ca

uses

.

66 of 187

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eric

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ate:

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ary

2011

12

Aut

hor:

Kat

hy S

ente

na

Ther

e w

as lo

w-s

tren

gth

of e

vide

nce

that

dab

igat

ran

was

non

infe

rior

to

enox

apar

in fo

r th

e pr

imar

y ou

tcom

e m

easu

re in

TH

R. T

here

was

als

o lo

w-

stre

ngth

of e

vide

nce

of r

educ

ed V

TE r

elat

ed m

orta

lity

with

dab

igat

ran

220m

g co

mpa

red

to e

noxa

pari

n, a

lthou

gh n

ot s

tatis

tical

ly s

igni

fican

t. D

ata

for

maj

or b

leed

ing

rate

s de

mon

stra

ted

a m

oder

ate-

stre

ngth

of

evid

ence

tha

t da

biga

tran

220

mg

was

ass

ocia

ted

with

mor

e m

ajor

ble

edin

g th

an

enox

apar

in a

nd d

abig

atra

n 15

0mg

was

ass

ocia

ted

with

less

maj

or b

leed

ing.

H

igh

num

bers

of

patie

nts

wer

e ex

clud

ed b

ecau

se o

f th

e in

abili

ty t

o ad

equa

tely

ass

ess

thro

mbo

embo

lism

by

cont

rast

ven

ogra

phy.

Th

e pr

imar

y ou

tcom

e w

as a

com

posi

te m

easu

rem

ent

of s

ympt

omat

ic a

nd v

enog

raph

ic d

ata,

in w

hich

asy

mpt

omat

ic D

VTs

acco

unte

d fo

r th

e m

ajor

ity o

f th

e ev

ents

. T

he c

linic

al im

port

ance

of

asym

ptom

atic

DVT

s ha

s ye

t to

be

dete

rmin

ed a

nd a

bia

s in

det

ectin

g ev

ents

may

hav

e be

en p

rese

nt t

o do

un

ilate

ral i

nste

ad o

f bi

late

ral v

enog

raph

y.

Cana

dian

Age

ncy

for

Dru

gs a

nd T

echn

olog

ies

in H

ealth

(CA

DTH

) pr

efor

med

a s

yste

mat

ic r

evie

w a

nd

foun

d no

sta

tistic

ally

sig

nific

ant

diff

eren

ces

betw

een

dabi

gatr

an a

nd e

noxa

pari

n in

the

saf

ety

and

effic

acy

endp

oint

s w

hen

used

for

TKR

and

TH

R pr

ophy

laxi

s.9

The

Coch

rane

Dat

abas

e fo

r Sy

stem

atic

Rev

iew

s al

so e

valu

ated

dire

ct t

hrom

bin

inhi

bito

rs (

DTI

) fo

r th

e pr

even

tion

of V

TE f

ollo

win

g TK

R an

d TH

R.

They

con

clud

ed t

hat

no d

iffer

ence

was

fou

nd w

hen

only

sym

ptom

atic

VTE

eve

nts

wer

e co

mpa

red

betw

een

grou

ps.

They

cau

tion,

th

at t

he o

ccur

renc

e ra

te o

f sy

mpt

omat

ic V

TEs

are

so l

ow,

that

non

e of

the

stu

dies

enr

olle

d en

ough

par

ticip

ants

for

the

m t

o be

pow

ered

ap

prop

riat

ely

to m

ake

this

det

erm

inat

ion.

10 A

sen

sitiv

ity a

naly

sis

on th

e tim

ing

of a

ntic

oagu

latio

n in

itiat

ion

was

als

o pe

rfor

med

, bas

ed o

n ev

iden

ce

that

thi

s va

riab

le m

ay im

pact

the

eff

ectiv

enes

s of

the

rapy

as

muc

h as

the

act

ual t

reat

men

t its

elf.

The

ana

lysi

s fo

und

that

dir

ect

thro

mbi

n in

hibi

tor

trea

tmen

t st

arte

d be

fore

sur

gery

, re

sulte

d in

less

VTE

s th

an t

reat

men

t st

arte

d af

ter

surg

ery,

in c

ompa

riso

n w

ith L

MW

H.

Th

e Co

chra

ne r

epor

t co

nclu

des

that

DTI

s ar

e co

nsid

ered

equ

ally

eff

ectiv

e to

LM

WH

in t

he p

reve

ntio

n of

VTE

s in

pat

ient

s un

derg

oing

TKR

and

TH

R, b

ut, o

vera

ll th

ere

is

insu

ffic

ient

evi

denc

e to

sup

port

the

use

of

dabi

gatr

an in

pre

fere

nce

to L

MW

H.10

Th

e A

mer

ican

Aca

dem

y of

Ort

hope

dic

Surg

eons

Gui

delin

e on

Pr

even

ting

Veno

us T

hrom

boem

bolic

Dis

ease

in P

atie

nts

Und

ergo

ing

Elec

tive

Hip

and

Kne

e A

rthr

opla

sty

anal

yzed

dat

a on

pha

rmac

olog

ic a

gent

s,

incl

udin

g da

biga

tran

, for

the

prev

entio

n of

VTE

and

foun

d no

diff

eren

ce b

etw

een

trea

tmen

ts in

rega

rds

to e

ffic

acy

or s

afet

y.19

67 of 187

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2011

13

Aut

hor:

Kat

hy S

ente

na

DRU

G S

AFE

TY

Serio

us (R

EMS,

Bla

ck B

ox W

arni

ngs,

Con

trai

ndic

atio

ns):

Act

ive

path

olog

ical

ble

edin

g an

d hi

stor

y of

ser

ious

hyp

erse

nsiti

vity

rea

ctio

n ar

e co

ntra

indi

catio

ns to

dab

igat

ran

ther

apy.

1

Blee

ding

: Lik

e al

l ant

icoa

gula

nts,

dab

igat

ran

incr

ease

s th

e ri

sk o

f ble

edin

g an

d ca

n ca

use

sign

ifica

nt o

r ev

en fa

tal b

leed

ing

in c

erta

in p

atie

nts.

The

ri

sk fo

r ble

edin

g in

crea

ses

with

dos

e an

d w

hen

othe

r dru

gs th

at a

lso

incr

ease

the

risk

of b

leed

ing

are

used

con

curr

ently

. The

se in

clud

e an

ti-pl

atel

et

agen

ts, h

epar

in, f

ibri

noly

tic th

erap

y, a

nd c

hron

ic u

se o

f non

-ste

roid

al a

nti-i

nfla

mm

ator

y m

edic

atio

ns.1,

2 O

vera

ll, th

e ra

te o

f maj

or b

leed

ing

was

com

para

ble

to a

ctiv

e co

ntro

ls in

the

stud

ies

exce

pt fo

r a

low

er r

ate

for

dabi

gatr

an 1

10m

g in

RE-

LY.

In th

e RE

-LY

tria

l, th

ere

was

a lo

wer

rat

e of

life

-thr

eate

ning

ble

eds,

esp

ecia

lly in

trac

rani

al b

leed

s w

ith th

e da

biga

tran

gro

up c

ompa

red

to w

arfa

rin, w

hile

ra

tes

of G

I ble

eds

wer

e m

ore

com

mon

with

dab

igat

ran.

Whe

n pa

tient

’s IN

R is

with

in ra

nge

>65.

5% o

f the

tim

e, r

ates

of m

ajor

ble

eds

are

high

er

with

dab

igat

ran

150m

g tr

eatm

ent.

2 A

lso,

in p

atie

nt’s

>80

yea

rs o

f age

, dab

igat

ran

150

mg

was

ass

ocia

ted

with

sig

nific

antly

mor

e m

ajor

ble

edin

g ev

ents

com

pare

d to

war

fari

n.2

Myo

card

ial I

nfar

ctio

n: A

hig

her n

umbe

r of

myo

card

ial i

nfar

ctio

ns w

ere

seen

in th

e da

biga

tran

gro

ups

com

pare

d to

war

farin

in th

e RE

-LY

tria

l.2 A

ccor

ding

to th

e FD

A’s

revi

ew o

f the

dat

a, th

e re

ason

for t

he e

xces

s ev

ents

is u

ncle

ar a

nd c

anno

t be

adeq

uate

ly e

xpla

ined

by

base

line

char

acte

rist

ics

or c

onco

mita

nt tr

eatm

ents

.3 Rat

es w

ere

not d

ose-

depe

nden

t and

cou

ld b

e m

ore

sign

ifica

nt in

a b

road

er p

opul

atio

n.

Tole

rabi

lity

(Dro

p-ou

t rat

es, m

anag

emen

t str

ateg

ies)

:

Gas

troi

ntes

tinal

eve

nts

wer

e th

e m

ost

freq

uent

ly c

ited

adve

rse

even

t re

sulti

ng in

trea

tmen

t di

scon

tinua

tion.

The

ris

k of

dys

peps

ia w

ith d

abig

atra

n th

erap

y w

as h

ighe

st w

ithin

the

first

few

wee

ks o

f tre

atm

ent.

Ann

ual t

reat

men

t dis

cont

inua

tion

rate

s du

e to

dys

peps

ia w

ere

high

er w

ith d

abig

atra

n co

mpa

red

to w

arfa

rin,

2%

vs.

0.6

%,

resp

ectiv

ely.

2 O

vera

ll dr

opou

t ra

tes

due

to a

dver

se e

vent

s w

ere

also

hig

her

with

dab

igat

ran

150m

g (2

1%)

com

pare

d to

war

farin

(16%

).2

Preg

nanc

y/La

ctat

ion

ratin

g:

Dab

igat

ran

is P

regn

ancy

Cat

egor

y C

and

has

been

sho

wn

to d

ecre

ase

the

num

ber o

f im

plan

tatio

ns a

nd in

crea

se th

e nu

mbe

r of d

ead

offs

prin

g w

hen

used

in fe

mal

e ra

ts.1,

3 It

is n

ot k

now

n if

dab

igat

ran

is e

xcre

ted

in h

uman

milk

.1

68 of 187

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2011

14

Aut

hor:

Kat

hy S

ente

na

Una

nsw

ered

saf

ety

ques

tions

: Re

vise

d da

ta s

how

ed a

hig

her

inci

denc

e of

MI i

n bo

th d

abig

atra

n gr

oups

com

pare

d to

war

fari

n bu

t the

y w

ere

not s

tatis

tical

ly s

igni

fican

t.5

Card

iova

scul

ar e

ffec

ts w

ill n

eed

to b

e fo

llow

ed a

s da

biga

tran

is u

sed

in th

e ge

nera

l pop

ulat

ion

to e

nsur

e th

ere

is n

o in

crea

sed

risk

. U

nlik

e w

arfa

rin,

vita

min

K a

dmin

istr

atio

n w

ill n

ot r

educ

e th

e an

ticoa

gula

nt e

ffec

ts o

f dab

igat

ran

in th

e ev

ent o

f a m

ajor

ble

ed. W

hile

ther

e is

no

antid

ote

to

dabi

gatr

an, a

dmin

istr

atio

n of

fres

h fr

ozen

pla

sma,

red

blo

od c

ells

, or d

ialy

sis

are

unpr

oven

opt

ions

to re

duce

hem

orrh

agic

com

plic

atio

ns.1 O

ther

qu

estio

ns in

clud

e th

e sa

fety

of u

sing

tiss

ue p

lasm

inog

en a

ctiv

ator

in p

atie

nts

taki

ng d

abig

atra

n.

Dos

e In

dex

(eff

icac

y/to

xic)

: Fo

r pa

tient

s w

ith a

cre

atin

ine

clea

ranc

e (C

rCl)

>30

mL/

min

, the

reco

mm

ende

d do

se o

f dab

igat

ran

is 1

50 m

g tw

ice

daily

with

out r

egar

ds to

mea

ls.

For

patie

nts

with

CrC

l bet

wee

n 15

-30m

L/m

in, t

he r

ecom

men

ded

dose

of d

abig

atra

n in

75

mg

oral

ly tw

ice

daily

.1 Use

of d

abig

atra

n in

pat

ient

s w

ith

a Cr

Cl <

15 m

L/m

in o

r on

dial

ysis

is n

ot r

ecom

men

ded1 .

In p

atie

nts

with

mod

erat

e re

nal i

mpa

irmen

t(Cr

Cl 3

0-50

mL/

min

), co

ncom

itant

use

of t

he P

-gp

inhi

bito

r dro

neda

rone

or

syst

emic

ket

ocon

azol

e w

ould

pro

duce

dab

igat

ran

conc

entr

atio

ns s

imila

r to

thos

e w

ith s

ever

e re

nal i

mpa

irm

ent.

The

m

anuf

actu

rer

reco

mm

ends

red

ucin

g th

e do

se to

dab

igat

ran

75m

g tw

ice

daily

.1 It i

s no

t rec

omm

ende

d to

use

dab

igat

ran

and

P-gp

inhi

bito

rs in

pa

tient

s w

ith s

ever

e re

nal i

mpa

irmen

t (Cr

Cl 1

5-30

mL/

min

). D

abig

atra

n co

ncen

trat

ions

incr

ease

with

sev

erity

of r

enal

impa

irm

ent,

bas

ed o

n ph

arm

acok

inet

ic m

odel

ing.

21 N

o do

se a

djus

tmen

t is

nece

ssar

y fo

r pat

ient

s w

ith m

ild h

epat

ic d

ysfu

nctio

n.

Caps

ules

mus

t be

swal

low

ed w

hole

. Ch

ewin

g, c

rush

ing,

bre

akin

g, o

r em

ptyi

ng th

e co

nten

ts o

f the

cap

sule

can

resu

lt in

up

to a

75%

incr

ease

in o

ral

bioa

vaila

bilit

y1 . O

nce

open

ed, t

he p

rodu

ct s

houl

d be

use

d w

ithin

4 m

onth

s an

d ke

pt in

its

orig

inal

bot

tle.21

If a

dose

is m

isse

d, it

sho

uld

be ta

ken

as s

oon

as p

ossi

ble,

unl

ess

it is

with

in s

ix h

ours

of t

he n

ext s

ched

uled

dos

e, th

en th

e do

se s

houl

d be

ski

pped

.1 In

itial

ly,

liver

fun

ctio

n te

sts

wer

e pe

rfor

med

mon

thly

, du

e to

hep

atox

icity

re

late

d to

ano

ther

dir

ect

thro

mbi

n in

hibi

tor,

xim

elag

atra

n.

At s

ix

mon

ths

the

safe

ty m

onito

ring

boa

rd d

eem

ed t

his

freq

uenc

y of

tes

ting

to b

e un

nece

ssar

y as

dab

igat

ran

ther

apy

resu

lted

in s

imila

r liv

er f

unct

ion

test

ele

vatio

ns a

s w

arfa

rin, 1

.9%

vs.

2.2

%, r

espe

ctiv

ely.

2

Look

-alik

e /

Soun

d-al

ike

(LA

/SA

) Err

or R

isk

Pote

ntia

l: LA

/SA

nam

es a

re a

sses

sed

duri

ng th

e PD

L se

lect

ion

of d

rugs

. Ba

sed

on c

linic

al ju

dgm

ent a

nd a

n ev

alua

tion

of L

A/SA

info

rmat

ion

from

four

dat

a so

urce

s (L

exi-C

omp,

USP

Onl

ine

LASA

Fin

der,

Fir

st D

atab

ank,

and

ISM

P Co

nfus

ed D

rug

Nam

e Li

st),

the

follo

win

g dr

ug n

ames

may

cau

se L

ASA

co

nfus

ion:

N

ME

Dru

g N

ame

Lexi

-Com

p U

SP O

nlin

e Fi

rst D

ataB

ank

ISM

P Cl

inic

al Ju

dgm

ent

LA/S

A fo

r da

biga

tran

(gen

eric

) N

one

Non

e N

one

Non

e D

alte

parin

LA/S

A fo

r Pr

adax

a (b

rand

) N

one

N

one

Non

e N

one

Plav

ix

Pacl

itaxe

l

69 of 187

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eric

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Aut

hor:

Kat

hy S

ente

na

Proc

ardi

a XL

Pr

enex

a

70 of 187

Gen

eric

Nam

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n

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ate:

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2011

16

Aut

hor:

Kat

hy S

ente

na

Co

mm

on D

rug-

Rela

ted

Adv

erse

Eve

nts

*2

Adv

erse

Eve

nts

(1)

(Med

DRA

Sys

tem

Org

an C

lass

and

Pre

ferr

ed T

erm

)

Dab

igat

ran

110

mg

bid

n (%

)

Dab

igat

ran

150

mg

bid

n (%

)

War

fari

n

n (%

)

Num

ber

of P

atie

nts

n=60

15

n= 6

076

n=60

22

Card

iac

Dis

orde

rs

Ches

t Pai

n 31

2 (5

.2)

377

(6.2

) 35

7 (5

.9)

Atr

ial F

ibri

llatio

n 30

3 (5

.1)

313

(5.2

) 32

7 (5

.5)

Gas

troi

ntes

tina

l Dis

orde

rs

Dia

rrhe

a 33

0 (5

.5)

357

(5.9

) 34

9 (5

.8)

Dys

peps

ia

707

(11.

8)

688

(11.

3)

348

(5.8

) Re

spir

ator

y D

isor

ders

Co

ugh

344

(5.7

) 34

8 (5

.7)

364

(6.0

) D

yspn

ea

557

(9.3

) 58

0 (9

.5)

586

(9.7

) M

uscu

losk

elet

al D

isor

ders

A

rthr

algi

a 27

0 (4

.5)

335

(5.5

) 34

6 (5

.7)

Back

Pai

n 31

6 (5

.3)

314

(5.2

) 33

7 (5

.6)

Ner

vous

Sys

tem

Dis

orde

rs

Hea

dach

e 45

7 (7

.6)

458

(7.6

) 55

4 (9

.2)

Diz

zine

ss

486

(8.1

) 50

6 (8

.3)

568

(9.4

) V

ascu

lar

Dis

orde

rs

Peri

pher

al E

dem

a 47

3 (7

.9)

478

(7.9

) 46

8 (7

.8)

Oth

er

Fatig

ue

399

(6.6

) 40

1 (6

.6)

372

(6.2

) N

asop

hary

ngiti

s 33

7 (5

.6)

330

(5.4

) 33

6 (5

.6)

* A

dver

se e

vent

s oc

curr

ing

in m

ore

than

5%

of p

atie

nts

in d

abig

atra

n tr

eatm

ent g

roup

s.

71 of 187

Gen

eric

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2011

17

Aut

hor:

Kat

hy S

ente

na

DO

SE &

AV

AIL

ABI

LITY

1

STRE

NG

TH

FORM

RO

UTE

FR

EQU

ENCY

RE

NA

L A

DJ

HEP

ATI

C A

DJ

Pedi

atri

c

Dos

e El

derl

y D

ose

OTH

ER D

OSI

NG

CO

NSI

DER

ATI

ON

S D

abig

atra

n 15

0 m

g

Caps

ule

Ora

l

Twic

e da

ily

CrC

l 15-

30m

g/m

L us

e el

derly

do

sing

No

chan

ge s

een

in m

oder

ate

hepa

tic

dysf

unct

ion

N/A

75m

g tw

ice

daily

* M

ay b

e ta

ken

with

or w

ithou

t fo

od

Dab

igat

ran

110m

g do

sage

form

us

ed in

stu

dies

is n

ot a

vaila

ble

*

The

75

mg

twic

e da

ily d

ose

has

not b

een

stud

ied.

Con

cern

s ov

er d

abig

atra

n ac

cum

ulat

ion

in p

atie

nts

with

nor

mal

ren

al fu

nctio

n ha

ve b

een

rais

ed.

Patie

nts

with

ren

al

impa

irm

ent m

ay h

ave

a hi

gher

ris

k of

dru

g ac

cum

ulat

ion

and

subs

eque

nt b

leed

ing.

PH

ARM

ACO

KIN

ETIC

S1 Pa

ram

eter

Re

sult

O

ral B

ioav

aila

bilit

y 3

-7%

* Pr

otei

n Bi

ndin

g 3

5%

Elim

inat

ion

7%

uri

ne, 8

6% fe

ces

Hal

f-Li

fe

12-

17 h

ours

M

etab

olis

m

Conj

ugat

ion

to a

cyl g

lucu

roni

des

* D

o no

t cru

sh c

apsu

les,

bio

avai

labi

lity

incr

ease

s 75

%.

ALL

ERG

IES/

INTE

RACT

ION

S

Dru

g-D

rug:

Conc

omita

nt u

se o

f dab

igat

ran

with

P-g

p in

duce

rs (e

.g.,

rifa

mpi

n) r

educ

es e

xpos

ure

to d

abig

atra

n an

d sh

ould

be

avoi

ded.

1 P-g

p in

hibi

tion

and

impa

ired

ren

al fu

nctio

n ar

e th

e m

ost i

mpo

rtan

t ris

k fa

ctor

s th

at m

ay c

ause

incr

ease

s in

dab

igat

ran

conc

entr

atio

ns1 I

n cl

inic

al s

tudi

es e

xplo

ring

the

impa

ct o

f dab

igat

ran

on o

ther

dru

g th

erap

ies,

dab

igat

ran

did

not m

eani

ngfu

lly im

pact

the

phar

mac

okin

etic

s of

am

ioda

rone

, ato

rvas

tatin

, cl

arith

rom

ycin

, dic

lofe

nac,

clo

pido

grel

, dig

oxin

, pan

topr

azol

e, o

r ra

nitid

ine.

1 In

pat

ient

s w

ith m

oder

ate

rena

l im

pair

men

t, c

onco

mita

nt u

se o

f the

P-

gp in

hibi

tor d

rone

daro

ne o

r sys

tem

ic k

etoc

onaz

ole

wou

ld p

rodu

ce d

abig

atra

n co

ncen

trat

ions

sim

ilar

to th

ose

with

sev

ere

rena

l im

pair

men

t. T

he

man

ufac

ture

r re

com

men

ds r

educ

ing

the

dose

to d

abig

atra

n 75

mg

twic

e da

ily.21

72 of 187

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18

Aut

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Kat

hy S

ente

na

Food

-Dru

g:

No

food

-dru

g in

tera

ctio

ns h

ave

been

rep

orte

d.1

Alle

rgy/

Cros

s Re

activ

e Su

bsta

nces

:

In th

e RE

-LY

tria

l, dr

ug h

yper

sens

itivi

ty w

as re

port

ed in

<0.

1% o

f pat

ient

s. N

o cr

oss-

sens

itivi

ties

have

bee

n re

port

ed.1

73 of 187

Gen

eric

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19

Aut

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Kat

hy S

ente

na

APP

END

IX:

Ora

l D

irec

t T

hro

mb

in In

hib

ito

rs

Go

al(

s):

Pro

mote

safe

and e

ffective

thera

pie

s f

or

ora

l direct

thro

mbin

inh

ibitors

.

Len

gth

of

Au

tho

rizati

on

: 1 y

ear

Co

vere

d

Alt

ern

ati

ves

: Lis

ted a

t; h

ttp://w

ww

.ore

go

n.g

ov/D

HS

/hea

lth

pla

n/t

ools

_pro

v/p

dl.shtm

l

A

pp

roval

Cri

teri

a

1. D

oes the p

atien

t ha

ve

a d

iagnosis

of

non

va

lvula

r atr

ial fibrilla

tio

n?

Yes:

Go to #

2

N

o:

Go to #

4

2. W

ill the p

rescrib

er

consid

er

a c

ha

ng

e to w

arf

arin?

Yes:

Add

itio

nal in

form

ation

can b

e

found a

t:

http://w

ww

.dhs.s

tate

.or.

us/p

olic

y/h

ea

lthpla

n/g

uid

es/p

harm

acy/c

linic

al.htm

l

No

: G

o to #

3

3. Is th

e p

atient

una

ble

to t

ake p

refe

rred o

ral a

ntico

ag

ula

nt,

warf

arin,

du

e to o

ne o

f th

e f

ollo

win

g:

-

unsta

ble

IN

R

- w

arf

arin a

llerg

y

- c

ontr

ain

dic

atio

ns to w

arf

arin th

era

py

- d

rug-d

rug

in

tera

ctions

- into

lera

ble

sid

e e

ffects

Yes:

Appro

ve f

or

1 y

r.

N

o:

Den

y. R

ecom

mend

warf

arin tria

l.

4. D

oes the

patie

nt h

ave a

dia

gnosis

re

qu

irin

g a

cute

or

recurr

ent D

VT

tre

atm

ent?

Yes: G

o t

o #

5

No

: D

en

y (

Me

dic

al

Appro

pria

ten

ess)

5. W

ill the p

rescriber

consid

er

a c

ha

ng

e to a

pre

ferr

ed

anticoag

ula

nt?

Yes:

Add

itio

nal in

form

ation

can b

e

found a

t:

No

: G

o to #

6

74 of 187

http://www.oregon.gov/DHS/healthplan/tools_prov/pdl.shtml�

http://www.dhs.state.or.us/policy/healthplan/guides/pharmacy/clinical.html�


Gen

eric

Nam

e: D

abig

atra

n

R

evie

w D

ate:

Janu

ary

2011

20

Aut

hor:

Kat

hy S

ente

na

http://w

ww

.dhs.s

tate

.or.

us/p

olic

y/h

ea

lthpla

n/g

uid

es/p

harm

acy/c

linic

al.htm

l

6. Is th

e p

atient

una

ble

to t

ole

rate

pre

ferr

ed a

nticoag

ula

nts

du

e to

on

e o

f th

e

follo

win

g:

-

alle

rgy

- c

ontr

ain

dic

atio

ns to t

hera

py

- d

rug-d

rug

in

tera

ctions

- into

lera

ble

sid

e e

ffects

Yes:

Appro

ve u

p to 1

ye

ar

No

: D

en

y. R

ecom

mend trial

of

pre

ferr

ed a

ntico

agu

lants

.

REFE

REN

CES

1.

Prad

axa®

Pre

scri

bing

Info

rmat

ion.

Boe

hrin

ger

Inge

lhei

m P

harm

aceu

tical

s, In

c. R

idge

field

, CT.

Nov

embe

r 20

10.

2.

Conn

olly

SJ,

Ezek

owitz

MD

, Yus

uf S

, et a

l. D

abig

atra

n ve

rsus

war

fari

n in

pat

ient

s w

ith a

tria

l fib

rilla

tion

(RE-

LY).

N E

ngl J

Med

. 200

9;36

1:11

39-5

1.

3.

Dab

igat

ran,

FD

A C

ente

r fo

r D

rug

Eval

uatio

n an

d Re

sear

ch.

Sum

mar

y Re

view

Doc

umen

t. O

ctob

er 1

9, 2

010.

A

cces

sed

6/13

/11.

w

ww

.acc

essd

ata.

fda.

gov/

drug

satf

da_d

ocs/

nda/

2010

/022

512O

rig1

s000

Sum

R.pd

f 4.

W

alle

ntin

L, Y

usuf

S, E

zeko

witz

MD

, et a

l. Ef

ficac

y an

d sa

fety

of d

abig

atra

n co

mpa

red

with

war

fari

n at

diff

eren

t lev

els

of in

tern

atio

nal n

orm

aliz

ed r

atio

con

trol

for

stro

ke

prev

entio

n in

atr

ial f

ibri

llatio

n: a

n an

alys

is o

f the

RE-

LY tr

ial.

Lanc

et. 2

010;

376:

975-

83.

5.

Conn

olly

S, E

zeko

witz

M, Y

usuf

S, e

t al.

New

ly Id

entif

ied

Even

ts in

the

RE-L

Y Tr

ial.

N E

ngl J

Med

201

0;36

3;18

75-1

876.

6.

RE

-MO

BILI

ZE W

ritin

g Co

mm

itte

e, G

insb

erg

JS, D

avid

son

BL, C

omp

PC e

t al.

Ora

l thr

ombi

n in

hibi

tor

dabi

gatr

an e

texi

late

vs.

Nor

th A

mer

ican

eno

xapa

rin

regi

men

for

prev

entio

n of

ven

ous

thro

mbo

embo

lism

aft

er k

nee

arth

ropl

asty

sur

gery

. J A

rthr

opla

sty.

200

9;24

(1):

1-9.

7.

Er

ikss

on B

I, D

ahl O

E, R

osen

cher

N, e

t al.

Ora

l dab

igat

ran

etex

ilate

vs.

sub

cuta

neou

s en

oxap

arin

for

the

prev

entio

n of

ven

ous

thro

mbo

embo

lism

aft

er to

tal k

nee

repl

acem

ent:

the

RE-M

OD

EL r

ando

miz

ed tr

ial.

J Thr

omb

Hae

mos

t. 2

007;

5:21

78-8

5.

8.

Erik

sson

BI,

Dah

l OE,

Ros

ench

er N

, et a

l. D

abig

atra

n et

exila

te v

ersu

s en

oxap

arin

for

the

prev

entio

n of

ven

ous

thro

mbo

embo

lism

aft

er to

tal h

ip r

epla

cem

ent:

a

rand

omiz

ed, d

oubl

e-bl

ind,

non

-infe

rior

ity tr

ial.

Lanc

et. 2

007;

370:

949-

956.

(RE-

NO

VA

TE)

9.

Nde

gwa

S, M

oulto

n K,

Arg

áez

C. D

abig

atra

n an

d Ri

varo

xaba

n ve

rsus

Oth

er A

ntic

oagu

lant

s fo

r Th

rom

bopr

ophy

laxi

s A

fter

Maj

or O

rtho

pedi

c Su

rger

y: S

yste

mat

ic R

evie

w

of C

ompa

rati

ve C

linic

al-E

ffec

tive

ness

and

Saf

ety.

Ott

awa:

Can

adia

n A

genc

y fo

r D

rugs

and

Tec

hnol

ogie

s in

Hea

lth; 2

009.

10

. Sa

laza

r, C

arlo

s A

, Mal

aga,

Ger

man

, Mal

asqu

ez. G

iulia

na.

Dir

ect t

hrom

bin

inhi

bito

rs v

ersu

s vi

tam

in K

ant

agon

ists

or

low

mol

ecul

ar w

eigh

t hep

arin

s fo

r pr

even

tion

of

veno

us th

rom

boem

bolis

m fo

llow

ing

tota

l hip

or

knee

rep

lace

men

t. T

he C

ochr

ane

Dat

abas

e of

Sys

t Rev

. 201

1(3)

: CD

0059

81.

11

. Sc

hulm

an S

, Kea

ron

C, K

akka

r A

K, e

t al.

Dab

igat

ran

vers

us w

arfa

rin

in th

e tr

eatm

ent o

f acu

te v

enou

s th

rom

boem

bolis

m. N

Eng

l J M

ed. 2

009;

361(

24):2

342-

52.

12.

Har

t R, P

earc

e L,

Agu

ilar

M.

Met

a-an

alys

is: A

ntith

rom

boti

c Th

erap

y to

Pre

vent

Str

oke

in P

atie

nts

Who

Hav

e N

onva

lvul

ar A

tria

l Fib

rilla

tion.

Ann

Inte

rn M

ed.

2007

;146

:857

-867

. 13

. A

guila

r, M

, Har

t R.

Ora

l ant

icoa

gula

nts

for

prev

entin

g st

roke

in p

atie

nts

with

non

-val

vula

r at

rial

fibr

illat

ion

and

no p

revi

ous

hist

ory

of s

trok

e or

tran

sien

t isc

hem

ic

atta

cks.

The

Coc

hran

e D

atab

ase

of S

yst R

ev.

2009

(1):

CD00

1927

. 14

. Co

umad

in®

Pres

crib

ing

Info

rmat

ion.

Bri

stol

-Mye

rs S

quib

b, In

c. P

rinc

eton

, NJ.

Janu

ary

2010

. 15

. Bi

rman

-Dey

ch E

, Rad

ford

M, N

ilase

na D

, et a

l. U

se a

nd E

ffec

tiven

ess

of W

arfa

rin

in M

edic

are

Bene

ficia

ries

with

Atr

ial F

ibri

llatio

n. S

trok

e. 2

006;

37:1

070-

1074

.

75 of 187



http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022512Orig1s000SumR.pdf�

Gen

eric

Nam

e: D

abig

atra

n

R

evie

w D

ate:

Janu

ary

2011

21

Aut

hor:

Kat

hy S

ente

na

16.

Sing

er D

E, A

lber

s G

W, D

alen

JE, e

t al.

Ant

ithro

mbo

tic th

erap

y in

atr

ial f

ibri

llatio

n. C

HES

T. 2

008;

133(

6): 5

46S-

592S

. 17

. G

age

BF, W

ater

man

AD

, Sha

nnon

W, e

t al.

Valid

atio

n of

clin

ical

cla

ssifi

catio

n sc

hem

es fo

r pr

edic

ting

stro

ke. R

esul

ts fr

om th

e N

atio

nal R

egis

try

of A

tria

l Fib

rilla

tion.

JA

MA

. 200

1;28

64-7

0.

18.

Hir

sh J,

Guy

att G

, Alb

ers

G, e

t al

. Ex

ecut

ive

Sum

mar

y: A

mer

ican

Col

lege

of C

hest

Phy

sici

ans

Evid

ence

-Bas

ed C

linic

al P

ract

ice

Gui

delin

es (8

th E

ditio

n).

Ches

t 20

08;1

33;7

1S-1

09S.

19

. A

mer

ican

Aca

dem

y of

Ort

hopa

edic

Sur

geon

s. P

reve

ntin

g V

enou

s Th

rom

boem

bolic

Dis

ease

in P

atie

nts

Und

ergo

ing

Elec

tive

Hip

and

Kne

e A

rthr

opla

sty

Evid

ence

-Bas

ed

Gui

delin

e an

d Ev

iden

ce R

epor

t, 2

011.

(A

cces

sed

Oct

ober

27,

201

1, a

t htt

p://

ww

w.a

aos.

org/

rese

arch

/gui

delin

es/V

TE/V

TE_f

ull_

guid

elin

e.pd

f.)

20.

Vard

i M, Z

ittan

E, B

itter

man

H, e

t al.

Sub

cuta

neou

s un

frac

tiona

ted

hepa

rin

for

the

initi

al tr

eatm

ent o

f ven

ous

thro

mbo

embo

lism

. Co

chra

ne D

atab

ase

of S

yste

mat

ic

Revi

ews.

200

9, Is

sue

4.

21.

Food

and

Dru

g A

dmin

istr

atio

n.

Supp

lem

enta

l New

Dru

g A

pplic

atio

n fo

r Pr

adax

a. 1

1/09

/201

1. A

cces

sed

11/2

0/20

11.

http

://w

ww

.acc

essd

ata.

fda.

gov/

drug

satf

da_d

ocs/

appl

ette

r/20

11/0

2251

2s00

7ltr

.pdf

.

76 of 187

D

rug

Use

Res

earc

h &

Man

agem

ent P

rogr

am

Ore

gon

Stat

e U

nive

rsity

, 500

Sum

mer

Stre

et N

E, E

35, S

alem

, Ore

gon

9730

1-10

79

Phon

e 50

3-94

5-52

20 |

Fax

503-

947-

1119

1 M

onth

/Yea

r of

Rev

iew

: Ja

nuar

y 20

12

En

d da

te o

f lit

erat

ure

sear

ch: N

ovem

ber 2

011

Gen

eric

Nam

e: R

ivar

oxab

an

Bran

d N

ame

(Man

ufac

ture

r):

Xare

lto (J

anss

en P

harm

aceu

tical

s)

PDL

Clas

s: N

o cu

rren

t PD

L cl

ass

Co

mpa

rato

r Th

erap

ies:

Eno

xapa

rin a

nd w

arfa

rin

Pref

erre

d A

ntic

oagu

lant

s: e

noxa

parin

and

dal

tepa

rin

Non

-pre

ferr

ed A

ntic

oagu

lant

s: fo

ndip

arin

ux, t

inza

pari

n, r

ivar

oxab

an (p

endi

ng) a

nd d

abig

atra

n (p

endi

ng)

No

PDL-

stat

us/n

o re

stri

ctio

ns: w

arfa

rin

FDA

App

rove

d In

dica

tion

s:

Riva

roxa

ban

is in

dica

ted

for t

he p

roph

ylax

is o

f dee

p ve

in th

rom

bosi

s (D

VT) w

hich

may

lead

to p

ulm

onar

y em

bolis

m

(PE)

in p

atie

nts

unde

rgoi

ng to

tal k

nee

repl

acem

ent (

TKR)

or t

otal

hip

rep

lace

men

t (TH

R) s

urge

ry.

Riva

roxa

ban

is a

lso

appr

oved

to re

duce

the

risk

of

stro

ke in

pat

ient

s w

ith n

on-v

alvu

lar

atri

al fi

brill

atio

n (A

F).

Dos

sier

rec

eive

d:

Yes

Su

mm

ary:

-

Riva

roxa

ban

is th

e fir

st o

ral f

acto

r Xa

inhi

bito

r. R

ivar

oxab

an d

iffer

s fr

om w

arfa

rin

with

res

pect

to m

inim

al fo

od a

nd d

rug

inte

ract

ions

, ab

senc

e of

rou

tine

labo

rato

ry m

onito

ring

and

qui

ck o

nset

of a

cton

.1 Pr

ophy

laxi

s of

DVT

-

Riva

roxa

ban

is d

osed

for p

roph

ylax

is o

f DVT

as

10m

g on

ce d

aily

with

out r

egar

d to

food

. U

se c

autio

usly

in m

oder

ate

rena

l im

pair

men

t (Cr

Cl

30-5

0 m

l/m

in).

Do

not u

se in

sev

ere

rena

l im

pairm

ent (

CrCl

<30

ml/

min

) due

to in

crea

sed

rivar

oxab

an e

xpos

ure

and

phar

mac

odyn

amic

ef

fect

s in

thes

e pa

tient

s. M

onito

r pa

tient

s w

ith m

oder

ate

rena

l im

pairm

ent (

CrCl

30

to 5

0 m

L/m

in) f

or s

igns

or s

ympt

oms

of b

leed

ing.

A

void

use

in m

oder

ate

or s

ever

e he

patic

impa

irm

ent o

r in

hep

atic

dis

ease

with

coa

gulo

path

y.

Non

valv

ular

Atr

ial F

ibril

latio

n -

Riva

roxa

ban

is a

ppro

ved

for

atri

al fi

brill

atio

n, g

iven

as

20m

g da

ily w

ith th

e ev

enin

g m

eal,

for p

atie

nts

with

CrC

l >50

mL/

min

. Fo

r pat

ient

s w

ith

CrCl

of 1

5 to

50

mL/

min

a d

ose

of 1

5 m

g w

ith th

e ev

enin

g m

eal i

s re

com

men

ded.

Riv

arox

aban

is n

ot re

com

men

ded

for

a Cr

CL o

f <15

mL/

min

.

77 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

2 A

utho

r: K

athy

Sen

tena

Effic

acy

and

Safe

ty S

umm

ary

on F

DA

App

rove

d In

dica

tion

s Su

rger

y Pr

ophy

laxi

s -

Riva

roxa

ban

appr

oval

for p

atie

nts

unde

rgoi

ng to

tal h

ip r

epla

cem

ent (

THR)

or t

otal

kne

e re

plac

emen

t (TK

R) s

urge

ry w

as b

ased

on

thre

e la

rge,

pro

spec

tive,

ran

dom

ized

, dou

ble

blin

d, d

oubl

e du

mm

y tr

ials

.2,3,

4 R

ECO

RD 2

and

4 a

re in

clud

ed in

the

evid

ence

tabl

e, h

owev

er, t

hey

wer

e de

emed

poo

r st

udie

s ba

sed

on F

DA

sum

mar

ies

on th

e qu

ality

of d

ata.

-

Ther

e w

as lo

w-s

tren

gth

of e

vide

nce

from

REC

ORD

1 a

nd 3

that

riv

arox

aban

was

sim

ilar t

o en

oxap

arin

in r

egar

ds to

the

com

pone

nt

outc

omes

of a

ll-ca

use

mor

talit

y, s

ympt

omat

ic v

enou

s th

rom

boem

bolis

m (V

TE) a

nd n

on-f

atal

pul

mon

ary

embo

lism

. H

owev

er, t

he u

se o

f the

Eu

rope

an e

noxa

parin

dos

ing

regi

men

of 4

0mg

once

dai

ly in

REC

ORD

3, l

imits

the

appl

icab

ility

of t

he r

esul

ts to

pat

ient

s in

the

Uni

ted

Stat

es

wer

e th

e re

com

men

ded

dosi

ng re

gim

en fo

r DVT

pro

phyl

axis

in p

atie

nts

unde

rgoi

ng T

KR is

30m

g tw

ice

daily

.

- Th

ere

was

low

-str

engt

h of

evi

denc

e to

sug

gest

maj

or b

leed

ing

rate

s w

ere

slig

htly

hig

her f

or r

ivar

oxab

an c

ompa

red

to e

noxa

pari

n in

bot

h RE

CORD

1 a

nd 3

stu

dies

, alth

ough

not

sta

tistic

ally

sig

nific

ant.

Atr

ial F

ibri

llatio

n -

ROCK

ET A

F w

as a

pha

se II

I, D

B, D

D, R

CT in

ove

r 14,

000

patie

nts

in 4

5 co

untr

ies

with

non

valv

ular

atr

ial f

ibri

llatio

n w

ho w

ere

at m

oder

ate

to

high

ris

k of

str

oke.

Pat

ient

s w

ere

rand

omly

ass

igne

d to

riv

arox

aban

20m

g da

ily o

r do

se-a

djus

ted

war

fari

n (IN

R 2.

0-3.

0).

The

prim

ary

effic

acy

anal

ysis

was

the

com

posi

te o

f str

oke

(isch

emic

and

hem

orrh

agic

) and

sys

tem

ic e

mbo

lism

.6 -

Ther

e w

as lo

w-s

tren

gth

of e

vide

nce

from

RO

C KE

T A

F th

at r

ivar

oxab

an w

as n

onin

feri

or to

war

farin

for t

he c

ompo

site

out

com

e of

str

oke

and

syst

emic

em

bolis

m (H

R 0.

88; 9

5% C

I, 0.

75 to

1.0

3; p

<0.0

01 fo

r non

infe

riorit

y, p

=0.1

2 fo

r sup

erio

rity)

. Th

ere

was

low

-str

engt

h of

evi

denc

e th

at m

ajor

ble

edin

g ra

tes

wer

e si

mila

r bet

wee

n riv

arox

aban

and

war

farin

(HR

1.04

; 95%

CI,

0.90

to 1

.20,

p=0

.58)

. -

Conc

erns

ove

r su

bopt

imal

war

fari

n us

e in

RO

CKET

AF

mak

es c

oncl

usio

ns o

n re

lativ

e ef

ficac

y an

d sa

fety

unk

now

n. T

he s

hort

hal

f-lif

e of

ri

varo

xaba

n co

mbi

ned

with

onc

e da

ily d

osin

g m

ay b

e pr

oble

mat

ic if

ther

e ar

e ad

here

nce

conc

erns

. Th

ere

are

conc

erns

on

how

to b

est

tran

sitio

n pa

tient

s of

f of r

ivar

oxab

an a

s th

ere

was

a n

oted

incr

ease

in e

vent

s af

ter t

reat

men

t dis

cont

inua

tion

(see

full

pres

crib

ing

info

rmat

ion

for t

rans

ition

ing

patie

nts

from

riv

arox

aban

to o

ther

ani

tcoa

gula

nts)

.

Effic

acy

and

Safe

ty S

umm

ary

of O

ff-la

bel U

ses

Acu

te D

VT a

nd C

ontin

uatio

n Tr

eatm

ent

- Ri

varo

xaba

n w

as s

tudi

ed in

two

poor

qua

lity

stud

ies

for a

cute

DVT

and

con

tinua

tion

trea

tmen

t (EI

NST

EIN

-DVT

and

EIN

STEI

N-E

XTEN

SIO

N).

Cu

rren

tly, t

here

is in

suff

icie

nt e

vide

nce

to s

uppo

rt r

ivar

oxab

an u

se fo

r thi

s in

dica

tion

and

is n

ot re

com

men

ded

until

furt

her d

ata

beco

mes

av

aila

ble.

Acu

te C

oron

ary

Synd

rom

e -

Mos

t rec

ently

riv

arox

aban

was

stu

died

in p

atie

nts

pres

entin

g w

ith A

cute

Cor

onar

y Sy

ndro

me

(ACS

) in

the

ATL

AS

ACS

2-T

IMI 5

1. P

atie

nts

wer

e ra

ndom

ized

to r

ivar

oxab

an 2

.5m

g tw

ice

daily

, riv

arox

aban

5m

g tw

ice

daily

or

plac

ebo,

alo

ng w

ith s

tand

ard

med

ical

car

e fo

r A

CS.

78 of 187

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eric

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ivar

oxab

an

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ate:

Janu

ary

2011

3 A

utho

r: K

athy

Sen

tena

Ther

e is

mod

erat

e ev

iden

ce to

sug

gest

riv

arox

aban

is b

ette

r tha

n pl

aceb

o fo

r thi

s in

dica

tion,

how

ever

, the

re a

re n

o st

udie

s co

mpa

ring

the

stan

dard

of c

are,

asp

irin

and

clo

pido

grel

, to

riva

roxa

ban.

Dos

es u

sed

in th

is s

tudy

are

not

cur

rent

ly a

vaila

ble

and

use

for t

his

indi

catio

n w

ill

need

to b

e re

visi

ted

in th

e fu

ture

.

Cost

Con

side

rati

ons:

Co

sts

will

be

disc

usse

d in

the

exec

utiv

e se

ssio

n.

PDL

Plac

emen

t Re

com

men

dati

on:

Ther

e is

low

-str

engt

h of

dat

a to

sug

gest

that

riv

arox

aban

is a

t lea

st a

s ef

fect

ive

as e

noxa

pari

n fo

r pro

phyl

axis

of D

VT in

pat

ient

s un

derg

oing

TH

R an

d TK

R. T

he R

ECO

RD s

tudi

es d

emon

stra

ted

effic

acy

favo

ring

riv

arox

aban

, with

the

limita

tion

of u

sing

the

Euro

pean

dos

ing

regi

men

in th

e on

e of

th

e TK

R st

udie

s, e

xclu

ding

hig

h pe

rcen

tage

s of

pat

ient

s fr

om a

naly

sis,

and

resu

lts b

eing

dri

ven

by a

sym

ptom

atic

DVT

s.

It is

reco

mm

ende

d th

at

riva

roxa

ban

be a

dded

to th

e PD

L fo

r thi

s in

dica

tion,

aft

er c

ost c

onsi

dera

tions

are

take

n in

to a

ccou

nt, a

nd d

ose

limita

tions

sho

uld

be a

pplie

d.

Ther

e is

one

fair

qual

ity tr

ial t

o de

mon

stra

ting

effic

acy

of r

ivar

oxab

an u

se i

n A

F. C

once

rns

over

sub

optim

al w

arfa

rin u

se i

n RO

CKET

AF

mak

es

conc

lusi

ons

on r

elat

ive

effic

acy

and

safe

ty u

nkno

wn.

Eff

icac

y re

lativ

e to

dab

igat

ran

has

not b

een

esta

blis

hed.

War

fari

n is

reco

mm

ende

d as

the

first

line

age

nt fo

r thi

s in

dica

tion.

79 of 187

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eric

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ivar

oxab

an

R

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ary

2011

4 A

utho

r: K

athy

Sen

tena

BACK

GRO

UN

D/C

URR

ENT

LAN

DSC

APE

FD

A A

ppro

ved

Indi

cati

on:T

hrom

bopr

ophy

laxi

s af

ter

THR

and

TKR

For

patie

nts

unde

rgoi

ng T

HR

or T

KR p

roph

ylac

tic a

ntic

oagu

lant

s ar

e co

nsid

ered

sta

ndar

d pr

actic

e. A

rec

ent g

uide

line

by th

e A

mer

ican

Aca

dem

y of

O

rtho

paed

ic S

urge

ons

give

s a

mod

erat

e re

com

men

datio

n fo

r the

use

of p

roph

ylac

tic p

harm

acol

ogic

al a

gent

s fo

r VT

E pr

even

tion

in th

ose

patie

nts

that

are

not

at e

leva

ted

risk.

Due

to in

suff

icie

nt e

vide

nce

they

are

una

ble

to re

com

men

d an

y pa

rtic

ular

pre

vent

ativ

e st

rate

gy o

r tr

eatm

ent

dura

tion.

9 Th

e A

mer

ican

Col

lege

of C

hest

Phy

sici

ans

(ACC

P) E

vide

nce-

Base

d Cl

inic

al P

ract

ice

Gui

delin

es (C

HES

T) o

n an

tithr

ombo

tic a

nd

thro

mbo

lytic

ther

apy

reco

mm

ends

trea

tmen

t with

war

farin

, LM

WH

, or f

onda

pari

nux

for

at le

ast 1

0 da

ys a

nd u

p to

35

days

for T

KR a

nd T

HR.

10

Ore

gon

Hea

lth P

lan

(OH

P) fe

e-fo

r-se

rvic

e FF

S c

urre

ntly

list

s LM

WH

s, e

noxa

pari

n an

d da

ltepa

rin,

as

pref

erre

d, a

nd fo

ndap

arin

ux (A

rixt

ra®)

and

tin

zapa

rin (I

nnoh

ep®)

as

not p

refe

rred

. Des

irudi

n (Ip

riva

sk®)

is n

ot m

anag

ed v

ia P

DL

and

curr

ently

has

no

utili

zatio

n re

stri

ctio

ns.

In th

e pr

evio

us

six

mon

ths

appr

oxim

atel

y 20

0 pa

tient

s re

ceiv

ed s

hort

term

ant

icoa

gula

tion

(<45

day

s) a

ccou

ntin

g fo

r al

mos

t 200

pre

scri

ptio

n cl

aim

s (t

here

wer

e no

cla

ims

for d

abig

atra

n or

riv

arox

aban

).

FDA

App

rove

d In

dica

tion

: Atr

ial F

ibri

llati

on

Patie

nts

with

AF

are

at a

four

to fi

ve-f

old

incr

ease

d ri

sk o

f str

oke

and

syst

emic

em

bolis

m c

ompa

red

to th

ose

with

out A

F.11

Ant

icoa

gula

nts

are

a ke

y co

mpo

nent

to

man

agin

g pa

tient

s w

ith A

F th

at a

re a

t an

incr

ease

d ri

sk o

f str

oke

from

car

dioe

mbo

lic e

vent

s. T

he C

HA

DS 2

ris

k st

ratif

icat

ion

sche

me

is r

ecom

men

d to

est

imat

e st

roke

ris

k in

pat

ient

s w

ith A

F ba

sed

on: p

rese

nce

of h

eart

failu

re, p

rese

nce

of h

yper

tens

ion,

age

≥75

yea

rs, p

rese

nce

of

diab

etes

mel

litus

, an

d a

hist

ory

of p

revi

ous

stro

ke o

r tr

ansi

ent

isch

emic

att

ack (T

able

1).12

Th

e gr

eate

r th

e nu

mbe

r of

ris

k fa

ctor

s pr

esen

t, t

he

grea

ter

the

risk

of s

trok

e.

CHES

T gu

idel

ines

on

antit

hrom

botic

and

thr

ombo

lytic

the

rapy

rec

omm

end

antic

oagu

latio

n fo

r pa

tient

s w

ith A

F an

d su

gges

t as

pirin

the

rapy

for

patie

nts

with

up

to o

ne r

isk

fact

or a

nd t

reat

men

t w

ith a

VKA

for

patie

nts

with

one

or

mor

e ris

k fa

ctor

s or

in s

econ

dary

pr

even

tion

patie

nts.

10

The

guid

elin

es a

lso

reco

mm

ends

VKA

ther

apy

for p

atie

nts

with

a C

HA

DS 2

sco

re o

f ≥2.

Ta

ble 1

. CHA

DS2 C

lassif

icatio

n Sc

hem

e for

Stro

ke R

isk12

Risk

Fac

tor

Poin

ts

C Co

nges

tive H

eart

Failu

re

1 H

Hype

rtens

ion

1 A

Age ≥

75 ye

ars

1 D

Diab

etes

1 S 2

Hi

story

of str

oke o

r TIA

2

80 of 187

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eric

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ary

2011

5 A

utho

r: K

athy

Sen

tena

Off

-labe

l Use

s: A

cute

/Chr

onic

DV

T A

cute

DVT

trea

tmen

t is

an a

dditi

onal

indi

catio

n fo

r an

ticoa

gula

tion.

DVT

is a

ser

ious

med

ical

con

ditio

n th

at a

ffec

ts 1

in 1

000

peop

le a

nd c

an le

ad

to P

E an

d re

late

d ri

sk o

f mor

bidi

ty a

nd m

orta

lity.

13 C

HES

T gu

idel

ines

rec

omm

end

initi

al tr

eatm

ent w

ith L

MW

H, u

nfra

ctio

nate

d he

pari

n (U

FH) o

r fo

ndap

arin

ux fo

r at l

east

5 d

ays

to b

ridge

the

patie

nts

to e

ffec

tive

war

farin

ther

apy,

whi

ch s

houl

d be

gin

on th

e fir

st tr

eatm

ent d

ay.10

D

isco

ntin

uatio

n of

bri

dgin

g sh

ould

occ

ur a

fter

the

fifth

day

of t

hera

py, p

rovi

de th

e IN

R ha

s be

en 2

.0 o

r mor

e fo

r at

leas

t 24

hour

s. F

or p

atie

nts

with

DVT

or

PE s

econ

dary

to a

rev

ersi

ble

risk

fact

or, t

he g

uide

lines

rec

omm

end

trea

tmen

t with

war

fari

n fo

r 3

mon

ths.

Tre

atm

ent

reco

mm

enda

tions

for p

atie

nts

with

unp

rovo

ked

DVT

or P

E in

clud

e w

arfa

rin fo

r at

leas

t 3 m

onth

s an

d up

to a

yea

r or l

onge

r bas

ed o

n cl

inic

al

judg

men

t.

The

VKA

, war

fari

n, h

as s

erve

d as

the

gold

sta

ndar

d fo

r ora

l ant

icoa

gula

tion

and

is a

cov

ered

ther

apy,

with

out r

estr

ictio

n fo

r O

HP

FFS

patie

nts.

A

ppro

xim

atel

y 35

0 pa

tient

s ut

ilize

d lo

ng te

rm a

ntic

oagu

latio

n (>

45 d

ays)

, rep

rese

ntin

g ov

er 2

,000

pre

scri

ptio

n cl

aim

s w

ithin

the

last

six

mon

ths

with

in th

e O

HP

popu

latio

n.

Off

-labe

l Use

s: A

cute

Cor

onar

y Sy

ndro

me

(ACS

) A

ntip

late

let d

rugs

are

use

d to

pre

vent

car

diov

ascu

lar

even

ts a

nd p

rem

atur

e de

ath

in p

atie

nts

with

mul

tiple

ris

k fa

ctor

s an

d in

pat

ient

s w

ho h

ave

expe

rien

ced

Acu

te C

oron

ary

Synd

rom

e (i.

e. u

nsta

ble

angi

na, n

on-S

T se

gmen

t ele

vatio

n m

yoca

rdia

l inf

arct

ion,

or

ST s

egm

ent e

leva

tion

myo

card

ial

infa

rctio

n), t

rans

ient

isch

emic

att

acks

or t

hrom

boem

bolic

str

oke,

or

sym

ptom

atic

per

iphe

ral a

rter

ial d

isea

se.

Asp

irin

has

been

con

side

red

the

gold

st

anda

rd.

Asp

irin

is e

ffec

tive

in r

educ

ing

the

occu

rren

ce o

f maj

or c

ardi

ovas

cula

r ev

ents

incl

udin

g de

ath,

recu

rren

t myo

card

ial i

nfar

ctio

n, r

ecur

rent

an

gina

, or p

rogr

essi

on to

sev

ere

angi

na a

nd n

onfa

tal s

trok

e. S

ever

al p

ract

ice

guid

elin

es h

ave

been

pub

lishe

d th

at p

rovi

de re

com

men

datio

ns

rega

rdin

g th

e ro

le o

f asp

irin.

14,1

5,16

,17,

18,1

9 Li

mite

d tr

ials

with

fact

or X

a an

d IIa

inhi

bito

rs h

ave

been

stu

died

in p

atie

nts

afte

r an

ACS

sho

win

g pr

omis

ing

resu

lts in

redu

ctio

n of

car

diov

ascu

lar e

vent

s.

CLIN

ICA

L PH

ARM

ACO

LOG

Y

Riva

roxa

ban

sele

ctiv

ely

bloc

ks th

e ac

tive

site

of f

acto

r Xa

, with

out a

cof

acto

r re

quir

emen

t (su

ch a

s A

nti-t

hrom

bin

III) f

or a

ctiv

ity. B

lock

ing

the

conv

ersi

on o

f fac

tor

X to

fact

or X

a (F

Xa) i

nhib

its in

trin

sic

and

extr

insi

c pa

thw

ays

that

pla

y a

mai

n ro

le in

the

bloo

d co

agul

atio

n ca

scad

e.1

81 of 187

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eric

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ary

2011

6 A

utho

r: K

athy

Sen

tena

COM

PARA

TIV

E CL

INIC

AL

EFFI

CACY

Rele

vant

End

poin

ts

Prim

ary

Stud

y En

dpoi

nt:

All

Stud

ies:

A

ll-ca

use

Mor

talit

y

RE

CORD

1-4

: Co

mpo

site

of D

VT, n

onfa

tal P

E an

d de

ath

Maj

or b

leed

ing

ROCK

ET-A

F: C

ompo

site

of s

trok

e an

d sy

stem

ic e

mbo

lism

DVT

:

Recu

rren

t VT

E

EI

NST

EIN

-DVT

and

EIN

STEI

N-E

xten

sion

: Re

curr

ent V

TE

DVT

Pro

phyl

axis

:

PE

ATL

AS

ACS

2-T

IMI 5

1: C

ompo

site

of d

eath

from

Sy

mpt

omat

ic V

TE

card

iova

scul

ar c

ause

s, M

I, or

str

oke

A

F:

St

roke

ACS

:

Ca

rdio

vasc

ular

mor

talit

y

Sten

t Thr

ombo

sis

Evid

ence

Tab

le

Ref.

/ St

udy

Des

ign1

Dru

g Re

gim

ens

Pati

ent

Popu

lati

on

N

Dur

atio

n Ef

ficac

y Re

sult

s2

ARR

/

NN

T3

Safe

ty

Resu

lts^

ARI

/

NN

H3

Qua

lity

Rati

ng4 ; C

omm

ents

RECO

RD 1

2 Er

ikss

on

B, e

t al

Phas

e III

, D

B, R

CT,

PG, D

D

1. R

ivar

oxab

an

10m

g Q

D

(sta

rted

aft

er

surg

ery)

2.

Eno

xapa

rin

40m

g SQ

QD

(s

tart

ed e

veni

ng

befo

re s

urge

ry)

Age

: 63

yrs

Fem

ale:

55%

Pr

ior

VTE:

2.

1-2.

5%

Incl

usio

n Cr

iter

ia;

Sche

dule

d fo

r

THR

Excl

usio

n Cr

iter

ia:

Blee

ding

, co

ntra

indi

catio

ns

to a

ntic

oagu

lant

us

e, p

regn

ancy

, la

ctat

ion,

sev

ere

liver

or

rena

l im

pair

men

t,

conc

omita

nt u

se

of p

rote

ase

inhi

bito

rs o

r

1. n

= 22

09

2. n

= 22

24

Mea

n tx

du

ratio

n: 3

3

days

F/

U: 3

0-42

day

s af

ter

last

dos

e

Com

posi

te o

f DVT

, no

nfat

al P

E, o

r de

ath:

R:

18

(1.1

%)

E: 5

8 (3

.7%

) RR

0.3

0 95

% C

I 0.1

2 to

0.5

1 Al

l-cau

se M

orta

lity:

R:

5 (0

.3%

) E:

4 (0

.3%

) RR

1.2

2 95

% C

I 0.3

3 to

4.5

PE

: R:

4 (0

.3%

) E:

1 (0

.1%

) RR

3.9

ARR

2.6%

N

NT

38

NS

NS

Maj

or B

leed

ing:

R:

6 (0

.3%

) E:

2 (0

.1%

) RR

3.0

95

% C

I 0.6

1 to

14

.9

NS

• St

udy

Ratin

g: F

air

• Co

mpo

site

end

poin

t res

ults

dri

ven

by

asym

ptom

atic

find

ings

. •

Larg

e nu

mbe

r of

pat

ient

s un

acco

unte

d fo

r – s

ensi

tivity

ana

lysi

s st

ates

tha

t m

issi

ng d

ata

didn

’t e

ffec

t pow

er

estim

ates

•

Sym

ptom

atic

VTE

sim

ilar

in e

ach

trea

tmen

t gr

oup

(0.3

% r

ivar

oxab

an a

nd

0.5%

eno

xapa

rin)

•

Prim

ary

outc

ome

was

a c

ompo

site

en

dpoi

nt in

clud

ing

sym

ptom

atic

and

as

ympt

omat

ic D

VTS.

The

impo

rtan

ce

and

clin

ical

rel

evan

ce o

f asy

mpt

omat

ic

DVT

s is

unk

now

n.

• Pe

r-pr

otoc

ol p

opul

atio

n w

as u

sed

for

effic

acy

outc

omes

exc

ept s

ympt

omat

ic

VTE

whi

ch u

sed

mIT

T po

pula

tion

.

82 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

7 A

utho

r: K

athy

Sen

tena

fibri

noly

tic a

gent

s 95

% C

I 0.4

4 to

35.

0 Sy

mpt

omat

ic V

TE:

R: 7

(0.3

%)

E: 1

5 (0

.7%

) RR

0.4

7 95

% C

I 0.1

9 to

1.1

5

NS

* S

afet

y po

pula

tion

used

fo

r ab

ove

resu

lt

RECO

RD2

Kakk

ar A

, e

t al

Phas

e III

, RC

T, D

B, D

D

1. R

ivar

oxab

an 1

0 m

g da

ily

(sta

rted

6-8

hrs

. af

ter

wou

nd

clos

ure)

2. E

noxa

pari

n 40

mg

SQ Q

D

(sta

rted

12

hour

s be

fore

su

rger

y)

Age:

61

year

s Fe

mal

e: 5

3.7%

In

clus

ion:

Sc

hedu

led

for

TH

R Ex

clus

ion:

Se

e RE

CORD

1

1. n

= 86

4 2.

n=

869

Riva

roxa

ban

Tx:

Mea

n 33

.5 d

ays

Enox

apar

in T

x:

Mea

n 12

.4 d

ays

F/U

: 30-

35 d

ays

afte

r la

st d

ose

of

med

icat

ion

Com

posi

te o

f DVT

+

nonf

atal

PE

or

deat

h R:

17

(2.0

%)

E: 8

1 (9

.3%

) RR

0.2

1 9

5% C

I 0.1

3 to

0.3

5 Al

l-cau

se M

orta

lity:

R:

2 (0

.2%

) E:

8 (0

.7%

) RR

0.3

3 95

% C

I 0.0

7 to

1.7

PE

: R:

1 (0

.1%

) E:

4 (0

.5%

) RR

0.2

5 95

% C

I 0.0

3 to

2.2

Sy

mpt

omat

ic V

TE:

R: 3

(0.2

%)

E: 1

5 (1

.2%

) RR

0.2

0 95

% C

I 0.0

6 to

0.6

9

ARR

7.3%

N

NT

14

NS

NS

ARR

1.0%

N

NT

100

Maj

or b

leed

ing

R: 1

(<0.

1%)

E: 1

(<0.

1%)

RR 1

.0

95%

CI 0

.06

to

16.0

NS

•

Stud

y Ra

ting:

Poo

r •

Com

posi

te e

ndpo

int r

esul

ts d

rive

n by

as

ympt

omat

ic fi

ndin

gs

• H

igh

num

ber

of e

xclu

ded

patie

nts

from

mIT

T •

Com

pare

d D

VT

even

ts fo

r 33

day

s of

ri

varo

xaba

n ve

rsus

12

days

for

enox

apar

in

• H

ighe

r th

an e

xpec

ted

inva

lidity

rat

e fo

r ve

nogr

ams

– se

nsit

ivity

ana

lysi

s sh

owed

that

did

n’t e

ffec

t pow

er

• In

crea

se n

umbe

r of

car

diov

ascu

lar

even

ts a

fter

riv

arox

aban

di

scon

tinua

tion

83 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

8 A

utho

r: K

athy

Sen

tena

RECO

RD34

Lass

en M

, et

al

Phas

e III

, RCT

D

B, D

D

1. R

ivar

oxab

an

10m

g Q

D

(sta

rted

6-8

hr

s. a

fter

w

ound

clo

sure

)

2. E

noxa

pari

n 40

mg

SQ Q

D

(sta

rted

12

hour

s be

fore

su

rger

y)

Age:

67

year

s Fe

mal

e: 7

0%

riva

roxa

ban

/ 66

%

enox

apar

in

Incl

usio

n Cr

iter

ia:

Sche

dule

d fo

r

TKR

Excl

usio

n Cr

iter

ia:

See

RECO

RD1

1. n

= 82

4 2.

n=8

78

Tx d

urat

ion:

1

0-14

day

s Ve

nogr

aphy

: 11

-15

days

F/

U: 3

0-35

day

s af

ter

last

dos

e of

tx

Com

posi

te o

f DVT

, no

nfat

al P

E, o

r de

ath:

R:

79

(9.6

%)

E: 1

66 (1

8.9%

) RR

0.5

1 95

% C

I 0.3

9 to

0.6

5 Al

l-cau

se M

orta

lity:

R:

0 (0

%)

E: 6

(0.5

%)

PE:

R: 0

(0%

) E:

4 (0

.3%

) Sy

mpt

omat

ic V

TE:

R: 1

3 (1

.1%

) E:

27

(2.2

%)

RR 0

.50

95%

CI 0

.25

to 0

.94

ARR

9.2%

N

NT

11

NS

NS

NS

Maj

or B

leed

s:

R: 7

(0.6

%)

E: 6

(0.5

%)

RR 1

.2

95%

CI 0

.40

to

3.5

NS

•

Stud

y Ra

ting:

Fai

r •

Util

ized

Eur

opea

n do

sing

of

enox

apar

in 4

0mg

daily

for

TKR

• A

ntic

oagu

lant

allo

wed

dur

ing

follo

w-u

p pe

riod

•

Non

-infe

rior

ity m

argi

n se

t at 4

%

• O

nly

67%

of p

opul

atio

n us

ed in

m

ITT

anal

ysis

RECO

RD 4

5 Tu

rpie

A, e

t a

Phas

e III

, DB,

RC

T, D

D

1. R

ivar

oxab

an

10m

g Q

D

(sta

rted

6-8

hr

s. a

fter

w

ound

clo

sure

) 2.

Eno

xapa

rin

30m

g SQ

BID

(s

tart

ed 1

2 ho

urs

post

oper

ativ

ely)

Age:

64

year

s Fe

mal

e:

Riva

roxa

ban

66%

En

oxap

arin

64%

In

clus

ion

Crit

eria

: Sc

hedu

led

for

TK

R Ex

clus

ion

Crit

eria

: Se

e RE

CORD

1

1. 9

65

2. 9

59

Tx D

urat

ion:

10

-14

days

Fo

llow

-Up:

30

-35

days

aft

er

last

dos

e

Com

posi

te o

f DVT

+

nonf

atal

PE

or

deat

h:

R: 6

7 (6

.9%

) E:

97

(10.

1%)

RR 0

.67

95%

CI 0

.51

to 0

.93

All-c

ause

Mor

talit

y:

R: 6

(0.1

%)

E: 6

(0.2

%)

RR 0

.99

95%

CI 0

.32

to 3

.1

PE:

R: 5

(0.3

%)

E: 8

(0.5

%)

RR 0

.62

95%

CI 0

.20

to 1

.9

ARR

3.2%

N

NT

31

NS

NS

Maj

or b

leed

ing:

R:

10

(0.7

%)

E: 4

(0.3

%)

RR 2

.5

95%

CI 0

.78

to

7.9

NS

•

Stud

y Ra

ting:

Poo

r •

Com

posi

te e

ndpo

int r

esul

ts

driv

en b

y as

ympt

omat

ic fi

ndin

gs

• D

ata

deem

ed n

ot r

elia

ble

by F

DA

du

e to

com

plia

nce

defic

ienc

ies

with

stu

dy p

roce

dure

s •

Onl

y 61

% o

r pa

tient

s el

igib

le fo

r pr

imar

y en

dpoi

nt a

naly

sis

84 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

9 A

utho

r: K

athy

Sen

tena

Sym

ptom

atic

VTE

: R:

14

(0.7

%)

E: 2

1 (2

.0%

) RR

0.6

6 95

% C

I 0.3

4 to

1.3

NS

ROCK

ET A

F6

Pate

l M, e

t al

Phas

e III

, RCT

D

B, D

D

1. R

ivar

oxab

an

20m

g Q

D

2. W

arfa

rin

(dos

e-ad

just

ed

to IN

R of

2.

0-3.

0)

Age

: 73

yrs

Fem

ale:

40%

A

SA u

se: 3

6%

Mea

n CH

ADS 2

Sc

ore:

3.5

Co

exis

ting

Cond

ition

s: 5

5%

Mea

n TT

R fo

r w

arfa

rin

patie

nts:

55

%

Incl

usio

n:

Non

valv

ular

a-f

ib

with

mod

erat

e to

hi

gh r

isk

of s

trok

e Ex

clus

ion:

Ca

rdia

c re

late

d

cond

ition

s, a

ctiv

e bl

eedi

ng,

unco

ntro

lled

hype

rten

sion

, di

sabl

ing

stro

ke,

chro

nic

NSA

ID,

antic

oag

tx, u

se o

f st

rong

CYP

3A4

inhi

bito

rs ,

cont

rain

dica

tion

to

war

fari

n, s

ever

e re

nal o

r he

patic

di

seas

e

1. 7

081

2. 7

090

Med

ian

Tx

dura

tion:

59

0 da

ys

Follo

w u

p:

707

day

s

Stro

ke o

r S

yste

mic

Em

bolis

m:

R: 2

69 (2

.1%

) W

: 306

(2.4

%)

HR

0.88

95

% C

I 0.7

5 to

1.0

3

P <0

.001

for

infe

rior

ity

p=0.

12 fo

r su

peri

ority

Al

l Cau

se M

orta

lity:

R:

582

(4.5

%)

W: 6

32 (4

.9%

) H

R: 0

.92

95%

CI,

0.82

to 1

.03

P= 0

.15

NS

NS

Maj

or B

leed

s:

R: 3

95 (5

.6%

) W

: 386

(5.4

%)

HR

1.04

95

% C

I 0.9

0 to

1.

20

P= 0

.58

NS

•

Stud

y ra

ting:

fair

•

War

fari

n IN

R va

lues

wer

e

• w

ithin

the

ther

apeu

tic r

ange

55

% w

hich

sug

gest

s su

bopt

imal

w

arfa

rin

man

agem

ent

• In

form

atio

n on

man

agem

ent o

f IN

R w

as n

ot p

rovi

ded

• Re

sults

sho

wn

non-

infe

rior

ity

but u

nabl

e to

cla

im s

uper

iori

ty

to w

arfa

rin

in IT

T an

alys

is

• Ri

varo

xaba

n gr

oup

had

mor

e st

roke

s an

d em

bolis

ms

duri

ng

tran

sitio

n to

ope

n-la

bel p

ortio

n of

stu

dy (I

TT a

naly

sis)

sho

win

g no

n-in

feri

ority

but

not

su

peri

ority

•

No

com

pone

nt e

ndpo

int r

esul

ts

prov

ided

•

32 p

atie

nts

lost

to fo

llow

-up

• 23

.7%

of p

atie

nts

in r

ivar

oxab

an

grou

p an

d 22

.2%

of p

atie

nts

in

war

fari

n gr

oup

disc

ontin

ued

trea

tmen

t pr

ior

to a

n en

d po

int

even

t or

befo

re t

he e

nd o

f stu

dy

• Co

ncer

ns o

ver

shor

t hal

f-lif

e

and

once

dai

ly d

osin

g.

EIN

STEI

N-D

VT7

The

Eins

tein

1. R

ivar

oxab

an

15m

g tw

ice

daily

X 3

wee

ks

then

20m

g

Age:

56

year

s Fe

mal

e: 4

3%/4

4%

Incl

usio

n:

1. 1

731

Med

ian

Tx

dura

tion:

3, 6

, or

12

mon

ths

Recu

rren

t VTE

: R:

36

(2.1

%)

E-VK

A: 5

1 (3

.0%

) H

R 0.

68

M

ajor

Ble

edin

g:

R: 1

4 (0

.8%

) E-

VKA:

20

(1.2

%)

HR

0.65

NS

• St

udy

Ratin

g: P

oor

• O

pen

labe

l des

ign

lend

s re

sults

su

bjec

t to

bias

•

Patie

nts

on w

arfa

rin

in T

TR 5

8%

85 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

10

Aut

hor:

Kat

hy S

ente

na

Inve

stig

ator

s Ph

ase

III,

RCT,

Ope

n-la

bel,

PG,

non-

infe

rior

ity

stud

y

once

dai

ly

2. E

noxa

pari

n +

eith

er w

arfa

rin

or

acen

ocou

mar

ol

(vita

min

K

anta

goni

st)

Acut

e sy

mpt

omat

ic

DVT

Ex

clus

ion:

Ad

ditio

nal V

KA

indi

catio

n, C

rCl <

30

ml/

min

, sig

nific

ant l

iver

di

seas

e, a

ctiv

e bl

eedi

ng

unco

ntro

lled

HTN

, pr

egna

nt/b

reas

tfee

ding

co

ncom

itant

CYP

-450

3A

4 in

hibi

tors

2. 1

718

95%

CI 0

.44-

1.04

p<

0.00

1

PE:

R:

3

E-VK

A: 6

Al

l-cau

se m

orta

lity:

R:

38

(2.2

%)

E-VK

A: 4

9 (2

.9%

) H

R 0.

67

95%

CI,

0.33

to 1

.30

95%

CI 0

.33

to

1.30

p=

0.21

NS

• 73

% in

riv

arox

aban

gro

up a

nd

71%

in th

e w

arfa

rin

grou

p w

ere

pr

etre

ated

wit

h pa

rent

eral

an

ticoa

gula

nts

•

Low

dro

pout

rat

es

• O

nly

sym

ptom

atic

DVT

s ev

alua

ted

EIN

STEI

N-E

xten

sion

7 Th

e Ei

nste

in

Inve

stig

ator

s Ph

ase

III, D

B,

PG

1. R

ivar

oxab

an

20m

g da

ily

2. P

lace

bo

Age:

58

yrs

Fem

ale:

41%

/43%

In

clus

ion:

ob

ject

ivel

y co

nfir

med

, sy

mpt

omat

ic D

VT

or P

E w

ith 1

2 m

onth

pri

or

trea

tmen

t wit

h w

arfa

rin

or

acen

ocou

mar

ol

Excl

usio

n:

addi

tiona

l VKA

in

dica

tion,

CrC

l <30

m

l/m

in, s

igni

fican

t liv

er d

isea

se, a

ctiv

e bl

eedi

ng, u

ncon

trol

led

HTN

, pre

gnan

t/

brea

stfe

edin

g,

conc

omita

nt C

YP-4

50

3A4

inhi

bito

rs

1. 6

02

2. 5

94

Tx d

urat

ion:

6

or

12

mon

ths

Recu

rren

t VTE

: R:

8 (1

.3%

) P:

42

(7.1

%)

HR

0.18

; 95

% C

I 0.0

9 to

0.3

9 p<

0.00

1 PE

:

R: 1

P:

0

All-c

ause

mor

talit

y:

R: 1

(0.2

%)

P: 2

(0.3

%)

ARR

5.8%

N

NT

17

Maj

or B

leed

ing:

R:

4 (0

.7%

) P:

0 (0

.0%

) p=

0.11

NS

•

Stud

y Ra

ting:

Poo

r •

53%

of p

atie

nts

from

pre

viou

s st

udie

s –

bias

res

ults

to th

ose

alre

ady

able

to to

lera

te t

hera

py

• Pl

aceb

o co

mpa

riso

n lim

its

clin

ical

app

licab

ility

•

Lost

to fo

llow

-up

rate

s lo

w

86 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

11

Aut

hor:

Kat

hy S

ente

na

ATL

AS

ACS

2-T

IMI 5

1 8

ATLA

S AC

S 2-

TIM

I 51

Inve

stig

ator

s RC

T, D

B, P

C,

Phas

e III

1. R

ivar

oxab

an

2.5m

g or

5m

g tw

ice

daily

2.

Pla

cebo

Mea

n ag

e: 6

1 yr

s M

ales

: 74-

75%

In

clus

ion:

pat

ient

s 18

an

d ov

er w

ith

sym

ptom

s of

ACS

and

ST

EMI,

NST

EMI,

or

unst

able

ang

ina.

Tho

se

<55

also

had

DM

or

prev

ious

MI.

NST

EMI:

50%

ea.

grou

p ST

EMI:

26%

ea.

Gro

up

Uns

tabl

e an

gina

: 24

% e

a. g

roup

Ex

clus

ion:

Re

duce

d pl

atel

ets

and

hem

oglo

bin

leve

ls, C

rCL

<30m

l/m

in, p

revi

ous

blee

ding

, pre

viou

s st

roke

or

TIA

on A

SA o

r th

ieno

pyri

dine

Al

so o

n st

anda

rd

med

ical

ther

apy

incl

udin

g lo

w-d

ose

ASA

an

d th

ieno

pyri

dine

R 2.

5mg

5174

R

5 m

g 51

76

Plac

ebo

5176

Mea

n tx

du

ratio

n 1

3.1

mon

ths

Com

posi

te o

f dea

th fr

om

CV, M

I or

stro

ke:

R 2.

5mg:

9.1

%

HR

0.84

95

% C

I 0.7

2 to

0.9

7 P=

0.0

07

P: 1

0.7%

R

5mg:

8.8

%

HR

0.85

95

% C

I 0.7

3 to

0.9

8 P=

0.01

P:

10.

7%

CV M

orta

lity:

R

2.5m

g: 2

.7%

H

R 0.

66

95%

CI,

0.51

to 0

.86

P=0.

005

P: 4

.1%

R

5mg:

4.0

%

HR

0.94

95

% C

I 0.7

5 to

1.2

0 P

=0.5

7 P:

4.1

%

Sten

t Thr

ombo

sis:

R

2.5m

g: 2

.2%

H

R 0.

65

95%

CI 0

.45

to 0

.94

P= 0

.02

R 5m

g: 2

.3%

H

R 0.

73

95%

CI 0

.51

to 1

.04

P=0.

04

P: 2

.9%

ARR

1.6%

N

NT

63

ARR

1.9%

N

NT

53

ARR

1.4%

N

NT

71

NS

ARR

0.7%

N

NT

143

ARR

0.6%

N

NT

166

Maj

or B

leed

ing:

R

2.5m

g: 1

.8%

P:

0.6

%

HR

3.46

95

% C

I 2.0

8 to

5.

77

P<0.

001

R 5m

g: 2

.4%

P:

0.6

%

HR

4.47

95

% C

I 2.7

1 to

7.

36

P<0.

001

Intr

acra

nial

Bl

eeds

: R

2.5m

g: 1

4 (0

.4%

H

R 2.

83

95%

CI 1

.02

to

7.86

P=

0.0

4 P:

0.2

%

R 5.

0mg:

18

(0.7

%

HR

3.74

95

% C

I 1.3

9 to

10

.07

P=0.

005

P: 0

.2%

Fa

tal B

leed

s:

R 2.

5mg:

6 (0

.1%

) P:

9 (0

.2%

) H

R 0.

67

95%

CI 0

.24

to

1.89

P=

0.45

P:

0.2

%

R 5m

g: 1

5

ARI

1.

2%

NN

H

83

ARI

1.

8%

NN

H

56

ARI

0.

2%

NN

H

500

ARI

0.

5%

NN

H

200

NS

•

Stud

y Ra

ting:

Fai

r •

Incr

ease

d m

ajor

ble

eds

and

intr

acra

nial

ble

eds

but f

atal

bl

eeds

sim

ilar

• Yo

unge

r po

pula

tion

stud

ied.

Po

tent

ial f

or in

crea

sed

risk

o

blee

ding

in e

lder

ly.

• Pr

emat

ure

disc

ontin

uatio

n in

29

.4%

of r

ivar

oxab

an a

nd

26.4

% o

f pla

cebo

87 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

12

Aut

hor:

Kat

hy S

ente

na

All-c

ause

mor

talit

y:

R 2.

5mg:

320

(9.3

%)

P: 1

53 (4

.5%

) H

R 0.

68

95%

CI,

0.53

to 0

.87

P=0.

004

R 5m

g: 3

21 (9

.1%

) P:

153

(4.5

%)

HR

0.95

95

% C

I, 0.

76 to

1.1

9 P=

0.89

(0.4

%)

P: 9

(0.2

%)

HR

1.72

95

% C

I 0.7

5 to

3.

92

P= 0

.20

NS

1 St

udy

desi

gn: D

B =

doub

le-b

lind,

RCT

= r

ando

miz

ed tr

ial,

PC =

pla

cebo

-con

trol

led,

PG

= p

aral

lel -

grou

p, X

O =

cro

ssov

er, D

D =

dou

ble

dum

my.

2 Re

sult

s ab

brev

iati

ons:

RRR

= r

elat

ive

risk

red

ucti

on, R

R =r

elat

ive

risk

, OR=

Odd

s Ra

tio, H

R =

Haz

ard

Ratio

, AR

R =

abso

lute

ris

k re

duct

ion,

ARI

= a

bsol

ute

risk

incr

ease

N

NT

= nu

mbe

r ne

eded

to tr

eat,

NN

H =

num

ber

need

ed to

har

m, C

I = c

onfid

ence

inte

rval

, ITT

= in

tent

ion-

to-t

reat

ana

lysi

s, m

ITT-

mod

ified

inte

ntio

n-to

-tre

at a

naly

sis

3 NN

T/N

NH

are

rep

orte

d on

ly fo

r st

atis

tical

ly s

igni

fican

t res

ults

4 Q

ualit

y Ra

ting

: (G

ood-

like

ly v

alid

, Fai

r- li

kely

val

id/p

ossi

bly

valid

, Poo

r- fa

tal f

law

-not

val

id)

Clin

ical

Abb

revi

atio

ns:

TTR=

tim

e in

ther

apeu

tic r

ange

, SQ

-sub

cuta

neou

s, S

TEM

I – S

T-se

gmen

t ele

vatio

n m

yoca

rdia

l inf

arct

ion,

NST

EMI –

non

-ST-

segm

ent e

leva

tion

myo

card

ial i

nfar

ctio

n

88 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

13

Aut

hor:

Kat

hy S

ente

na

Tria

l Det

ails

DV

T Pr

ophy

laxi

s

Riva

roxa

ban

was

app

rove

d fo

r the

pro

phyl

axis

of D

VT a

nd P

E in

ove

r 9,5

00 p

atie

nts

unde

rgoi

ng to

tal h

ip r

epla

cem

ent (

THR)

and

tota

l kne

e re

plac

emen

t (TK

R) b

ased

on

data

from

four

mul

ti-ce

nter

, RCT

s; R

ECO

RD 1

-4.2,

3,4 R

ECO

RD 1

and

2 e

nrol

led

patie

nts

sche

dule

d fo

r TH

R an

d RE

CORD

3

and

4 in

clud

ed p

atie

nts

sche

dule

d fo

r TKR

. Pa

tient

s w

ere

trea

ted

for a

mea

n du

ratio

n of

33

days

in R

ECO

RD 1

and

2, 1

0-14

day

s in

REC

ORD

3 a

nd

4. P

atie

nts

wer

e ra

ndom

ized

to r

ivar

oxab

an 1

0 m

g da

ily, s

tart

ing

afte

r su

rger

y, o

r eno

xapa

rin, s

tart

ing

on th

e ev

enin

g pr

ior

to s

urge

ry.

Enox

apar

in

dose

s w

ere

40m

g sq

dai

ly fo

r RE

CORD

1-3

and

30m

g sq

twic

e da

ily in

REC

ORD

4.

The

prim

ary

effic

acy

anal

ysis

was

the

com

posi

te o

f DVT

, non

fata

l PE

and

dea

th w

ith th

e pr

imar

y sa

fety

ana

lysi

s be

ing

maj

or b

leed

ing.

The

pri

mar

y ef

ficac

y an

alys

is re

sults

wer

e ba

sed

on a

Mod

ified

Inte

nt to

Tre

at

(MIT

T) p

opul

atio

n w

hich

incl

uded

8,5

12 p

atie

nts

(67%

) of t

he o

rigi

nal s

tudy

pop

ulat

ion.

Ther

e w

as lo

w to

mod

erat

e-st

reng

th o

f evi

denc

e fr

om R

ECO

RD 1

that

riv

arox

aban

was

sim

ilar t

o en

oxap

arin

in r

egar

ds to

the

com

pone

nt

outc

omes

of a

ll-ca

use

mor

talit

y an

d no

n-fa

tal p

ulm

onar

y em

bolis

m. T

here

was

als

o lo

w to

mod

erat

e-st

reng

th o

f evi

denc

e th

at ri

varo

xaba

n w

as

mor

e ef

fect

ive

than

eno

xapa

rin

in re

gard

s to

inci

denc

e of

DVT

s ( A

RR -2

.7%

; 95%

CI,

-3.7

to -1

.7; p

<0.0

01).

In R

ECO

RD 3

ther

e w

as a

lso

low

-m

oder

ate

stre

ngth

of e

vide

nce

for n

o di

ffer

ence

in a

ll-ca

use

mor

talit

y an

d no

n-fa

tal p

ulm

onar

y em

bolis

m r

ates

bet

wee

n ri

varo

xaba

n an

d en

oxap

arin

. Th

ere

was

low

to m

oder

ate-

stre

ngth

of e

vide

nce

that

riv

arox

aban

was

sup

erio

r to

enox

apar

in in

reg

ards

to D

VTs

(ARR

-8.4

%; 9

5% C

I, -

11.7

to -5

.2; p

=<0.

001)

. H

owev

er, t

he u

se o

f the

Eur

opea

n en

oxap

arin

dos

ing

regi

men

of 4

0mg

once

dai

ly in

REC

ORD

3, l

imits

the

appl

icab

ility

of

the

resu

lts to

Uni

ted

Stat

es p

atie

nts

wer

e th

e re

com

men

ded

dosi

ng re

gim

en fo

r DVT

pro

phyl

axis

in p

atie

nts

unde

rgoi

ng T

KR is

30m

g tw

ice

daily

. Th

ere

was

mod

erat

e-st

reng

th o

f evi

denc

e to

sug

gest

maj

or b

leed

ing

rate

s w

ere

high

er fo

r riv

arox

aban

com

pare

d to

eno

xapa

rin

in b

oth

RECO

RD 1

an

d 3

stud

ies,

alth

ough

not

sta

tistic

ally

sig

nific

ant.

The

Cana

dian

Age

ncy

for D

rugs

and

Tec

hnol

ogie

s in

Hea

lth (C

AD

TH) r

ecom

men

d ri

varo

xaba

n as

an

effe

ctiv

e tr

eatm

ent o

ptio

n fo

r VTE

pro

phyl

axis

af

ter T

HR

or T

KR, a

s an

alte

rnat

ive

to e

noxa

parin

, with

no

com

pelli

ng e

vide

nce

to s

ugge

st a

n in

crea

sed

inci

denc

e of

adv

erse

eff

ects

.21

RECO

RD 2

and

4 w

ere

deem

ed p

oor

stud

ies

due

to F

DA

anal

ysis

sta

ting

data

was

unr

elia

ble.

REC

ORD

2 c

ompa

red

riva

roxa

ban

to e

noxa

pari

n, u

sing

di

ffer

ent d

urat

ions

of t

reat

men

t, w

hich

lim

it th

e ap

plic

abili

ty o

f the

eff

icac

y co

nclu

sion

s.20

O

ne o

f tw

o cl

inic

al in

vest

igat

ors

conf

irmed

dat

a fr

om

RECO

RD 4

was

not

con

side

red

relia

ble

in s

uppo

rt o

f the

New

Dru

g Ap

plic

atio

n (N

DA

). T

wo

addi

tiona

l clin

ical

inve

stig

ator

insp

ectio

ns w

ere

cond

ucte

d pr

ior t

o th

e N

DA

sub

mis

sion

, reg

ardi

ng R

ECO

RD 2

and

REC

ORD

4, a

nd fo

und

that

dat

a fr

om b

oth

thes

e si

tes

wer

e un

relia

ble.

Aft

er a

n an

alys

is o

f all

the

RECO

RD s

tudi

es, w

ith r

emov

al o

f que

stio

nabl

e da

ta, t

he F

DA

foun

d ef

ficac

y re

sults

favo

ring

riva

roxa

ban,

dri

ven

by a

sym

ptom

atic

D

VTs

dete

cted

by

veno

grap

hy.

89 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

14

Aut

hor:

Kat

hy S

ente

na

Atr

ial F

ibri

llati

on

ROCK

ET A

F w

as a

pha

se II

I, D

B, D

D, R

CT in

ove

r 14,

000

patie

nts

in 4

5 co

untr

ies

with

non

valv

ular

atr

ial f

ibri

llatio

n w

ho w

ere

at m

oder

ate

to h

igh

risk

of

str

oke.

Pat

ient

s w

ere

rand

omly

ass

igne

d to

riv

arox

aban

20m

g da

ily o

r dos

e-ad

just

ed w

arfa

rin (I

NR

2.0-

3.0)

. Pa

rtic

ipan

ts h

ad a

med

ian

age

of 7

3 ye

ars

and

60%

wer

e m

ale.

The

mea

n CH

AD

2 sco

re w

as 3

.5 a

nd 5

5% o

f par

ticip

ants

had

coe

xist

ing

cond

ition

s. T

he m

edia

n tr

eatm

ent d

urat

ion

was

59

0 da

ys w

ith 7

07 d

ays

of fo

llow

-up.

The

pri

mar

y ef

ficac

y an

alys

is w

as th

e co

mpo

site

of s

trok

e (is

chem

ic a

nd h

emor

rhag

ic) a

nd s

yste

mic

em

bolis

m.

A n

onin

feri

ority

ana

lysi

s (m

argi

n of

1.4

6) w

as p

refo

rmed

on

the

per-

prot

ocol

pop

ulat

ion.

If n

onin

ferio

rity

was

ach

ieve

d th

en

noni

nfer

iorit

y an

d su

perio

rity

test

ing

wou

ld b

e pe

rfor

med

on

the

ITT

popu

latio

n. T

he m

ajor

saf

ety

endp

oint

was

com

posi

te o

f maj

or a

nd n

onm

ajor

cl

inic

ally

rel

evan

t ble

edin

g ev

ents

. M

ajor

ble

eds

is r

epor

ted

as th

e m

ore

clin

ical

ly r

elev

ant s

afet

y en

dpoi

nt.6

Ther

e w

as lo

w-s

tren

gth

of e

vide

nce

from

RO

C KE

T A

F th

at r

ivar

oxab

an w

as n

onin

feri

or to

war

farin

for t

he c

ompo

site

out

com

e of

str

oke

and

syst

emic

em

bolis

m (H

R 0.

88; 9

5% C

I, 0.

75 to

1.0

3; p

<0.0

01 fo

r non

infe

riorit

y, p

=0.1

2 fo

r sup

erio

rity)

. Th

ere

was

low

-str

engt

h of

evi

denc

e th

at

maj

or b

leed

ing

rate

s w

ere

sim

ilar b

etw

een

riva

roxa

ban

and

war

farin

(HR

1.04

; 95%

CI,

0.90

to 1

.20,

p=0

.58)

and

intr

acra

nial

ble

eds

wer

e le

ss w

ith

riva

roxa

ban.

TTR

was

onl

y 55

% fo

r w

arfa

rin p

atie

nts

in R

OCE

T-A

F. C

once

rns

over

sub

optim

al u

se o

f war

farin

mak

e co

nclu

sion

s on

com

para

ble

effic

acy

and

safe

ty d

iffic

ult.

The

re is

insu

ffic

ient

evi

denc

e co

mpa

ring

riva

roxa

ban

to w

ell c

ontr

olle

d w

arfa

rin m

anag

emen

t. T

he s

hort

hal

f-lif

e of

ri

varo

xaba

n co

mbi

ned

with

onc

e da

ily d

osin

g m

ay b

e pr

oble

mat

ic if

ther

e ar

e ad

here

nce

conc

erns

.

Off

-labe

l Use

s

DV

T Tr

eatm

ent

Riva

roxa

ban

was

stu

died

in a

pha

se II

I, pa

ralle

l gro

up, n

on-in

feri

ority

, ope

n-la

bel,

RCT

in o

ver

3,40

0 pa

tient

s w

ith a

cute

sym

ptom

atic

DVT

with

out

PE in

the

EIN

STEI

N-D

VT tr

ial.

Pat

ient

s w

ere

rand

omiz

ed to

riv

arox

aban

15m

g tw

ice

daily

for 3

wee

ks a

nd th

en 2

0mg

once

dai

ly o

r en

oxap

arin

and

a

vita

min

K a

ntag

onis

t (w

arfa

rin

or a

ceno

coum

arol

) for

3, 6

, or

12 m

onth

s.7

Ther

e w

as lo

w-s

tren

gth

of e

vide

nce

that

riv

arox

aban

was

non

-infe

rior t

o st

anda

rd tr

eatm

ent (

enox

apar

in p

lus

VKA

) for

the

prev

entio

n of

recu

rren

t VT

E in

pat

ient

s w

ith a

cute

DVT

. Th

e pr

imar

y en

dpoi

nt w

as e

xper

ienc

ed b

y 2.

1% o

f the

riv

arox

aban

gro

up a

nd 3

.0%

for t

he e

noxa

pari

n/VK

A gr

oup

(HR

0.68

; 95%

CI,

0.44

-1.0

4; p

<0.0

01 fo

r non

infe

riori

ty).

The

re w

as lo

w-s

tren

gth

of e

vide

nce

of s

imila

r ra

tes

of m

ajor

ble

edin

g ,8

.1%

in b

oth

grou

ps.

The

EIN

STEI

N-E

XTEN

SIO

N s

tudy

was

a P

C, d

oubl

e-bl

ind,

pha

se II

I con

tinua

tion

stud

y in

ove

r 1,0

00 p

atie

nts

with

a c

onfir

med

sym

ptom

atic

DVT

or

PE p

revi

ousl

y tr

eate

d w

ith a

VKA

or

riva

roxa

ban

for

6 or

12

mon

ths

(EIN

STEI

N-D

VT, E

INST

EIN

-PE(

ongo

ing)

), th

at th

ere

was

equ

ipoi

se w

ith re

spec

t to

the

need

for c

ontin

ued

antic

oagu

latio

n. P

atie

nts

wer

e ra

ndom

ly a

ssig

ned

to r

ivar

oxab

an 2

0mg

daily

or

plac

ebo

for a

n ad

ditio

nal 6

or 1

2

90 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

15

Aut

hor:

Kat

hy S

ente

na

mon

ths.

The

ave

rage

pat

ient

was

58

year

s ol

d w

ith a

roun

d 40

% b

eing

fem

ale.

The

pri

mar

y ef

ficac

y an

alys

is w

as r

ecur

rent

ven

ous

thro

mbo

embo

lism

and

maj

or b

leed

ing

was

the

prim

ary

safe

ty a

naly

sis.

7

Ther

e is

low

-str

engt

h of

evi

denc

e th

at r

ivar

oxab

an is

mor

e ef

fect

ive

than

pla

cebo

in p

reve

ntin

g VT

E w

ith e

xten

ded

trea

tmen

t (H

R 0.

18; 9

5% C

I 0.0

9 to

0.3

9; p

<0.0

01).

The

re is

als

o lo

w-s

tren

gth

of e

vide

nce

that

riva

roxa

ban

caus

es m

ore

maj

or b

leed

ing

than

pla

cebo

. Ex

tens

ion

stud

y de

sign

may

bi

as e

ffic

acy

and

safe

ty re

sults

bas

ed o

n en

rollm

ent o

f pat

ient

s al

read

y ab

le to

tole

rate

/res

pond

to tr

eatm

ents

.

Acu

te C

oron

ary

Synd

rom

e Th

e AT

LAS

ACS

2-T

IMI 5

1 st

udy

was

a D

B, P

C, R

CT in

volv

ing

15,5

26 p

atie

nts

in 4

4 co

untr

ies

pres

entin

g w

ith A

cute

Cor

onar

y Sy

ndro

me

(ACS

) and

an

ST-s

egm

ent e

leva

tion

myo

card

ial i

nfar

ctio

n (N

STEM

I), n

on-S

T-se

gmen

t ele

vatio

n m

yoca

rdia

l inf

arct

ion

(NST

EMI)

or u

nsta

ble

angi

na.

Patie

nts

wer

e ra

ndom

ized

to r

ivar

oxab

an 2

.5m

g tw

ice

daily

, riv

arox

aban

5m

g tw

ice

daily

or

plac

ebo,

alo

ng w

ith s

tand

ard

med

ical

car

e fo

r A

CS.

Patie

nts

wer

e tr

eate

d fo

r a m

ean

dura

tion

of 1

3.1

mon

ths.

The

pri

mar

y ef

ficac

y en

dpoi

nt w

as a

com

posi

te o

f dea

th fr

om c

ardi

ovas

cula

r ca

uses

, myo

card

ial

infa

rctio

n or

str

oke.

8 Th

ere

was

mod

erat

e-st

reng

th o

f evi

denc

e th

at r

ivar

oxab

an 2

.5m

g de

crea

sed

card

iova

scul

ar d

eath

, MI a

nd a

ll-ca

use

mor

talit

y ra

tes

com

pare

d to

pl

aceb

o, b

eing

sta

tistic

ally

sig

nific

ant f

or c

ardi

ovas

cula

r m

orta

lity

and

all-c

ause

mor

talit

y. R

ivar

oxab

an 5

mg

twic

e da

ily d

ecre

ased

car

diov

ascu

lar

mor

talit

y an

d M

I com

pare

d to

pla

cebo

with

mod

erat

e-st

reng

th o

f evi

denc

e, w

ith o

nly

MI r

ates

bei

ng s

tatis

tical

ly s

igni

fican

t. T

here

was

mod

erat

e-st

reng

th o

f evi

denc

e th

at r

ivar

oxab

an 2

.5m

g an

d 5m

g tw

ice

daily

incr

ease

d th

e ri

sk o

f str

oke,

alth

ough

nei

ther

wer

e st

atis

tical

ly s

igni

fican

t. T

here

w

as m

oder

ate

stre

ngth

of e

vide

nce

that

riva

roxa

ban

incr

ease

s th

e ri

sk o

f maj

or b

leed

s. T

here

wer

e al

so n

oted

incr

ease

s in

intr

acra

nial

ble

eds,

co

mpa

red

to p

lace

bo, i

n bo

th r

ivar

oxab

an tr

eatm

ent g

roup

s, w

ith a

NN

H o

f 500

and

200

in th

e 2.

5mg

and

5mg

grou

ps, r

espe

ctiv

ely.

The

ave

rage

ag

e of

stu

dy p

artic

ipan

t was

62

year

s ol

d, w

hich

mak

es e

xtra

pola

ting

resu

lts to

a m

ore

elde

rly

popu

latio

n di

ffic

ult.

D

RUG

SA

FETY

Se

rious

(REM

S, B

lack

Box

War

ning

s, C

ontr

aind

icat

ions

):

As

with

oth

er a

ntic

oagu

lant

s, r

ivar

oxab

an m

ay c

ause

epi

dura

l or

spin

al h

emat

omas

in p

atie

nts

who

m a

re r

ecei

ving

neu

raxi

al a

nest

hesi

a.

Act

ive

maj

or b

leed

ing

and

hype

rsen

sitiv

ity a

re c

ontr

aind

icat

ions

to r

ivar

oxab

an th

erap

y.1

Riva

roxa

ban

shou

ld b

e us

ed c

autio

usly

in

patie

nts

with

ble

edin

g di

sord

ers,

sev

ere

hype

rten

sion

, pr

egna

ncy

and

rena

l and

hep

atic

im

pairm

ent.

O

ther

ser

ious

adv

erse

eve

nts

desc

ribe

d in

pos

t-m

arke

ting

repo

rts

incl

ude

cere

bral

hem

orrh

age,

epi

dura

l hem

atom

a, a

nd h

yper

sens

itivi

ty r

eact

ions

in

clud

ing

anap

hyla

ctic

sho

ck, a

gran

uloc

ytos

is a

nd S

teve

n-Jo

hnso

n Sy

ndro

me.

1,20

91 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

16

Aut

hor:

Kat

hy S

ente

na

In p

atie

nts

with

AF,

dis

cont

inui

ng r

ivar

oxab

an t

reat

men

t has

put

pat

ient

s at

incr

ease

d ri

sk o

f thr

ombo

tic e

vent

s. I

n RO

CKET

AF

an in

crea

sed

risk

of

stro

kes

wer

e se

en f

ollo

win

g ri

varo

xaba

n di

scon

tinua

tion.

Co

nsid

er c

ontin

uing

pat

ient

s on

ano

ther

ant

icoa

gula

nt i

f ri

varo

xaba

n is

to

be

disc

ontin

ued.

1

Blee

ding

: Riv

arox

aban

incr

ease

s th

e ri

sk o

f ble

edin

g an

d ca

n ca

use

sign

ifica

nt o

r ev

en fa

tal b

leed

ing

in c

erta

in p

atie

nts.

The

ris

k fo

r bl

eedi

ng

incr

ease

s w

hen

othe

r dru

gs th

at a

lso

incr

ease

the

risk

of b

leed

ing

are

used

con

curr

ently

and

was

mos

t com

mon

dur

ing

the

first

wee

k of

sur

gery

. Ri

varo

xaba

n sh

ould

be

used

with

cau

tion

in p

regn

ant w

omen

due

to p

regn

ancy

rel

ated

hem

orrh

age.

1

In tr

ials

eva

luat

ing

riva

roxa

ban

for p

roph

ylax

is in

pat

ient

s un

derg

oing

hip

or

knee

rep

lace

men

t ble

edin

g w

as th

e m

ost c

omm

on a

dver

se e

vent

. M

ajor

ble

edin

g ev

ents

wer

e hi

gher

with

riv

arox

aban

in th

e RE

CORD

tria

ls c

ompa

red

to e

noxa

parin

, 0.

39%

vs.

0.2

1%, r

espe

ctiv

ely.

20

Tabl

e 2.

0 B

leed

ing

Even

ts in

Pat

ient

s U

nder

goin

g H

ip o

r Kn

ee R

epla

cem

ent

Surg

erie

s1

Tota

l Tre

ated

Pat

ient

s in

Rec

ord

1-3*

Riva

roxa

ban

10m

g N

= 44

87

(n/%

)

Enox

apar

in 4

0mg

Dai

ly†

N=4

524

(n/%

) M

ajor

Ble

edin

g Ev

ent

14 (0

.3)

9 (0

.2)

Fata

l Ble

edin

g 1

(<0.

1)

0 Bl

eedi

ng in

to a

Cri

tical

Org

an

2 (<

0.1)

3

(0.1

) Bl

eedi

ng th

at R

equi

red

Re-o

pera

tion

7 (0

.2)

5 (0

.1)

Extr

a-su

rgic

al s

ite b

leed

ing

Requ

irin

g tr

ansf

usio

n of

>2

units

of w

hole

blo

od o

r pa

cked

cel

ls

4 (0

.1)

1 (<

0.1)

Any

Ble

edin

g Ev

ent*

* 26

1 (5

.8)

251

(5.6

) *

Dat

a fr

om R

ECO

RD 4

exc

lude

d fr

om p

oole

d da

ta

** I

nclu

des

maj

or b

leed

ing

even

ts.

† In

clud

es p

lace

bo-c

ontr

olle

d pe

riod

for

RECO

RD2

To

lera

bilit

y (D

rop-

out r

ates

, man

agem

ent s

trat

egie

s):

Ove

rall

riva

roxa

ban

was

wel

l tol

erat

ed w

ith s

imila

r di

scon

tinua

tion

rate

s as

eno

xapa

rin,

3.7

% a

nd 4

.6%

, res

pect

ivel

y.

Preg

nanc

y/La

ctat

ion

ratin

g:

Riva

roxa

ban

is r

ated

Pre

gnan

cy C

ateg

ory

C.

Dos

ing

hasn

’t b

een

stud

ied

in p

regn

ant w

omen

and

it s

houl

d on

ly b

e gi

ven

if th

e po

tent

ial b

enef

it ou

twei

ghs

the

risk

to th

e m

othe

r and

fetu

s.1

Riv

arox

aban

was

sho

wn

to b

e se

cret

ed in

to m

ilk w

hen

stud

ied

in r

ats.

92 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

17

Aut

hor:

Kat

hy S

ente

na

Una

nsw

ered

saf

ety

ques

tions

: Th

e sa

fety

of t

akin

g ri

varo

xaba

n lo

ng te

rm is

unk

now

n. T

here

is n

o an

tidot

e fo

r riv

arox

aban

in a

ble

edin

g em

erge

ncy.

Ble

edin

g sh

ould

be

man

aged

by

hol

ding

riv

arox

aban

trea

tmen

t and

giv

ing

reco

mbi

nant

fact

or V

IIa o

r ac

tivat

ed p

roth

rom

bin

com

plex

con

cent

rate

cou

ld b

e co

nsid

ered

, alth

ough

no

t stu

died

. Pr

othr

ombi

n co

mpl

ex c

once

ntra

te h

as b

een

show

n to

be

effe

ctiv

e in

a s

mal

l pop

ulat

ion

but a

dditi

onal

dat

a is

nee

ded.

22 P

rota

min

e an

d vi

tam

in K

wou

ld n

ot b

e ex

pect

ed to

reve

rse

antic

oagu

lant

eff

ects

of r

ivar

oxab

an.23

O

f con

cern

was

an

incr

ease

d in

cide

nce

of c

ardi

ovas

cula

r ev

ents

dur

ing

the

follo

w-u

p pe

riod

in R

OCE

T A

F in

the

riva

roxa

ban

grou

p co

mpa

red

to w

arfa

rin.

Thi

s in

crea

se w

as th

ough

t to

be d

ue to

a g

ap in

pr

otec

tive

effe

ct d

urin

g dr

ug tr

ansi

tion

off o

f riv

arox

aban

and

to w

arfa

rin

afte

r stu

dy c

ompl

etio

n.6

Dos

e In

dex

(eff

icac

y/to

xic)

: D

VT P

roph

ylax

is

For

mos

t pat

ient

s th

e do

se o

f riv

arox

aban

10m

g da

ily, w

ithou

t reg

ards

to m

eals

is r

ecom

men

ded.

The

initi

al d

ose

shou

ld b

e ta

ken

6-10

hou

rs p

ost

surg

ery

once

hem

osta

sis

has

been

est

ablis

hed.

Tre

atm

ent s

houl

d co

ntin

ue fo

r 35

day

s fo

r pat

ient

s un

derg

oing

hip

repl

acem

ent s

urge

ries

and

12

days

for p

atie

nts

unde

rgoi

ng k

nee

repl

acem

ent s

urge

ries

.

Non

valv

ular

Atr

ial F

ibril

latio

n Ri

varo

xaba

n is

giv

en a

s 20

mg

with

the

even

ing

mea

l, fo

r pat

ient

s w

ith C

rCl >

50 m

L/m

in.

For p

atie

nts

with

CrC

l of 1

5 to

50

mL/

min

a d

ose

of 1

5 m

g w

ith th

e ev

enin

g m

eal i

s re

com

men

ded.

Riv

arox

aban

is n

ot re

com

men

ded

for a

CrC

L of

<15

mL/

min

.

Incr

ease

d ex

posu

re to

riva

roxa

ban

was

not

ed in

eld

erly

pat

ient

s, w

hich

may

be

due

to a

ge r

elat

ed c

hang

es in

ren

al fu

nctio

n. A

void

usi

ng

riva

roxa

ban

in p

atie

nts

with

a C

rCl <

30 m

L/m

in.

Patie

nts

with

mod

erat

e re

nal f

ailu

re (C

rCl 3

0-<5

0 m

L/m

in) s

houl

d be

obs

erve

d cl

osel

y fo

r ble

edin

g.

Due

to s

igni

fican

t inc

reas

es in

riva

roxa

ban

conc

entr

atio

ns w

ith im

pair

ed h

epat

ic fu

nctio

n, p

atie

nts

with

mod

erat

e (C

hild

-Pug

h B)

, sev

ere

(Chi

ld-

Pugh

C) h

epat

ic im

pair

men

t or

any

hepa

tic d

isea

se a

ssoc

iate

d w

ith c

oagu

lopa

thy

shou

ld n

ot ta

ke r

ivar

oxab

an.

For p

atie

nts

with

ren

al in

suff

icie

ncy

(CrC

l 15-

50 m

L/m

in) t

akin

g ri

varo

xaba

n fo

r AF

the

reco

mm

ende

d do

se is

15m

g on

ce d

aily

, with

the

even

ing

mea

l.

Riva

roxa

ban

abso

rptio

n is

dep

ende

nt u

pon

the

site

of d

rug

rele

ase

in th

e G

I tra

ct.

Dru

g de

liver

y di

rect

ly to

the

prox

imal

sm

all i

ntes

tine

(e.g

., fe

edin

g tu

be) c

an r

esul

t in

redu

ced

drug

abs

orpt

ion.

1 M

onito

ring:

D

ose

–dep

ende

nt in

hibi

tion

of F

acto

r Xa

and

in p

roth

rom

bin

time

(PT)

, act

ivat

ed p

artia

l thr

ombo

plas

tin ti

me

(aPT

T) a

nd H

epTe

st®

are

prol

onge

d do

se-d

epen

dent

ly.

Riva

roxa

ban

also

influ

ence

s An

ti-fa

ctor

Xa

activ

ity.

93 of 187

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eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

18

Aut

hor:

Kat

hy S

ente

na

Look

-alik

e /

Soun

d-al

ike

(LA

/SA

) Err

or R

isk

Pote

ntia

l: LA

/SA

nam

es a

re a

sses

sed

duri

ng th

e PD

L se

lect

ion

of d

rugs

. Ba

sed

on c

linic

al ju

dgm

ent a

nd a

n ev

alua

tion

of L

A/SA

info

rmat

ion

from

four

dat

a so

urce

s (L

exi-C

omp,

USP

Onl

ine

LASA

Fin

der,

Fir

st D

atab

ank,

and

ISM

P Co

nfus

ed D

rug

Nam

e Li

st),

the

follo

win

g dr

ug n

ames

may

cau

se L

ASA

co

nfus

ion:

N

ME

Dru

g N

ame

Lexi

-Com

p U

SP O

nlin

e M

icro

Med

ex

ISM

P Cl

inic

al Ju

dgm

ent

LA/S

A f

or r

ivar

oxab

an (g

ener

ic)

Non

e N

one

Non

e N

one

Non

e

LA/S

A f

or X

arel

to (b

rand

)

Non

e N

one

N

one

Non

e N

one

Adv

erse

Eve

nts

Repo

rted

in ≥

1% o

f Riv

arox

aban

Tre

ated

Pat

ient

s in

REC

ORD

tri

als

1-31

Adv

erse

Eve

nts

(1)

(Med

DRA

Sys

tem

Org

an C

lass

and

Pre

ferr

ed T

erm

)

Riva

roxa

ban

10m

g

n (%

)

Enox

apar

in 4

0mg

Dai

ly†

n (%

)

Num

ber

of P

atie

nts

n=44

87

n= 4

524

Inju

ry, p

oiso

ning

and

pro

cedu

ral c

ompl

icat

ions

W

ound

sec

retio

n 12

5 (2

.8)

89 (2

.0))

M

uscu

losk

elet

al a

nd c

onne

ctiv

e ti

ssue

dis

orde

rs

Pain

in e

xtre

mity

74

(1.7

) 55

(1.2

) M

uscl

e sp

asm

5

2 (1

.2)

32 (0

.7)

Ner

vous

Sys

tem

Dis

orde

r

Sy

ncop

e 55

(1.2

) 32

(0.7

) S

kin

and

subc

utan

eous

tiss

ue d

isor

ders

Pr

uritu

s 96

(2.1

) 79

(1.8

) Bl

iste

r 63

(1.4

) 40

(0.9

) †

Incl

udes

pla

cebo

-con

trol

led

peri

od fo

r RE

CORD

2

94 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

19

Aut

hor:

Kat

hy S

ente

na

DO

SE &

AV

AIL

ABI

LITY

1

STRE

NG

TH

FORM

RO

UTE

FR

EQU

ENCY

RE

NA

L A

DJ

HEP

ATI

C A

DJ

Pedi

atri

c

Dos

e El

derl

y D

ose

OTH

ER D

OSI

NG

CO

NSI

DER

ATI

ON

S

Riva

roxa

ban

10m

g fo

r D

VT

prop

hyla

xis

prio

r to

TKR

or

TH

R Ri

varo

xaba

n 20

mg

once

da

ily fo

r A

F

Tabl

et

Ora

l

Onc

e da

ily

DVT

Pro

phyl

axis

: U

se c

autio

usly

in

mod

erat

e re

nal

impa

irm

ent (

CrCl

30

-50

ml/

min

) D

o no

t use

in

seve

re r

enal

im

pair

men

t (Cr

Cl

<30

ml/

min

) N

onva

lvul

ar

Atr

ial F

ibri

llatio

n:

CrCl

15-

50

ml/

min

giv

e 15

mg

once

dai

ly

Avo

id if

CrC

l 30-

50 m

l/m

in.

Avo

id u

se in

m

oder

ate

or

seve

re h

epat

ic

impa

irm

ent o

r in

he

patic

dis

ease

w

ith

coag

ulop

athy

N/A

Incr

ease

d ri

varo

xaba

n co

ncen

trat

ions

wer

e se

en in

eld

erly

pat

ient

s,

perh

aps

due

to a

ge-

rela

ted

chan

ges

in r

enal

fu

nctio

n.

Rena

l fun

ctio

n as

sess

men

t sho

uld

be

cons

ider

ed in

pat

ient

s ≥6

5 ye

ars

old.

- Tx

dur

atio

n of

35

days

re

com

men

ded

for

hip

repl

acem

ent

surg

ery

- Tx

dur

atio

n of

12

days

re

com

men

ded

for

knee

rep

lace

men

t su

rger

y -

Abs

orpt

ion

is in

crea

sed

wit

h fo

od

and

is r

ecom

men

ded

for

AF

dosi

ng

95 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

20

Aut

hor:

Kat

hy S

ente

na

PHA

RMA

COKI

NET

ICS1

Para

met

er

Resu

lt

Ora

l Bio

avai

labi

lity*

10m

g do

se: 8

0-10

0% (n

ot a

ffec

ted

by fo

od)

20m

g do

se: 6

6% (f

astin

g), i

ncre

ases

with

food

Pr

otei

n Bi

ndin

g 9

2-95

%

Elim

inat

ion

66%

uri

ne, 2

8% fe

ces

Hal

f-Li

fe

5-9

hou

rs

Met

abol

ism

Oxi

dativ

e de

grad

atio

n an

d hy

drol

ysis

via

CY

P3A

4/5

and

CYP2

J2

Subs

trat

e of

tran

spor

ter

prot

eins

P-g

p an

d A

BCG

2 *

Dos

e-de

pend

ent a

bsol

ute

biov

aila

bilit

y

ALL

ERG

IES/

INTE

RACT

ION

S

Dru

g-D

rug:

Riva

roxa

ban

is a

sub

stra

te fo

r CY

P3A

4, C

YP2J

2, a

nd th

e P-

gp a

nd A

TP-b

indi

ng c

asse

tte

G2

(ABC

G2)

tran

spor

ters

. In

hibi

tors

or

indu

cers

of t

hese

en

zym

es/t

rans

port

ers

may

cha

nge

riva

roxa

ban

expo

sure

. Co

ncom

itant

use

of r

ivar

oxab

an w

ith d

rugs

that

are

com

bine

d p-

glyc

opro

tein

(P-g

p) a

nd

stro

ng C

YP3A

4 in

duce

rs (c

arba

maz

epin

e, p

heny

toin

, rifa

mpi

n, S

t.Jo

hn’s

wor

t) s

houl

d be

avo

ided

. Av

oid

riva

roxa

ban

use

with

P-g

p an

d st

rong

CY

P3A

4 in

hibi

tors

(ket

ocon

azol

e, it

raco

nazo

le, l

opin

avir

/rito

navi

r, ri

tona

vir,

indi

navi

r/ri

tona

vir a

nd c

oniv

apta

n) w

hich

sig

nific

ant i

ncre

ases

in

riva

roxa

ban

expo

sure

has

bee

n ob

serv

ed, w

hich

may

incr

ease

ble

edin

g ris

k.1

Whe

n us

ing

riva

roxa

ban

for p

roph

ylax

is o

f DVT

, if d

ata

sugg

ests

a c

hang

e in

exp

osur

e is

unl

ikel

y to

aff

ect b

leed

ing

risk

(e.g

., cl

arith

rom

ycin

, er

ythr

omyc

in) t

hen

no p

reca

utio

ns a

re n

eces

sary

whe

n us

ing

riva

roxa

ban

conc

omita

ntly

with

P-g

p an

d CY

P3A

4 in

hibi

tors

.

Riva

roxa

ban

shou

ld n

ot b

e us

ed w

ith o

ther

ant

icoa

gula

nts.

Use

with

clo

pido

grel

sho

uld

be a

void

ed u

nles

s th

e be

nefit

out

wei

ghs

the

blee

ding

ris

k.

Prom

ptly

eva

luat

e an

y si

gns

or s

ympt

oms

of b

lood

loss

. N

o ph

arm

acok

inet

ic o

r pha

rmac

odyn

amic

inte

ract

ions

hav

e be

en n

oted

with

nap

roxe

n or

as

piri

n bu

t saf

ety

of c

oadm

inis

trat

ion

long

-ter

m h

as n

ot b

een

stud

ied.

1 It

is n

ot r

ecom

men

ded

that

riva

roxa

ban

be u

sed

with

NSA

IDS

due

to a

n in

crea

sed

risk

of b

leed

ing.

Cau

tion

is a

dvis

ed w

hen

trea

ting

patie

nts

conc

omita

ntly

with

asp

irin,

oth

er p

late

let a

ggre

gatio

n in

hibi

tors

or N

SAID

S.1

96 of 187

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

21

Aut

hor:

Kat

hy S

ente

na

Food

-Dru

g:

No

food

-dru

g in

tera

ctio

ns h

ave

been

rep

orte

d.1

Alle

rgy/

Cros

s Re

activ

e Su

bsta

nces

:

In th

e RE

-LY

tria

l, dr

ug h

yper

sens

itivi

ty w

as re

port

ed in

<0.

1% o

f pat

ient

s. N

o cr

oss-

sens

itivi

ties

have

bee

n re

port

ed.1

Post

mar

ketin

g re

port

s of

an

aphy

laxi

s to

riv

arox

aban

hav

e oc

curr

ed.

Do

not u

se in

pat

ient

s w

ith s

ever

e hy

pers

ensi

tivity

rea

ctio

ns to

riv

arox

aban

. A

PPEN

DIX

: Su

gges

ted

PA C

rite

ria

Ora

l D

irec

t F

acto

r X

a In

hib

ito

rs

Go

al(

s):

Pro

mote

safe

and e

ffective

thera

pie

s f

or

ora

l direct fa

cto

r X

a in

hib

itors

.

Len

gth

of

Au

tho

rizati

on

: 1 y

ear

Co

vere

d

Alt

ern

ati

ves

: Lis

ted a

t; h

ttp://w

ww

.ore

go

n.g

ov/D

HS

/hea

lth

pla

n/t

ools

_pro

v/p

dl.shtm

l

A

pp

roval

Cri

teri

a

1. D

oes the p

atien

t ha

ve

a d

iagnosis

re

qu

irin

g s

hort

-te

rm (

<45 d

ays)

antico

agu

latio

n (

i.e. to

tal knee r

ep

lacem

ent or

tota

l hip

repla

cem

ent)

?

Yes:

Yes:

Ap

pro

ve f

or

12 d

ays f

or

TK

R. A

ppro

ve f

or

35 d

ays f

or

TH

R.

N

o:

Go to #

2

2. D

oes the

patie

nt h

ave a

dia

gnosis

of

non

va

lvula

r atr

ial fibrilla

tio

n?

Yes: G

o t

o #

3

No

: D

en

y. (

Medic

al

appro

priate

ness)

3. W

ill the p

rescriber

consid

er

a c

ha

ng

e to t

he p

refe

rred o

ral a

ntico

agu

lant,

warf

arin?

Yes:

Appro

ve. A

dd

itio

na

l in

form

ation

can b

e f

ou

nd a

t:

http://w

ww

.dhs.s

tate

.or.

us/p

olic

y/h

ea

lt

No

: G

o to #

4

97 of 187



Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

22

Aut

hor:

Kat

hy S

ente

na

Message:

• P

refe

rred p

rod

ucts

do n

ot re

qu

ire P

A f

or

<4 d

ays/w

eek.

• P

refe

rred p

rod

ucts

ha

ve r

eceiv

ed e

vid

ence-b

ased

revie

ws f

or

com

para

tive

eff

ectiveness a

nd s

afe

ty b

y the H

ea

lth R

esourc

es C

om

mis

sio

n (

HR

C).

http://w

ww

.ore

go

n.g

ov/O

HP

PR

/HR

C/E

vid

ence_

Base

d_R

eport

s.s

htm

l

hpla

n/g

uid

es/p

harm

acy/c

linic

al.htm

l

4. Is th

e p

atient

una

ble

to t

ake p

refe

rred o

ral a

ntico

ag

ula

nts

du

e to o

ne

of

the

follo

win

g:

- u

nsta

ble

IN

R

- a

llerg

y

- c

ontr

ain

dic

atio

ns to t

hera

py

- d

rug-d

rug

in

tera

ctions

- into

lera

ble

sid

e e

ffects

Yes:

Appro

ve f

or

up t

o 1

yr.

N

o:

Den

y. R

ecom

mend trial

of

pre

ferr

ed a

ntico

agu

lants

.

Refe

renc

es

1.

Pr

oduc

t Inf

orm

atio

n fo

r Xa

relto

®. J

anss

en P

harm

aceu

tical

s, In

c. T

itusv

ille,

NJ.

2011

.

2.

Eri

ksso

n B,

Bor

ris

L, F

ried

man

R, e

t al.

Riv

arox

aban

Ver

sus

Enox

apar

in fo

r Th

rom

bopr

ophy

laxi

s A

fter

Hip

Art

hrop

last

y. N

Eng

l J M

ed 2

008;

358:

2765

-75.

3.

Ka

kkar

A,

Bren

ner

B, D

ahl O

, et

al.

Ext

ende

d D

urat

ion

Riva

roxa

ban

Vers

us S

hort

-ter

m E

noxa

pari

n Fo

r Th

e Pr

even

tion

of

Veno

us T

hrom

boem

bolis

m A

fter

Tot

al H

ip

Art

hrop

last

y: A

Dou

ble-

blin

d, R

ando

mis

ed, C

ontr

olle

d Tr

ial.

Lan

cet 2

008;

372:

31-3

9.

4.

Lass

en M

, Age

no W

, Bor

ris

L, e

t al.

Riv

arox

aban

Ver

sus

Enox

apar

in F

or T

hrom

bopr

ophy

laxi

s A

fter

Tot

al K

nee

Art

hrop

last

y. N

Eng

l J M

ed 2

008;

358:

2776

-86.

5.

Tu

rpie

A, L

asse

n M

, Dav

idso

n B,

et

al.

Riva

roxa

ban

Ver

sus

Enox

apar

in F

or T

hrom

bopr

ophy

laxi

s A

fter

Tot

al K

nee

Art

hrop

last

y (R

ECO

RD4)

: A R

ando

mis

ed T

rial

. La

ncet

20

09;3

73:1

673-

80.

6.

Pate

l M, M

ahaf

fey

K, G

arg

J, et

al.

Riv

arox

aban

Ver

sus

War

fari

n In

Non

valv

ular

Atr

ial F

ibri

llatio

n. N

Eng

l J M

ed 2

011;

365:

883-

891.

7.

Th

e Ei

nste

in In

vest

igat

ors.

Ora

l Riv

arox

aban

for

Sym

ptom

atic

Ven

ous

Thro

mbo

embo

lism

. N

Eng

l J M

ed 2

010;

363:

2499

-510

. 8.

M

ega

J, Br

aunw

ald

E, W

ivio

tt S

, et a

l. R

ivar

oxab

an in

Pat

ient

s w

ith a

Rec

ent A

cute

Cor

onar

y Sy

ndro

me.

N E

ngl J

Med

201

1; N

EJM

oa11

1227

7.

9.

Am

eric

an A

cade

my

of O

rtho

paed

ic S

urge

ons.

Pre

vent

ing

Ven

ous

Thro

mbo

embo

lic D

isea

se in

Pat

ient

s U

nder

goin

g El

ectiv

e H

ip a

nd K

nee

Art

hrop

last

y Ev

iden

ce-B

ased

G

uide

line

and

Evid

ence

Rep

ort,

201

1. (

Acc

esse

d O

ctob

er 2

7, 2

011,

at h

ttp:

//w

ww

.aao

s.or

g/re

sear

ch/g

uide

lines

/VTE

/VTE

_ful

l_gu

idel

ine.

pdf.)

10

. H

irsh

J,

Guy

att

G,

Alb

ers

G,

et a

l. E

xecu

tive

Sum

mar

y:

Am

eric

an C

olle

ge o

f Ch

est

Phys

icia

ns E

vide

nce-

Base

d Cl

inic

al P

ract

ice

Gui

delin

es (

8th E

ditio

n).

Che

st

2008

;133

;71S

-109

S.

11.

Sing

er D

E, A

lber

s G

W, D

alen

JE, e

t al.

Ant

ithro

mbo

tic th

erap

y in

atr

ial f

ibri

llatio

n. C

HES

T. 2

008;

133(

6): 5

46S-

592S

.

98 of 187

http://www.oregon.gov/OHPPR/HRC/Evidence_Based_Reports.shtml�

http://www.aaos.org/research/guidelines/VTE/VTE_full_guideline.pdf�

Gen

eric

Nam

e: R

ivar

oxab

an

R

evie

w D

ate:

Janu

ary

2011

23

Aut

hor:

Kat

hy S

ente

na

12.

Gag

e BF

, W

ater

man

AD

, Sh

anno

n W

, et

al.

Valid

atio

n of

clin

ical

cla

ssifi

catio

n sc

hem

es f

or p

redi

ctin

g st

roke

. Re

sult

s fr

om t

he N

atio

nal R

egis

try

of A

tria

l Fib

rilla

tion.

JA

MA

. 200

1;28

64-7

0.

13.

Vard

i M, Z

ittan

E, B

itter

man

H, e

t al

. Su

bcut

aneo

us u

nfra

ctio

nate

d he

pari

n fo

r th

e in

itia

l tre

atm

ent

of v

enou

s th

rom

boem

bolis

m.

Coch

rane

Dat

abas

e of

Sys

tem

atic

Re

view

s. 2

009,

Issu

e 4.

14

. Se

rebr

uany

VL.

Vie

wpo

int:

par

adox

ical

exc

ess

mor

talit

y in

PLA

TO tr

ial s

houl

d be

inde

pend

ently

ver

ified

. T

hrom

b H

aem

ost 2

011;

105

: 752

-759

.

15.

Alb

ers

GW

, Am

aren

co P

, Eas

ton

JD, S

acco

RL,

Tea

l P. A

ntith

rom

botic

and

Thr

ombo

lytic

The

rapy

for

Isch

emic

Str

oke:

Am

eric

an C

olle

ge o

f Che

st P

hysi

cian

s Ev

iden

ce-

Base

d Cl

inic

al P

ract

ice

Gui

delin

es (8

th E

ditio

n). C

hest

. 200

8;13

3(6

Supp

l):63

0S-6

69S.

16

. A

nder

son

JL, A

dam

s CD

, Ant

man

EM

, Bri

dges

CR,

Cal

iff R

M, e

t al.

ACC

/AH

A 2

007

Gui

delin

es fo

r th

e M

anag

emen

t of P

atie

nts

With

Uns

tabl

e A

ngin

a/N

on-S

T-El

evat

ion

Myo

card

ial I

nfar

ctio

n: A

Rep

ort o

f the

Am

eric

an C

olle

ge o

f Car

diol

ogy/

Am

eric

an H

eart

Ass

ocia

tion

Task

For

ce o

n Pr

acti

ce G

uide

lines

(Wri

ting

Com

mitt

ee to

Rev

ise

the

2002

Gui

delin

es fo

r th

e M

anag

emen

t of P

atie

nts

With

Uns

tabl

e A

ngin

a/N

on-S

T-El

evat

ion

Myo

card

ial I

nfar

ctio

n). C

ircul

atio

n. 2

007;

116(

7):e

148-

e304

17

. Ki

ng S

I, Sm

ith S

J, H

irsh

feld

JJ, J

acob

s A

, Mor

riso

n D

, et a

l. 20

07 F

ocus

ed U

pdat

e of

the

ACC

/AH

A/S

CAI 2

005

Gui

delin

e U

pdat

e fo

r Pe

rcut

aneo

us C

oron

ary

Inte

rven

tion:

A

Repo

rt o

f the

Am

eric

an C

olle

ge o

f Car

diol

ogy/

Am

eric

an H

eart

Ass

ocia

tion

Task

For

ce o

n Pr

actic

e G

uide

line.

Circ

ulat

ion.

200

8;11

7:26

1-29

5.

18.

Kush

ner

F, H

and

M, S

mith

SJ,

et a

l. 20

09 fo

cuse

d up

date

s: A

CC/A

HA

gui

delin

es fo

r th

e m

anag

emen

t of p

atie

nts

with

ST-

elev

atio

n m

yoca

rdia

l inf

arct

ion

(upd

atin

g th

e 20

04 g

uide

line

and

2007

focu

sed

upda

te) a

nd A

CC/A

HA

/SCA

I gui

delin

es o

n pe

rcut

aneo

us c

oron

ary

inte

rven

tion

(upd

atin

g th

e 20

05 g

uide

line

and

2007

focu

sed

upda

te):

a re

port

of t

he A

mer

ican

Col

lege

of C

ardi

olog

y Fo

unda

tion/

Am

eric

an H

eart

Ass

ocia

tion

Task

For

ce o

n Pr

actic

e G

uide

lines

. J A

m C

oll C

ardi

ol. 2

009;

54(2

3):2

205-

2241

. 19

. So

bel M

, Ver

haeg

he R

, Am

eric

an C

olle

ge o

f Che

st P

hysi

cian

s. A

ntith

rom

botic

ther

apy

for p

erip

hera

l arte

ry o

cclu

sive

dis

ease

: Am

eric

an C

olle

ge o

f Che

st P

hysi

cian

s Ev

iden

ce-B

ased

Clin

ical

Pra

ctic

e G

uide

lines

(8th

Edi

tion)

. Che

st. Ju

n 20

08;1

33(6

Sup

pl):8

15S-

843S

. 20

. Ri

varo

xaba

n, F

DA

Cen

ter

for

Dru

g Ev

alua

tion

and

Rese

arch

.Med

ical

Rev

iew

Doc

umen

t. J

uly

1, 2

011.

Acc

esse

d 9/

14/1

1.

http

://w

ww

.acc

essd

ata.

fda.

gov/

drug

satf

da_d

ocs/

nda/

2011

/022

406O

rig1

s000

TOC.

cfm

. 21

. N

degw

a S,

Mou

lton

K, A

rgáe

z C.

Dab

igat

ran

or R

ivar

oxab

an V

ersu

s O

ther

Ant

icoa

gula

nts

for

Thro

mbo

prop

hyla

xis

Aft

er M

ajor

Ort

hope

dic

Surg

ery:

Sys

tem

atic

Rev

iew

of

Com

para

tive

Clin

ical

-Eff

ecti

vene

ss a

nd S

afet

y. O

ttaw

a: C

anad

ian

Age

ncy

for

Dru

gs a

nd T

echn

olog

ies

in H

ealth

; 200

9.

22.

Eere

nber

g ES

, Kam

phui

sen

PW, S

ijpke

ns M

K, M

eije

rs JC

, Bul

ler

HR,

Lev

i M.

Reve

rsal

of r

ivar

oxab

an a

nd d

abig

atra

n by

pro

thro

mbi

n co

mpl

ex c

once

ntra

te: a

ran

dom

ized

, pl

aceb

o-co

ntro

lled,

cro

ssov

er s

tudy

in h

ealth

y su

bjec

ts.

Circ

ulat

ion

2011

:124

: 157

3-79

. 23

. D

elou

gher

y TG

. Pr

actic

al A

spec

ts o

f the

Ora

l New

Ant

icoa

gula

nts.

Am

J H

emat

ol 2

011;

86:5

86-9

0.

99 of 187

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022406Orig1s000TOC.cfm�

http://www.ncbi.nlm.nih.gov.liboff.ohsu.edu/pubmed?term=%22Eerenberg%20ES%22%5BAuthor%5D�

http://www.ncbi.nlm.nih.gov.liboff.ohsu.edu/pubmed?term=%22Kamphuisen%20PW%22%5BAuthor%5D�

http://www.ncbi.nlm.nih.gov.liboff.ohsu.edu/pubmed?term=%22Sijpkens%20MK%22%5BAuthor%5D�

http://www.ncbi.nlm.nih.gov.liboff.ohsu.edu/pubmed?term=%22Meijers%20JC%22%5BAuthor%5D�

http://www.ncbi.nlm.nih.gov.liboff.ohsu.edu/pubmed?term=%22Buller%20HR%22%5BAuthor%5D�

http://www.ncbi.nlm.nih.gov.liboff.ohsu.edu/pubmed?term=%22Levi%20M%22%5BAuthor%5D�

D

rug

Use

Res

earc

h &

Man

agem

ent P

rogr

am

Ore

gon

Stat

e U

nive

rsity

, 500

Sum

mer

Stre

et N

E, E

35, S

alem

, Ore

gon

9730

1-10

79

Phon

e 50

3-94

5-52

20 |

Fax

503-

947-

1119

1 H

epat

itis

C C

lass

Rev

iew

M

onth

/Yea

r of

Rev

iew

: Ja

nuar

y 20

12

PDL

Clas

s: H

epat

itis

C A

gent

s Su

gges

ted

Revi

sion

: Ex

pand

cur

rent

Hep

atiti

s C

PDL

clas

s to

incl

ude

all a

gent

s fo

r tre

atm

ent o

f Chr

onic

Hep

atiti

s C

(CH

C) V

irus

Cu

rren

t St

atus

of P

DL

Clas

s:

PA C

rite

ria

for P

egyl

ated

Inte

rfer

on a

nd R

ibav

irin

(App

endi

x 1)

Pr

efer

red

Age

nts:

Peg

asys

(peg

inte

rfer

on a

lfa 2

a), P

egin

tron

(peg

inte

rfer

on a

lfa 2

b)

Back

grou

nd:

Hep

atiti

s C

viru

s (H

CV) i

nfec

tion

is th

e le

adin

g ca

use

of c

hron

ic li

ver d

isea

se a

nd d

eath

from

live

r dis

ease

and

lead

ing

indi

catio

n fo

r liv

er

tran

spla

ntat

ion

in th

e U

nite

d St

ates

(U.S

.). T

here

fore

, the

goa

l of t

hera

py fo

r H

CV in

fect

ion

is to

pre

vent

com

plic

atio

ns a

nd d

eath

.1 A

n es

timat

ed 1

80 m

illio

n pe

ople

wor

ldw

ide

are

infe

cted

with

HCV

. The

pre

vale

nce

of H

CV in

fect

ion

in th

e U

.S. b

etw

een

1999

and

200

2 w

as 1

.6%

, or

abo

ut 4

.1 m

illio

n pe

ople

pos

itive

for h

epat

itis

C an

tibod

y (a

nti-H

CV).1

Abo

ut 5

5% to

85%

of t

hose

who

dev

elop

acu

te h

epat

itis

C re

mai

n in

fect

ed, r

athe

r tha

n ac

hiev

e sp

onta

neou

s re

solu

tion.

1 An

estim

ated

15

to 3

0%

of p

atie

nts

with

CH

C de

velo

p ci

rrho

sis

with

in 3

0 ye

ars.

One

to th

ree

perc

ent o

f pat

ient

s pe

r ye

ar w

ith H

CV-r

elat

ed c

irrh

osis

dev

elop

hep

atoc

ellu

lar

carc

inom

a.2

U.S

. gui

delin

es h

ave

reco

mm

ende

d co

mbi

natio

n pe

gint

erfe

ron

alfa

(P) a

nd r

ibav

irin

(R) a

s th

e st

anda

rd o

f car

e (S

OC)

for C

HC,

with

the

optim

al

dura

tion

of tr

eatm

ent b

ased

on

vira

l gen

otyp

e. R

espo

nse

to tr

eatm

ent (

i.e.,

SVR)

with

SO

C is

abo

ut 5

0% fo

r Cau

casi

ans

and

30%

for A

fric

an-

Am

eric

ans.

Gui

delin

es fo

r tr

eatin

g H

CV g

enot

ype

1 (H

CV-1

) wer

e up

date

d in

fall

2011

, fol

low

ing

FDA

app

rova

l of t

he d

irec

t act

ing

antiv

iral

s (D

AA

) bo

cepr

evir

(BO

C) a

nd te

lapr

evir

(TVR

).1,2

HVC

is c

lass

ified

into

at l

east

6 m

ajor

gen

otyp

es: g

enot

ype

1 (w

ith s

ubty

pes

1a a

nd 1

b), w

hich

is th

e m

ost c

omm

on in

the

U.S

.; ge

noty

pes

2 an

d 3,

w

hich

are

the

next

mos

t com

mon

; and

gen

otyp

es 4

, 5, a

nd 6

, whi

ch a

re, t

hus

far,

the

leas

t com

mon

.1 Gen

otyp

e 1

acco

unts

for

>70%

of C

HC

in th

e

100 of 187

2 U

.S. a

nd E

urop

e an

d ha

s th

e po

ores

t res

pons

e to

trea

tmen

t. G

enot

ypin

g H

CV is

use

ful f

or p

redi

ctin

g th

e lik

elih

ood

of r

espo

nse

to a

nd d

urat

ion

of

ther

apy.

3 A

ccor

ding

to A

ASL

D g

uide

lines

, wid

ely

acce

pted

cri

teri

a fo

r CH

C tr

eatm

ent i

nclu

de H

CV R

NA

seru

m p

ositi

ve, s

igni

fican

t fib

rosi

s, c

ompe

nsat

ed li

ver

dise

ase,

acc

epta

ble

bloo

d an

d bi

oche

mis

try

indi

ces,

will

ingn

ess

to b

e ad

here

nt to

ther

apy,

and

no

cont

rain

dica

tions

. Crit

eria

con

trai

ndic

atin

g th

erap

y in

clud

e un

cont

rolle

d m

ajor

dep

ress

ion,

sol

id o

rgan

tran

spla

nt, a

utoi

mm

une

hepa

titis

or

auto

imm

une

cond

ition

exa

cerb

ated

by

PR,

untr

eate

d th

yroi

d di

seas

e, p

regn

ancy

, ina

dequ

ate

cont

race

ptio

n, s

ever

e co

ncur

rent

med

ical

illn

esse

s, a

ge <

2, a

nd h

yper

sens

itivi

ty to

dru

g th

erap

ies.

How

ever

, the

se a

re n

ot a

bsol

ute

and

clin

ical

judg

men

t sho

uld

be e

xerc

ised

in e

ach

case

.1

Sust

aine

d vi

rolo

gic

resp

onse

(SVR

) is

asso

ciat

ed w

ith p

erm

anen

t viro

logi

c cu

re, l

ong-

term

cle

aran

ce o

f HCV

infe

ctio

n, a

s w

ell a

s im

prov

ed m

orbi

dity

an

d m

orta

lity

in th

e va

st m

ajor

ity o

f pat

ient

s. R

VR p

redi

cts

a hi

gh li

kelih

ood

of a

chie

ving

an

SVR.

Tho

se w

ho a

chie

ve a

n RV

R ha

ve a

n SV

R ra

te o

f ab

out 9

0%; h

owev

er, o

nly

15%

to 2

0% o

f tho

se w

ith H

CV-1

infe

ctio

n ac

hiev

e RV

R w

ith p

egin

terf

eron

alfa

. Ear

ly v

irolo

gic

resp

onse

(EVR

) is

the

mos

t ac

cura

te p

redi

ctor

of n

on-r

espo

nse,

as

97 to

100

% o

f tre

atm

ent-

naïv

e H

CV-1

pat

ient

s w

ho fa

il to

reac

h EV

R fa

il to

ach

ieve

SVR

. Whi

le e

nd-o

f-tr

eatm

ent r

espo

nse

(ETR

) is

an in

accu

rate

pre

dict

or o

f ach

ievi

ng S

VR, E

TR is

nec

essa

ry fo

r SV

R to

occ

ur.1,

4 O

n-tr

eatm

ent v

iral

kin

etic

s is

use

d to

gui

de th

e du

ratio

n of

ther

apy.

4 Stu

dies

hav

e pr

evio

usly

est

ablis

hed

patie

nts

with

HCV

-1 s

houl

d be

trea

ted

for

48 w

eeks

with

PEG

-2a

(180

µg/

wee

k sc

) plu

s w

eigh

t-ba

sed

RIB

(100

0 or

120

0 m

g pe

r day

) or P

EG-2

b (1

.5 µ

g/kg

sc)

plu

s w

eigh

t-ba

sed

RIB

(800

mg,

10

00 m

g, 1

200

mg,

or

1400

mg)

.7 Tre

atm

ent m

ay b

e di

scon

tinue

d in

pat

ient

s w

ho d

o no

t ach

ieve

EVR

. For

ty to

fift

y pe

rcen

t of p

atie

nts

with

HCV

-1

trea

ted

with

PEG

and

the

stan

dard

wei

ght-

base

d do

se o

f RIB

for 4

8 w

eeks

ach

ieve

SVR

. The

two

FDA

-app

rove

d PE

Gs

(Peg

asys

, Roc

he, a

nd

PegI

ntro

n, M

erck

) hav

e ha

d si

mila

r ef

ficac

y an

d sa

fety

pro

files

in h

ead-

to-h

ead

com

pari

sons

.4 Su

mm

ary:

Th

e st

anda

rd o

f car

e fo

r th

e tr

eatm

ent

of C

hron

ic H

epat

itis

C (C

HC)

has

bee

n pe

gyla

ted

inte

rfer

on (a

lfa 2

a or

alfa

2b)

in c

ombi

natio

n w

ith w

eigh

t-ba

sed

ribav

irin

(PR

) fo

r ei

ther

48

wee

ks o

r 24

wee

ks d

epen

ding

on

geno

type

1 . The

Am

eric

an A

ssoc

iatio

n fo

r th

e St

udy

of L

iver

Dis

ease

rec

ently

pu

blis

hed

an u

pdat

e on

the

tre

atm

ent

of g

enot

ype

1 ch

roni

c he

patit

is c

vir

us in

fect

ion

guid

elin

es t

o in

clud

e th

e ne

w d

irect

act

ing

antiv

iral

(D

AA)

ag

ents

of

BOC

and

TVR.

2 Th

ese

wer

e ba

sed

on a

rev

iew

and

ana

lysi

s of

pub

lishe

d lit

erat

ure,

gui

delin

e po

licie

s, a

nd e

xper

t op

inio

n.

Ther

e is

ev

iden

ce s

how

ing

a si

gnifi

cant

impr

ovem

ent

in S

VR r

ates

in p

atie

nts

with

gen

otyp

e 1

CHC

but

the

guid

elin

es s

tate

tha

t th

e re

com

men

datio

ns a

re

base

d on

new

dat

a th

at i

s st

ill q

uite

lim

ited

and

as m

ore

stud

ies

are

cond

ucte

d an

d be

com

e av

aila

ble

the

reco

mm

enda

tions

may

nee

d to

be

reco

nsid

ered

.2 Bot

h BO

C an

d TV

R ha

ve e

vide

nce

show

ing

a si

gnifi

cant

impr

ovem

ent

in d

emon

stra

ting

high

er r

ates

of v

irol

ogic

res

pons

e co

mpa

red

with

the

cur

rent

sta

ndar

d of

tre

atm

ent

and

also

bot

h in

pat

ient

s w

ho h

ad p

revi

ousl

y fa

iled

dual

the

rapy

, but

at

a si

gnifi

cant

ly h

ighe

r co

st a

nd w

ith

safe

ty c

once

rns

incl

udin

g an

emia

, dru

g in

tera

ctio

ns, s

kin

rash

es, a

nd a

dver

se e

vent

s5 .

The

upda

ted

guid

elin

es s

tate

:

101 of 187

3 1.

The

opt

imal

ther

apy

for g

enot

ype

1, c

hron

ic H

CV in

fect

ion

is th

e us

e of

boc

epre

vir o

r tel

apre

vir i

n co

mbi

natio

n w

ith p

egin

terf

eron

alfa

and

rib

aviri

n. (C

lass

1, L

evel

A)

2. B

ocep

revi

r and

tela

prev

ir sh

ould

not

be

used

wit

hout

peg

inte

rfer

on a

lfa a

nd w

eigh

t-ba

sed

ribav

irin.

(Cla

ss 1

, Lev

el A

). Th

e co

mbi

natio

n of

peg

ylat

ed in

terf

eron

and

rib

avir

in r

emai

ns t

he s

tand

ard

of c

are

for

all o

ther

gen

otyp

es.1 O

rego

n re

view

ed t

he in

terf

eron

s fo

r CH

C pr

evio

usly

and

dev

elop

ed P

A c

rite

ria

for

trea

tmen

t w

ith p

egin

terf

eron

and

rib

avir

in s

how

n in

App

endi

x 1.

Bo

th P

eg-In

tron

and

Peg

asys

are

lis

ted

as p

refe

rred

age

nts.

The

re is

com

para

tive

effe

ctiv

enes

s ev

iden

ce d

emon

stra

ting

that

the

re a

re n

o si

gnifi

cant

diff

eren

ces

in e

ffic

acy

or s

afet

y be

twee

n th

e tw

o ag

ents

.4 The

intr

oduc

tion

of t

hese

long

-act

ing

pegi

nter

fero

ns h

as b

ecom

e th

e st

anda

rd o

f car

e an

d ha

ve r

epla

ced

the

olde

r no

n-pe

gyla

ted

infe

rero

ns1 .

In 2

010,

the

FD

A a

ppro

ved

an e

xpan

ded

indi

catio

n fo

r in

terf

eron

alfa

con-

1 (In

ferg

en)

for

retr

eatm

ent

of C

HC

in c

ombi

natio

n w

ith r

ibav

irin

aft

er

failu

re t

o pr

evio

us t

reat

men

t w

ith a

peg

ylat

ed in

terf

eron

and

rib

avir

in6 .

Thi

s ap

prov

al w

as b

ased

on

a si

ngle

stu

dy (

DIR

ECT

tria

l) w

hich

was

a

rand

omiz

ed, o

pen-

labe

l, st

udy

com

pari

ng t

he s

afet

y an

d ef

ficac

y of

tw

o do

ses

of in

terf

eron

alfa

con-

1 pl

us r

ibav

irin

in p

revi

ous

nonr

espo

nder

s4 . Th

e AA

SLD

gui

delin

es d

o no

t dem

onst

rate

any

rol

e of

inte

rfer

on a

lfaco

n-1

in th

e tr

eatm

ent o

f CH

C an

d th

ere

is li

mite

d da

ta to

sup

port

its

use.

Th

ere

is c

urre

ntly

no

com

para

tive

evid

ence

eva

luat

ing

if th

ere

is a

diff

eren

ce in

eith

er e

ffic

acy

or s

afet

y be

twee

n BO

C an

d TV

R.

Ther

e w

ere

also

di

ffer

ence

s in

how

the

dru

g st

udie

s w

ere

cond

ucte

d as

wel

l as

maj

or d

iffer

ence

s in

sid

e ef

fect

pro

files

, mak

ing

a di

rect

com

pari

son

diff

icul

t. O

nly

tela

prev

ir w

as s

tudi

ed in

pri

or n

ull r

espo

nder

s to

PR

ther

apy,

BO

C w

as s

tudi

ed in

com

bina

tion

with

peg

inte

rfer

on a

lfa-2

b w

hile

TVR

was

giv

en w

ith

pegi

nter

fero

n al

fa-2

a, a

nd a

lthou

gh t

here

is a

hig

h in

cide

nce

of a

nem

ia a

ssoc

iate

d w

ith b

oth

drug

s it

was

man

aged

diff

eren

tly in

clin

ical

tri

als.

Use

of

ery

thro

poie

tin s

timul

atin

g ag

ents

(ES

As)

was

exc

lude

d fr

om T

VR s

tudi

es w

hile

ESA

s w

ere

allo

wed

for

the

man

agem

ent

of a

nem

ia a

t th

e di

scre

tion

of th

e cl

inic

ian

in th

e BO

C st

udie

s.2,

3 Ong

oing

stu

dies

are

furt

her

eval

uatin

g ho

w t

he m

anag

emen

t of

ane

mia

incl

udin

g ES

A u

se o

r R

dose

re

duct

ion

affe

cts

outc

omes

with

BO

C tr

eatm

ent.

Re

com

men

dati

ons:

• Ex

pand

cur

rent

Hep

atiti

s C

antiv

iral

PD

L cl

ass

to in

clud

e al

l age

nts

for t

reat

men

t of C

hron

ic H

epat

itis

C Vi

rus

•

Reco

mm

end

to m

aint

ain

eith

er o

ne o

r bo

th o

f peg

inte

rfer

on a

lfa-2

a (P

egas

ys) a

nd p

egin

terf

eron

alfa

-2b

(Peg

Intr

on) a

s pr

efer

red

pegy

late

d in

terf

eron

pro

duct

s de

pend

ing

on p

rice

. Th

ese

two

agen

ts a

re r

ecom

men

ded

in t

he c

urre

nt g

uide

lines

and

hav

e sh

own

to b

e si

mila

r in

te

rms

of s

afet

y an

d ef

ficac

y.

• D

esig

nate

int

erfe

ron

alfa

con-

1 (In

ferg

en)

as a

non

-pre

ferr

ed a

gent

due

to

the

lack

of

reco

mm

enda

tions

for

use

in

curr

ent

trea

tmen

t gu

idel

ines

. •

Dev

elop

PA

cri

teri

a to

sup

port

the

jud

icio

us u

se o

f th

e or

al p

rote

ase

inhi

bito

rs i

n pa

tient

s w

ith g

enot

ype

1 CH

C in

com

bina

tion

with

pe

gyla

ted

inte

rfer

on a

nd r

ibav

irin

.

102 of 187

4 A

PPEN

DIX

1: P

rior

aut

hori

zatio

n cr

iteri

a fo

r pe

gyla

ted

inte

rfer

on a

nd ri

bavi

rin

Peg

yla

ted

In

terf

ero

n a

nd

Rib

avir

in

Go

al(

s):

C

ov

er

dru

gs o

nly

fo

r th

os

e c

lien

ts w

here

th

ere

is m

ed

ical

ev

iden

ce o

f eff

ecti

ven

ess a

nd

safe

ty

L

en

gth

of

Au

tho

rizati

on

: 16 w

eeks p

lus 1

2-3

6 a

dd

itio

nal w

eeks o

r 12 m

on

ths

Req

uir

es p

a:

All

dru

gs in

HIC

3 =

W5G

A

pp

rov

al

Cri

teri

a

1. Is p

egin

terf

ero

n r

equeste

d p

refe

rred?

Y

es:

Go to #

3.

No

: G

o to #

2.

2. W

ill the p

rescrib

er

consid

er

a c

ha

ng

e to a

pre

ferr

ed

pro

duct?

M

essage:

- P

refe

rred p

rod

ucts

are

evid

ence-b

ased

re

vie

we

d f

or

com

para

tive e

ffectiven

ess &

safe

ty b

y t

he

Hea

lth R

esourc

es

Com

mis

sio

n (

HR

C).

R

eport

s a

re a

vaila

ble

at:

http://w

ww

.ore

go

n.g

ov/O

HP

PR

/HR

C/E

vid

ence_

Base

d_R

eport

s.s

htm

l

Yes:

Info

rm p

rovid

er

of

covere

d

altern

atives in c

lass.

http://w

ww

.ore

go

n.g

ov/D

HS

/he

althp

lan/too

ls_pro

v/p

dl.shtm

l.

No

: G

o to #

3.

3. Is

the

requ

est fo

r tr

eatm

ent of

Chro

nic

H

epatitis C

?

Docum

ent appro

pri

ate

IC

D9 c

ode:

(571.4

0; 5

71.4

1;

571.4

9)

Yes:

Go to #

4.

No

: G

o to #

10

4. Is th

e r

eq

uest fo

r contin

uation o

f th

era

py? (

Patien

t has b

een o

n H

CV

tre

atm

ent

in t

he p

rece

din

g 1

2 w

eeks a

ccord

ing

to t

he R

x p

rofile

) Y

es:

Go to “

Continu

ation o

f T

hera

py”

. N

o:

Go to #

5

5. D

oes the p

atien

t ha

ve

a h

isto

ry o

f tr

eatm

ent

with p

revio

us p

eg

yla

ted

inte

rfero

n-

riba

virin

com

bin

ation t

reatm

ent?

V

erify

by r

evie

win

g m

em

ber’s R

x p

rofile

for

PE

G-I

ntr

on o

r P

egasys, P

LU

S r

ibavirin

his

tory

. D

oes n

ot

inclu

de p

rior

trea

tment w

ith inte

rfero

n

monoth

era

py o

r n

on

-pe

gyla

ted inte

rfero

n.

Yes:

Forw

ard

to D

MA

P

Med

ical D

irecto

r N

o:

Go to #

6

6. D

oes the

patie

nt h

ave a

ny o

f th

e f

ollo

win

g c

ontr

ain

dic

ations t

o th

e u

se o

f in

terf

ero

n-r

ibavirin

th

era

py?

•

severe

or

uncontr

olle

d p

sychia

tric

dis

ord

er

• decom

pensate

d c

irrh

osis

or

hep

atic

enceph

alo

path

y

• he

mog

lobi

nopa

thyc

yto

pen

ias

• untr

eate

d h

ypert

hyro

idis

m

• severe

rena

l im

pairm

ent o

r tr

anspla

nt

Yes:

Den

y;

Pass to R

PH

(M

edic

al A

ppro

pria

ten

ess)

No

: G

o to #

7

103 of 187



5

• auto

imm

une d

isease

•

pre

gn

ancy

• unsta

ble

CV

D

7. If

app

lica

ble

, has t

he p

atient b

een

abstine

nt fr

om

IV

dru

g u

se o

r a

lcoho

l a

buse f

or

≥ 6

mon

ths?

Y

es:

Go to #

8

N

o:

Den

y; P

ass to R

PH

(M

edic

al A

ppro

pria

ten

ess)

8. D

oes the p

atien

t ha

ve

a d

ete

cta

ble

HC

V R

NA

(vira

l lo

ad)

> 5

0IU

/mL? R

ecord

H

CV

RN

A a

nd d

ate

: Y

es:

Go to #

9

N

o:

Den

y; P

ass to R

PH

(M

edic

al A

ppro

pria

ten

ess)

9. D

oes the

patie

nt h

ave a

docum

ente

d H

CV

Gen

oty

pe?

R

ecord

Gen

oty

pe:

Yes:

Ap

pro

ve f

or

16 w

eeks w

ith t

he

follo

win

g r

esponse:

Your

request fo

r has b

een a

ppro

ve

d f

or

an initia

l 16

weeks. S

ubseq

uent

ap

pro

val is

depe

nde

nt o

n d

ocum

enta

tion o

f re

sponse v

ia a

re

peat

viral lo

ad

dem

onstr

ating u

nd

ete

cta

ble

or

2-l

og

reductio

n in H

CV

vira

l lo

ad. P

lease o

rder

a r

epeat

vira

l lo

ad

aft

er

12 w

eeks s

ubm

it lab r

esults a

nd

rele

vant

medic

al

record

s w

ith a

ne

w P

A r

equ

est fo

r contin

uation

thera

py.

Note

: F

or

riba

virin

appro

ve t

he

generi

c o

nly

No

: D

en

y; P

ass to R

PH

(M

edic

al A

ppro

pria

ten

ess)

10. Is

th

e r

eq

uest fo

r P

ega

sys a

nd t

he

tr

eatm

ent of

confirm

ed, com

pensate

d C

hro

nic

He

patitis B

?

Yes:

Go to #

11

No

: D

en

y; P

ass to R

PH

(M

edic

al A

ppro

pria

ten

ess)

11. Is

th

e p

atient curr

ently o

n L

AM

IVU

DIN

E (

EP

IVIR

HB

V),

AD

EF

OV

IR

(HE

PS

ER

A),

EN

TE

CA

VIR

(B

AR

AC

LU

DE

), T

EL

BIV

UD

INE

(T

YZ

EK

A)

and t

he r

eq

uest

is f

or

com

bin

ation P

egasys-o

ral a

gent

thera

py?

Yes:

Den

y;

Pass to R

PH

(M

edic

al A

ppro

pria

ten

ess)

No

: G

o to #

12

12. H

as the m

em

ber

receiv

ed p

revio

us

treatm

ent w

ith

pe

gyla

ted inte

rfero

n?

Yes:

Den

y;

Pass to R

PH

(M

edic

al A

ppro

pria

ten

ess)

Recom

mend:

LA

MIV

UD

INE

(E

PIV

IR H

BV

) A

DE

FO

VIR

(H

EP

SE

RA

)

No

: A

ppro

ve

P

eg

asys #

4 x

1m

l via

ls o

r #

4 x

0.5

ml syri

ng

es p

er

month

for

12 m

onth

s (

maxim

um

per

lifetim

e).

104 of 187

6

Co

nti

nu

ati

on

of

Th

era

py-

HC

V

1. D

oes the c

lient h

ave

unde

tecta

ble

HC

V R

NA

or

at le

ast a 2

-lo

g r

ed

uctio

n

(+/-

on

e s

tan

dard

devia

tio

n)

in H

CV

RN

A

measure

d a

t 12 w

eeks?

Yes:

Appro

ve a

s f

ollo

ws:

Appro

va

l fo

r be

yo

nd q

uan

tity

and d

ura

tion lim

its r

equ

ires a

ppro

va

l fr

om

th

e m

edic

al directo

r.

Gen

oty

pe

A

pp

rov

e f

or

Ap

ply

1 o

r 4

A

n a

dd

itio

nal 3

6

weeks o

r fo

r up to

a

tota

l of

48 w

eeks o

f th

era

py (

wh

iche

ver

is

the lesser

of

the t

wo).

Rib

avirin

qua

ntity

lim

it

of

200 m

g table

ts Q

S#

180 /

25 d

ays (

for

max

daily

dose =

1200

mg).

2 o

r 3

A

n a

dd

itio

nal 1

2

weeks o

r fo

r up to

a

tota

l of

24 w

eeks o

f th

era

py (

wh

iche

ver

is

the lesser

of

the t

wo).

Rib

avirin

qua

ntity

lim

it

of

200 m

g tab Q

S# 1

20

/ 25 d

ays (

for

max d

aily

dose =

80

0 m

g).

For

all

geno

typ

es

and H

IV

co-

infe

ction

An

ad

dit

ion

al 3

6

weeks o

r fo

r up to

a

tota

l of

48 w

eeks o

f th

era

py (

wh

iche

ver

is

the lesser

of

the t

wo)

Rib

avirin

qua

ntity

lim

it

of

200 m

g table

ts Q

S#

180 /

25 d

ays (

for

max

daily

dose =

120

0 m

g).

No

: D

EN

Y

(Medic

al A

ppro

pria

ten

ess)

Tre

atm

ent w

ith p

eg

yla

ted inte

rfero

n-r

ibarv

irin

does n

ot m

eet m

edic

al necessity c

rite

ria b

ecause

th

ere

is p

oor

ch

ance o

f achie

vin

g a

n S

VR

.

Clin

ical

No

tes:

• S

eru

m tra

nsam

inases: U

p t

o 4

0 p

erc

ent

of

clie

nts

with c

hro

nic

hepatitis C

ha

ve

no

rmal seru

m a

lanin

e a

min

otr

ansfe

rase (

ALT

) le

vels

, e

ve

n w

he

n teste

d o

n

multip

le o

ccasio

ns.

• R

NA

: M

ost clie

nts

with c

hro

nic

he

patitis C

ha

ve le

ve

ls o

f H

CV

RN

A (

viral lo

ad)

betw

een 1

00

,00

0 (

10

5)

and 1

0,0

00,0

00

(10

7)

cop

ies p

er

ml. E

xpre

ssed a

s

IU, th

ese a

vera

ges a

re 5

0,0

00 t

o 5

mill

ion IU

. R

ate

s o

f re

sponse to a

co

urs

e o

f p

egin

terf

ero

n-r

iba

virin

are

hig

her

in c

lien

ts w

ith lo

w leve

ls o

f H

CV

RN

A.

There

are

severa

l defin

itio

ns o

f a “

low

level” o

f H

CV

RN

A, b

ut th

e u

su

al defin

itio

n is b

elo

w 8

00,0

00

IU

(~

2 m

illio

n c

opie

s)

per

ml.(5

)

• Liv

er

bio

psy: N

ot n

ecessary

for

dia

gnosis

but

he

lpfu

l fo

r gra

din

g t

he s

everi

ty o

f dis

ease a

nd s

tag

ing

the

de

gre

e o

f fibro

sis

an

d p

erm

anent arc

hitectu

ral

dam

age a

nd

for

rulin

g o

ut o

ther

causes o

f liv

er

dis

ease

, such a

s a

lcoho

lic liv

er

inju

ry, no

na

lcoho

lic f

att

y liv

er

dis

ease,

or

iron

overl

oad.

Sta

ge i

s in

dic

ati

ve o

f fi

bro

sis

:

Gra

de i

s in

dic

ati

ve o

f n

ec

rosis

: S

tag

e 0

N

o f

ibro

sis

Sta

ge 1

E

nla

rgem

ent of

the p

ort

al a

reas b

y f

ibro

sis

Sta

ge 1

N

one

Sta

ge 2

F

ibro

sis

exte

nd

ing o

ut fr

om

the p

ort

al are

as w

ith r

are

bridg

es b

etw

ee

n p

ort

al are

as

S

tag

e 2

M

ild

105 of 187

7

Sta

ge 3

F

ibro

sis

th

at

link u

p p

ort

al a

nd c

entr

al are

as o

f th

e liv

er

S

tag

e 3

M

odera

te

Sta

ge 4

C

irrh

osis

Sta

ge 4

M

ark

ed

Th

e f

ollo

win

g a

re c

on

sid

ere

d in

vesti

gati

on

al

an

d/o

r d

o n

ot

meet

med

ical n

ec

essit

y c

rite

ria:

Tre

atm

ent of

HB

V o

r H

CV

in c

linic

ally

decom

pensate

d c

irrh

osis

T

reatm

ent of

HC

V o

r H

BV

in liv

er

transp

lant

recip

ien

ts

Re-t

reatm

ent of

HC

V o

r H

BV

pre

vio

us n

on

-respo

nders

or

rela

psers

T

reatm

ent of

HC

V o

r H

BV

> 4

8 w

eeks

Tre

atm

ent of

adva

nced r

en

al ce

ll carc

inom

a

Tre

atm

ent of

thro

mbocyto

penia

T

reatm

ent of

hum

an p

apill

om

a v

irus

Tre

atm

ent of m

ultip

le m

ye

lom

a

106 of 187

8 Re

fere

nces

:

1. G

hany

MG

, Str

ader

DB,

Tho

mas

DL,

See

ff L

B. D

iagn

osis

, man

agem

ent,

and

trea

tmen

t of h

epat

itis

C: a

n up

date

. Hep

atol

ogy.

200

9;49

(4):

1335

-137

4.

2. G

hany

MG

, Nel

son

DR,

Str

ader

DB,

Tho

mas

DL,

See

ff L

B. A

n up

date

on

trea

tmen

t of g

enot

ype

1 ch

roni

c he

patit

is C

vir

us in

fect

ion:

201

1 pr

actic

e gu

idel

ine

by th

e A

mer

ican

A

ssoc

iatio

n fo

r th

e St

udy

of L

iver

Dis

ease

s. H

epat

olog

y. 2

011;

54(4

):143

3-14

44.

3. F

ood

and

Dru

g A

dmin

istr

atio

n Ce

nter

for

Dru

g Ev

alua

tion

and

Rese

arch

. App

licat

ion

Num

ber:

202

258O

rig1

s000

sum

mar

y re

view

. Ava

ilabl

e at

: ht

tp:/

/ww

w.a

cces

sdat

a.fd

a.go

v/dr

ugsa

tfda

_doc

s/nd

a/20

11/2

0225

8Ori

g1s0

00Su

mR.

pdf.

Acc

esse

d Se

ptem

ber

26, 2

011.

4.

Ros

en H

RM. C

hron

ic H

epat

itis

C In

fect

ion.

N. E

ngl.

J. M

ed. 2

011;

364(

25):2

429-

38.

5. T

ungo

l A, R

adem

ache

r K,

Sch

afer

JA. F

orm

ular

y m

anag

emen

t of t

he p

rote

ase

inhi

bito

rs b

ocep

revi

r an

d te

lapr

evir

for

chro

nic

hepa

titis

C v

irus

. J M

anag

Car

e Ph

arm

. 20

11;1

7(9)

:685

-694

.

6. In

ferg

en P

acka

ge In

sert

. Kad

mon

Cor

pora

tion,

LLC

. Ava

ilabl

e at

: htt

p://

kadm

on.c

om/f

iles/

infe

rgen

-pi.p

df.

107 of 187

http://kadmon.com/files/infergen-pi.pdf�

D

rug

Use

Res

earc

h &

Man

agem

ent P

rogr

am

Ore

gon

Stat

e U

nive

rsity

, 500

Sum

mer

Stre

et N

E, E

35, S

alem

, Ore

gon

9730

1-10

79

Phon

e 50

3-94

5-52

20 |

Fax

503-

947-

1119

1 M

onth

/Yea

r of

Rev

iew

: Ja

nuar

y 20

12

En

d da

te o

f lit

erat

ure

sear

ch:

4th Q

uart

er 2

011

Gen

eric

Nam

e: T

elap

revi

r M

anuf

actu

rer:

Ver

tex

Phar

mac

eutic

als

Bran

d N

ame:

Inci

vek™

Dos

sier

rec

eive

d: Y

es

PDL

Clas

s: H

epat

itis

C An

tivir

als

Com

para

tor

Ther

apie

s: p

egin

terf

eron

alfa

-2a

plus

rib

avir

in (P

R)

al

one

FDA

App

rove

d In

dica

tion

s:1 T

elap

revi

r is

indi

cate

d in

com

bina

tion

with

peg

inte

rfer

on a

lfa (P

) and

riba

viri

n (R

) for

trea

ting

geno

type

1 c

hron

ic

hepa

titis

C (C

HC)

in a

dult

patie

nts

who

: •

have

com

pens

ated

live

r di

seas

e, in

clud

ing

cirr

hosi

s.

• ar

e tr

eatm

ent-

naïv

e or

pre

viou

sly

have

bee

n tr

eate

d w

ith in

terf

eron

-bas

ed tr

eatm

ent,

incl

udin

g pr

ior n

ull r

espo

nder

s, p

artia

l res

pond

ers,

and

re

laps

ers.

Su

mm

ary:

Am

eric

an A

ssoc

iatio

n fo

r the

Stu

dy o

f Liv

er D

isea

ses

(AA

SLD

) gui

delin

es re

com

men

d tr

iple

ther

apy

with

tela

prev

ir (T

VR )

in c

ombi

natio

n w

ith P

R as

firs

t-lin

e tr

eatm

ent f

or g

enot

ype

1 CH

C. E

vide

nce

for u

se o

f trip

le th

erap

y co

mes

from

six

pha

se 2

and

thre

e ph

ase

3 st

udie

s.2,

3

Mod

erat

e le

vel e

vide

nce

show

s tr

iple

ther

apy

is s

uper

ior t

o PR

ther

apy

at p

rodu

cing

a s

usta

ined

viro

logi

c re

spon

se (S

VR).

The

ADVA

NCE

tria

l est

ablis

hed

that

a tr

eatm

ent r

egim

en in

clud

ing

TVR

for 1

2 w

eeks

and

PR

for 2

4 w

eeks

is s

uper

ior t

o PR

alo

ne in

trea

tmen

t-na

ive

patie

nts

who

hav

e ac

hiev

ed e

xten

ded

rapi

d vi

rolo

gica

l res

pons

e (e

RVR)

by

wee

k 4,

whi

le 4

8 w

eeks

of P

R w

ith 1

2 w

eeks

of T

VR is

rec

omm

ende

d in

pa

tient

s no

t ach

ievi

ng e

RVR.

The

diff

eren

ce in

sus

tain

ed v

irol

ogic

res

pons

e (S

VR) r

ate

for t

ripl

e th

erap

y w

ith 1

2 w

eeks

of T

VR v

ersu

s PR

alo

ne in

tr

eatm

ent-

naïv

e pa

tient

s w

as 3

1%, g

ivin

g a

num

ber

need

ed to

trea

t (N

NT)

of 3

. The

ILLU

MIN

ATE

tria

l est

ablis

hed

trea

ting

trea

tmen

t-na

ïve

patie

nts

who

had

ach

ieve

d eR

VR w

ith m

ore

than

24

wee

ks o

f PR

in c

ombi

natio

n w

ith T

VR p

rovi

ded

no a

dvan

tage

. The

REA

LIZE

tria

l sup

port

s th

e us

e of

TVR

-co

ntai

ning

regi

men

s in

pat

ient

s pr

evio

usly

trea

ted

with

PR

alon

e. A

lthou

gh r

esul

ts v

arie

d ba

sed

on ty

pe o

f pre

viou

s re

spon

se, t

he o

vera

ll di

ffer

ence

in S

VR r

ate

for t

riple

ther

apy

with

12

wee

ks o

f TVR

ver

sus

PR a

lone

in p

revi

ousl

y tr

eate

d pa

tient

s w

as 4

7%, g

ivin

g a

num

ber n

eede

d to

tr

eat (

NN

T) o

f 2.3–

6

108 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

2 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

Dat

a ar

e co

mpe

lling

des

pite

som

e in

tern

al a

nd e

xter

nal v

alid

ity c

once

rns

lead

ing

to “

fair

” qu

ality

ass

essm

ent r

atin

gs fo

r pha

se 3

stu

dies

. Als

o,

ques

tions

are

out

stan

ding

with

rega

rd to

dos

ing

and

resp

onse

in s

peci

al p

opul

atio

ns a

nd w

ith re

gard

to m

anag

ing

ther

apy

in a

gen

eral

clin

ical

se

ttin

g an

d CH

C po

pula

tion,

giv

en th

e ca

refu

l mon

itorin

g fo

r res

pons

e, s

afet

y, a

nd tr

eatm

ent a

dher

ence

requ

ired

for t

hera

py.

The

inci

denc

e of

adv

erse

rea

ctio

ns w

ith tr

iple

ther

apy,

and

eve

n fo

r PR

alon

e, a

re q

uite

hig

h an

d la

rgel

y dr

iven

by

the

rate

s of

ras

h (5

6%),

fatig

ue

(56%

), pr

uritu

s (4

7%),

naus

ea (3

9%),

anem

ia (3

6%),

and

diar

rhea

(26%

). Tr

eatm

ent i

s co

mpl

icat

ed a

nd re

quir

es p

atie

nt a

dher

ence

and

tim

ely

labo

rato

ry m

onito

ring

. Tri

ple

ther

apy

is a

lso

very

exp

ensi

ve n

eces

sita

ting

judi

ciou

s us

e of

thes

e ag

ents

in p

atie

nts.

Th

e be

nefit

s of

trip

le th

erap

y in

clud

e im

prov

ed S

VR r

ates

for p

atie

nts

as a

who

le, i

mpr

oved

SVR

rat

es fo

r diff

icul

t-to

-tre

at p

atie

nts,

sho

rter

du

ratio

n of

ther

apy

for t

reat

men

t-na

ïve

patie

nts

who

ach

ieve

SVR

, and

, a re

-tre

atm

ent o

ptio

n fo

r pat

ient

s w

ho h

ave

faile

d pr

evio

us th

erap

y w

ith

PR.

PDL

Plac

emen

t Re

com

men

dati

on:

• Re

com

men

d TV

R re

quir

e pr

ior a

utho

riza

tion

to li

mit

its u

se to

trea

tmen

t in

geno

type

1 H

CV w

ith c

linic

al, d

ose,

dur

atio

n lim

its (A

ppen

dix

1).

• Co

nsid

er o

ther

con

side

ratio

ns s

uch

as d

urat

ion

of th

erap

y, c

ompl

exity

of d

osin

g re

gim

en, p

ill b

urde

n, s

ide

effe

ct p

rofil

e, a

nd e

vide

nce

in

prev

ious

nul

l res

pond

ers

whe

n ev

alua

ting

both

TVR

and

BO

C.

• D

ue to

hig

h co

st o

f tre

atm

ent a

nd la

ck o

f com

para

tive

effe

ctiv

enes

s ev

iden

ce, r

ecom

men

d ev

alua

ting

OH

A c

osts

for b

oth

BOC

and

TVR

for

cons

ider

atio

n of

OH

A m

anag

emen

t.

BACK

GRO

UN

D/C

URR

ENT

LAN

DSC

APE

CH

C Tr

eatm

ent r

espo

nse

is d

efin

ed b

y su

rrog

ate

bioc

hem

ical

, his

tolo

gica

l, an

d vi

rolo

gica

l par

amet

ers,

rat

her t

han

clin

ical

end

poin

ts s

uch

as li

ver

dise

ase

and

deat

h, b

ecau

se th

e na

tura

l his

tory

of C

HC

evol

ves

over

dec

ades

.7 Sho

rt-t

erm

out

com

es in

clud

e no

rmal

izat

ion

of s

erum

ALT

leve

ls, >

2 po

int i

mpr

ovem

ent i

n ne

croi

nfla

mm

ator

y sc

ore

with

no

wor

seni

ng in

fibr

osis

sco

re, a

nd c

lear

ance

of H

CV R

NA

from

ser

um a

s m

easu

red

by P

CR.7

Viro

logi

cal p

aram

eter

s ar

e di

vide

d in

to th

e fo

llow

ing:

7,8

• su

stai

ned

viro

logi

cal r

espo

nse

(SVR

): th

e ab

senc

e of

HCV

RN

A fr

om s

erum

by

PCR

24 w

eeks

aft

er d

isco

ntin

uing

ther

apy;

•

end-

of-t

reat

men

t res

pons

e (E

TR):

unde

tect

able

viru

s at

the

end

of e

ither

a 2

4-w

eek

or 4

8-w

eek

cour

se o

f the

rapy

; •

rapi

d vi

rolo

gica

l res

pons

e (R

VR):

unde

tect

able

HCV

RN

A a

t wee

k 4

of tr

eatm

ent (

low

er li

mit

of d

etec

tion

50 IU

/mL

by P

CR);

109 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

3 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

• ex

tend

ed r

apid

viro

logi

cal r

espo

nse

(eRV

R): u

ndet

ecta

ble

HCV

RN

A at

wee

ks 4

and

12

(low

er li

mit

of d

etec

tion

10 IU

/mL

by P

CR u

sed

in

AD

VAN

CE tr

ial 6 );

• ea

rly

viro

logi

cal r

espo

nse

(EVR

): a

≥2 lo

g re

duct

ion

in o

r com

plet

e ab

senc

e of

ser

um H

CV R

NA

at w

eek

12 o

f the

rapy

com

pare

d w

ith th

e ba

selin

e le

vel;

• vi

rolo

gica

l bre

akth

roug

h: th

e re

appe

aran

ce o

f HCV

RN

A w

hile

stil

l on

ther

apy;

•

viro

logi

cal r

elap

se: t

he re

appe

aran

ce o

f HCV

RN

A in

ser

um fo

llow

ing

trea

tmen

t dis

cont

inua

tion

and

docu

men

ted

ETR;

•

null

resp

onde

rs: p

atie

nts

who

fail

to s

uppr

ess

seru

m H

CV R

NA

by a

t lea

st 2

logs

aft

er 2

4 w

eeks

of t

hera

py (1

2 w

eeks

in R

EALI

ZE tr

ial5 );

• pa

rtia

l non

-res

pond

ers:

pat

ient

s w

hose

HCV

RN

A le

vels

dec

reas

ed b

y ≥2

logs

IU/m

L bu

t nev

er b

ecam

e un

dete

ctab

le a

t 24

wee

ks (1

2 w

eeks

in

REA

LIZE

tria

l5 ); an

d •

non-

resp

onde

rs: p

atie

nts

who

fail

to c

lear

HCV

RN

A a

fter

24

wee

ks o

f the

rapy

. Si

nce

the

intr

oduc

tion

of D

AA

s, A

ALD

gui

delin

es fr

om th

e ha

ve b

een

upda

ted

and

stat

e:2

1. T

he o

ptim

al th

erap

y fo

r gen

otyp

e 1,

chr

onic

HCV

infe

ctio

n is

the

use

of b

ocep

revi

r or t

elap

revi

r in

com

bina

tion

with

peg

inte

rfer

on a

lfa a

nd

ribav

irin.

(Cla

ss 1

, Lev

el A

) 2.

Boc

epre

vir a

nd te

lapr

evir

shou

ld n

ot b

e us

ed w

itho

ut p

egin

terf

eron

alfa

and

wei

ght-

base

d rib

aviri

n. (C

lass

1, L

evel

A).

AA

SLD

dos

ing

guid

elin

es a

re a

s fo

llow

s:

1. T

he re

com

men

ded

dose

of t

elap

revi

r is

750

mg

adm

inis

tere

d w

ith fo

od (n

ot lo

w-f

at) t

hree

tim

es p

er d

ay (e

very

7-9

hou

rs) t

oget

her w

ith

pegi

nter

fero

n al

fa a

nd w

eigh

t-ba

sed

ribav

irin

for

12 w

eeks

follo

wed

by

an a

dditi

onal

12-

36 w

eeks

of p

egin

terf

eron

alfa

and

rib

aviri

n (C

lass

1, L

evel

A

). 2.

Pat

ient

s w

ithou

t cirr

hosi

s tr

eate

d w

ith te

lapr

evir,

peg

inte

rfer

on, a

nd ri

bavi

rin, w

hose

HCV

RN

A le

vel a

t wee

ks 4

and

12

is u

ndet

ecta

ble

shou

ld b

e co

nsid

ered

for a

sho

rten

ed d

urat

ion

of th

erap

y of

24

wee

ks (C

lass

2a,

Lev

el A

). 3.

Pat

ient

s w

ith c

irrho

sis

trea

ted

with

eith

er b

ocep

revi

r or t

elap

revi

r in

com

bina

tion

with

peg

inte

rfer

on a

nd ri

bavi

rin

shou

ld re

ceiv

e th

erap

y fo

r a

dura

tion

of 4

8 w

eeks

(Cla

ss 2

b, L

evel

B).

4. R

e-tr

eatm

ent w

ith b

ocep

revi

r or t

elap

revi

r, to

geth

er w

ith p

egin

terf

eron

alfa

and

wei

ght-

base

d ri

bavi

rin, c

an b

e re

com

men

ded

for p

atie

nts

who

ha

d vi

rolo

gica

l rel

apse

or

wer

e pa

rtia

l res

pond

ers

afte

r a p

rior c

ours

e of

trea

tmen

t with

sta

ndar

d in

terf

eron

alfa

or p

egin

terf

eron

alfa

and

/or

ribav

irin

(Cla

ss 1

, Lev

el A

). 5.

Re-

trea

tmen

t with

tela

prev

ir, to

geth

er w

ith p

egin

terf

eron

alfa

and

wei

ght-

base

d rib

aviri

n, m

ay b

e co

nsid

ered

for p

rior n

ull r

espo

nder

s to

a c

ours

e of

sta

ndar

d in

terf

eron

alfa

or p

egin

terf

eron

alfa

and

/or w

eigh

t-ba

sed

ribav

irin

(Cla

ss 2

b, L

evel

B).

110 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

4 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

6. R

espo

nse-

guid

ed th

erap

y of

trea

tmen

t-ex

perie

nced

pat

ient

s us

ing

eith

er a

boc

epre

vir-

or t

elap

revi

r-ba

sed

regi

men

can

be

cons

ider

ed fo

r re

laps

ers

(Cla

ss 2

a, L

evel

B fo

r boc

epre

vir;

Cla

ss 2

b, L

evel

C fo

r tel

apre

vir)

, may

be

cons

ider

ed fo

r par

tial r

espo

nder

s (C

lass

2b,

Lev

el B

for b

ocep

revi

r;

Clas

s 3,

Lev

el C

for t

elap

revi

r), b

ut c

anno

t be

reco

mm

ende

d fo

r nul

l res

pond

ers

(Cla

ss 3

, Lev

el C

). A

ALD

rec

omm

enda

tions

with

reg

ard

to s

topp

ing

trea

tmen

t are

as

follo

ws:

1.

Tre

atm

ent w

ith a

ll th

ree

drug

s (t

elap

revi

r, p

egin

terf

eron

alfa

, and

riba

virin

) sho

uld

be s

topp

ed if

the

HCV

RN

A le

vel i

s >1

,000

IU/m

L at

trea

tmen

t w

eeks

4 o

r 12

and/

or d

etec

tabl

e at

trea

tmen

t wee

k 24

(Cla

ss 2

a, L

evel

B).

2. P

atie

nts

re-t

reat

ed w

ith te

lapr

evir

plus

peg

inte

rfer

on a

lfa a

nd ri

bavi

rin w

ho c

ontin

ue to

hav

e de

tect

able

HCV

RN

A >

1,0

00 IU

at w

eeks

4 o

r 12

shou

ld b

e w

ithdr

awn

from

all

ther

apy

beca

use

of th

e hi

gh li

kelih

ood

of d

evel

opin

g an

tivira

l res

ista

nce

(Cla

ss 1

, Lev

el B

). 3.

Pat

ient

s w

ho d

evel

op a

nem

ia o

n pr

otea

se in

hibi

tor-

base

d th

erap

y fo

r chr

onic

hep

atiti

s C

shou

ld b

e m

anag

ed b

y re

duci

ng t

he ri

bavi

rin d

ose

(Cla

ss2a

, Lev

el A

). 4.

Pat

ient

s on

pro

teas

e in

hibi

tor-

base

d th

erap

y sh

ould

und

ergo

clo

se m

onito

ring

of H

CV R

NA

leve

ls a

nd th

e pr

otea

se in

hibi

tors

sho

uld

be

disc

ontin

ued

if bi

olog

ical

bre

akth

roug

h (>

1 lo

g in

crea

se in

ser

um H

CV R

NA

abo

ve n

adir

) is

obse

rved

(Cla

ss 1

,Lev

el A

). 5.

Pat

ient

s w

ho fa

il to

hav

e a

biol

ogic

al re

spon

se, w

hich

exp

erie

nce

biol

ogic

al b

reak

thro

ugh,

or w

ho re

laps

e on

one

pro

teas

e in

hibi

tor s

houl

d no

t be

re-t

reat

ed w

ith th

e ot

her p

rote

ase

inhi

bito

r (Cl

ass

2a, L

evel

C).

AA

SLD

dos

ing

guid

elin

es a

re a

s fo

llow

s:

3. T

he re

com

men

ded

dose

of b

ocep

revi

r is

800

mg

adm

inis

tere

d w

ith fo

od th

ree

times

per

day

(eve

ry 7

-9 h

ours

) tog

ethe

r with

peg

inte

rfer

on a

lfa

and

wei

ght-

base

d rib

aviri

n fo

r 24-

44 w

eeks

pre

cede

d by

4 w

eeks

of l

ead-

in tr

eatm

ent w

ith p

egin

terf

eron

alfa

and

riba

virin

alo

ne (C

lass

1, L

evel

A).

4. P

atie

nts

with

out c

irrho

sis

trea

ted

with

boc

epre

vir,

peg

inte

rfer

on, a

nd r

ibav

irin,

pre

cede

d by

4w

eeks

of l

ead-

in p

egin

terf

eron

and

riba

viri

n, w

hose

H

CV R

NA

leve

l at w

eeks

8 a

nd 2

4 is

und

etec

tabl

e, m

ay b

e co

nsid

ered

for a

sho

rten

ed d

urat

ion

of tr

eatm

ent o

f 28

wee

ks in

tota

l (4

wee

ks le

ad-in

w

ith p

egin

terf

eron

and

riba

virin

follo

wed

by

24 w

eeks

of t

riple

ther

apy)

(Cla

ss 2

a, L

evel

B).

8. P

atie

nts

with

cirr

hosi

s tr

eate

d w

ith e

ither

boc

epre

vir o

r tel

apre

vir i

n co

mbi

natio

n w

ith p

egin

terf

eron

and

riba

viri

n sh

ould

rece

ive

ther

apy

for a

du

ratio

n of

48

wee

ks (C

lass

2b,

Lev

el B

). 10

. Re-

trea

tmen

t with

boc

epre

vir o

r tel

apre

vir,

toge

ther

with

peg

inte

rfer

on a

lfa a

nd w

eigh

t-ba

sed

ribav

irin,

can

be

reco

mm

ende

d fo

r pat

ient

s w

ho

had

viro

logi

cal r

elap

se o

r w

ere

part

ial r

espo

nder

s af

ter a

prio

r cou

rse

of tr

eatm

ent w

ith s

tand

ard

inte

rfer

on a

lfa o

r peg

inte

rfer

on a

lfa a

nd/o

r rib

aviri

n (C

lass

1, L

evel

A).

12. R

espo

nse-

guid

ed th

erap

y of

trea

tmen

t-ex

perie

nced

pat

ient

s us

ing

eith

er a

boc

epre

vir-

or t

elap

revi

r-ba

sed

regi

men

can

be

cons

ider

ed fo

r re

laps

ers

(Cla

ss 2

a, L

evel

B fo

r boc

epre

vir;

Cla

ss 2

b, L

evel

C fo

r tel

apre

vir)

, may

be

cons

ider

ed fo

r par

tial r

espo

nder

s (C

lass

2b,

Lev

el B

for b

ocep

revi

r;

Clas

s 3,

Lev

el C

for t

elap

revi

r), b

ut c

anno

t be

reco

mm

ende

d fo

r nul

l res

pond

ers

(Cla

ss 3

, Lev

el C

). A

ASL

D re

com

men

datio

ns w

ith re

gard

to s

topp

ing

trea

tmen

t are

as

follo

ws:

111 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

5 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

5. T

reat

men

t with

all

thre

e dr

ugs

(boc

epre

vir,

peg

inte

rfer

on a

lfa, a

nd ri

bavi

rin) s

houl

d be

sto

pped

if th

e H

CV R

NA

leve

l is

>100

IU/m

L at

trea

tmen

t w

eek

12 o

r det

ecta

ble

at tr

eatm

ent w

eek

24 (C

lass

2a,

Lev

el B

). 13

. Pat

ient

s re

-tre

ated

with

boc

epre

vir p

lus

pegi

nter

fero

n al

fa a

nd ri

bavi

rin

who

con

tinue

to h

ave

dete

ctab

le H

CV R

NA

>10

0 IU

at w

eek

12

shou

ld b

e w

ithdr

awn

from

all

ther

apy

beca

use

of th

e hi

gh li

kelih

ood

of d

evel

opin

g an

tivira

l res

ista

nce

(Cla

ss 1

, Lev

el B

). 15

. Pat

ient

s w

ho d

evel

op a

nem

ia o

n pr

otea

se in

hibi

tor-

base

d th

erap

y fo

r chr

onic

hep

atiti

s C

shou

ld b

e m

anag

ed b

y re

duci

ng t

he ri

bavi

rin d

ose

(Cla

ss2a

, Lev

el A

). 16

. Pat

ient

s on

pro

teas

e in

hibi

tor-

base

d th

erap

y sh

ould

und

ergo

clo

se m

onito

ring

of H

CV R

NA

leve

ls a

nd th

e pr

otea

se in

hibi

tors

sho

uld

be

disc

ontin

ued

if bi

olog

ical

bre

akth

roug

h (>

1 lo

g in

crea

se in

ser

um H

CV R

NA

abo

ve n

adir

) is

obse

rved

(Cla

ss 1

,Lev

el A

). 17

. Pat

ient

s w

ho fa

il to

hav

e a

biol

ogic

al re

spon

se, w

ho e

xper

ienc

e bi

olog

ical

bre

akth

roug

h, o

r who

rel

apse

on

one

prot

ease

inhi

bito

r sho

uld

not b

e re

-tre

ated

with

the

othe

r pro

teas

e in

hibi

tor (

Clas

s 2a

, Lev

el C

). CL

INIC

AL

PHA

RMA

COLO

GY1

TVR

is a

reve

rsib

le, D

AA

aga

inst

HCV

. TVR

wor

ks b

y se

lect

ivel

y in

hibi

ting

the

HCV

NS3

/4A

ser

ine

prot

ease

, whi

ch is

ess

entia

l for

the

prod

uctio

n of

no

nstr

uctu

ral p

rote

ins

NS4

A, N

S4B,

NS5

A, a

nd N

S5B

and

for

vira

l rep

licat

ion.

Sev

eral

NS3

am

ino

acid

sub

stitu

tions

con

fer

resi

stan

ce to

TVR

. V3

6M/A

/L, T

54A

/S, R

155K

/T, a

nd A

156S

/T v

aria

nts

emer

ged

mos

t fre

quen

tly in

bio

logi

cal f

ailu

re a

nd r

elap

se p

atie

nts.

CO

MPA

RATI

VE

CLIN

ICA

L EF

FICA

CY

Rele

vant

End

poin

ts:

1) S

usta

ined

vir

olog

ical

resp

onse

(SVR

)

2) R

elap

se

3

) With

draw

als

due

to a

dver

se e

ffec

ts

4

) Ane

mia

5) R

ash/

Prur

itus

Prim

ary

Stud

y En

dpoi

nt:

1) S

usta

ined

viro

logi

cal r

espo

nse

112 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

6 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

Evid

ence

Tab

le

Ref./

Stud

y De

sign1

Drug

Reg

imen

s Pa

tient

Pop

ulat

ion

N Du

ratio

n (w

eeks

) Ef

ficac

y Res

ults

2 (C

I, p-v

alues

) AR

R/NN

T3 Sa

fety

Res

ults

^

(CI, p

-valu

es)

ARR/

NN

H4 Qu

ality

Rat

ing/

Com

men

ts

ADVA

NCE

Fair

Jaco

bson

123 c

enter

Phas

e 3

Feb t

o Jun

20

07

RCT,

PC,

DB,

str

atifie

d

1. T

12PR

: tela

prev

ir (T)

(7

50 m

g q8h

) plus

pe

ginter

feron

alfa-

2a (P

) (1

80 μ

g per

wee

k) an

d rib

avirin

(R)

(100

0 mg q

d for

weig

ht <7

5 kg o

r 120

0 mg

qd fo

r weig

ht ≥7

5 mg)

for

12 w

eeks

. Exte

nded

ra

pid vi

rolog

ic re

spon

se

(eRV

R) pa

tients

rece

ived

addit

ional

12 w

eeks

PR

and o

thers

36 w

eeks

2.

T8PR

: T pl

us P

R for

8 w

eeks

then

PR

plus

PLA

for 4

week

s. eR

VR pa

tients

re

ceive

d add

itiona

l 12

week

s PR

and t

he

other

s 36 w

eeks

3.

PR (c

ontro

l): PR

plu

s plac

ebo (

PLA)

12

week

s, the

n PR

for 36

we

eks

Note:

dose

s are

the

same

for e

ach d

rug i

n all

arms

.

Inclu

sion

crite

ria:

• age

d 18–

70

• chr

onic

HCV

geno

type 1

• n

o pre

vious

trea

tmen

t Ex

clusio

n cr

iteria

: • H

IV or

HBV

posit

ive

• sign

ifican

t live

r dise

ase

(e.g.

, can

cer,

deco

mpen

satio

n)

• abs

olute

neutr

ophil

coun

t <1

500 p

er m

l3 , pla

telet

coun

t <9

0K pe

r ml3 ,

hgb <

12 g/

dL

wome

n or <

13 g/

dL m

en

Patie

nt ch

arac

teris

tics:

Ag

e (me

an):

49 yr

s Ma

le: 58

%

Whit

e: 88

%

Blac

k: 9%

Hi

span

ic: 11

%

HCV

RNA

≥800

K IU

per m

l: 77

%

HCV

geno

type 1

a: 58

%

HCV

geno

type 1

b: 41

%

HCV

geno

type u

nk: <

1%

Cirrh

osis:

6%

Bridg

ing fib

rosis

: 15%

St

ratifi

ed fo

r gen

otype

1 su

btyp

(a

, b, u

nkno

wn) a

nd ba

selin

e HC

V RN

A <8

00K

IU/m

L or

≥800

K/mL

1. 36

3 2.

364

3. 36

1 mo

dified

IT

T

Trea

tmen

t dur

ation

24

or 48

wee

ks.

Prim

ary o

utcom

e as

sess

ed 24

wee

ks

after

end o

f trea

tmen

t (i.e

., wee

k 48 o

r 72)

Susta

ined v

irolog

ical

resp

onse

: 1.

T12P

R: 75

%

PR:

44%

(

p<0.0

01)

2.

T8PR

: 69%

P

R: 44

%

(p<

0.001

)

Ot

her r

eleva

nt en

dpoin

ts:

eRVR

1.

T12P

R: 58

%

2.

T8PR

: 57%

3. PR

: 8%

Re

lapse

amon

g pati

ents

with

unde

tectab

le HC

V RN

A at

end o

f trea

tmen

t per

iod:

1. T1

2PR:

9%

2.

T8PR

: 9%

3. PR

: 28%

31%

/ 3

(CI: 1

8–32

) 25

% / 4

(C

I: 18–

32)

50%

/ 2

49%

/ 2

19%

/ 5

19%

/ 5

Rash

1. T1

2PR:

37%

2.

T8PR

: 35%

3.

PR: 2

4%

Prur

itus: 1.

T12P

R: 50

%

2. T8

PR: 4

5%

3. 3.

PR:36

%

Anem

ia:

1. T1

2PR:

37%

2.

2. T8

PR: 3

9%

3. 3.

PR: 1

9%

All-d

rug d

iscon

tinua

tion

due t

o adv

erse

reac

tion:

1. T1

2PR:

10%

2.

T8PR

: 10%

3.

PR: 7

%

13%

/ 8

11%

/ 9

14%

/ 7

9% / 1

1 18

% / 6

20

% / 5

3%

/ 33

3% / 3

3

Note:

the

perce

ntag

es in

the

FDA

revie

w an

d pr

escri

bing

infor

matio

n ar

e up

to 5

point

s high

er

for e

ach

study

arm

for t

he p

rimar

y end

point

• B

lindin

g cou

ld be

comp

romi

sed b

y ob

vious

ness

and f

requ

ency

of ad

verse

re

actio

ns.

• Use

of er

ythro

poiet

in sti

mulat

ing ag

ents

was

exclu

ded f

rom

telap

revir

stud

ies.

• Lev

el of

treatm

ent a

dher

ence

uncle

ar

• Exte

nsive

inclu

sion/e

xclus

ion cr

iteria

foun

d in

study

proto

col. M

ay im

pact

appli

catio

n and

re

sults

in ge

nera

l clin

ical s

etting

. • T

oo fe

w Af

rican

-Ame

rican

and H

ispan

ic pa

tients

to ad

equa

tely a

sses

s res

pons

e in t

hese

po

pulat

ions.

Race

and e

thnic

grou

ps w

ere s

elf-

repo

rted a

nd no

t mutu

ally e

xclus

ive (e

.g.,

Hisp

anic)

• D

iscon

tinua

tion d

ue to

adve

rse re

actio

ns in

TV

R gr

oup h

igh bu

t ove

rall d

iscon

tinua

tion

rates

high

er in

PR

grou

p due

to st

oppin

g ru

les:

7% T

12PR

24, 5

2% T

12PR

48, 8

% T

8PR2

4, 56

% T

8PR4

8, 79

% P

R • S

ubgr

oup a

nalys

is: T

12PR

perfo

rmed

bette

r tha

n PR

in all

subg

roup

analy

ses (

sex,

age,

race

, ethn

icity,

HCV

subty

pe, b

aseli

ne H

CV,

fibro

sis st

atus,

BMI, b

aseli

ne H

CV R

NA,

diabe

tes hi

story,

geog

raph

ic re

gion;

howe

ver,

for ci

rrhos

is an

d bas

eline

HCV

RNA

<80

0K C

I ra

te of

SVR:

diffe

renc

es no

t sign

ifican

t: ≈0.3

(CI

≈ 0.0

to 0.

6) an

d ≈0.1

(CI ≈

–0.05

to 0.

25).

• Stop

ping r

ules t

o pre

vent

conti

nuing

trea

tmen

t in

patie

nts w

ithou

t ade

quate

resp

onse

appli

ed:

Patie

nts re

ceivi

ng te

lapre

vir w

ith H

CV R

NA

>100

0 IU/

mL at

wee

k 4 D

/C te

lapre

vir bu

t co

ntinu

ed P

R. A

ll pati

ents

with

<2 lo

g 10

decre

ase f

rom

base

line i

n HCV

RNA

at w

eek 1

2 D/

C tre

atmen

t. Pati

ents

with

HCV

RNA

detec

table

at an

y tim

e betw

een w

eeks

24 an

d 40

D/C

trea

tmen

t. St

oppin

g rule

s: 1.

D/C

TVR

or P

LA re

quire

d for

prog

ress

ive

grad

e 2 (m

oder

ate, d

iffuse

, invo

lving

up to

50%

of

body

), or

grad

e 3 (s

ever

e, inv

olving

mor

e

113 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

7 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

than 5

0% of

body

or sy

stemi

c cha

nges

) ras

h. 2.

D/C

TVR

or P

LA if

RIB

D/C

due t

o ane

mia.

REAL

IZE

Fair

Zeuz

em

Cente

rs in

17 co

untrie

s Ph

ase 3

Se

p 200

8–Ju

ly 20

10

RCT,

str

atifie

d, PC

, DB

1. T1

2PR4

8: T

(7

50 m

g q8h

) plu

s P (1

80 μ

g pe

r wee

k) an

d R

(100

0 mg t

o 120

0 mg

qd) f

or 12

we

eks,

then P

LA

plus P

R for

4 we

ek, th

en P

R for

32

wee

ks

2. lea

d-in

T12P

R48:

PLA

plus P

R for

4 we

eks,

the T

plus

PR

for 12

wee

ks,

then P

R for

32

week

s 3.

PR48

(co

ntrol)

: PLA

plu

s PR

for 16

we

eks,

then

PR fo

r 32

week

s No

te: do

ses

are t

he sa

me

for ea

ch dr

ug

in all

arms

.

Inclu

sion

crite

ria:

• age

d 18–

70

• chr

onic

HCV

geno

type 1

• n

o SVR

to on

e pre

vious

cour

se of

PR

desp

ite re

ceivi

ng 80

% of

inten

ded d

ose

• dete

ctable

HCV

RNA

• l

iver b

iopsy

with

in 18

mo.

of sc

reen

ing

Exclu

sion

crite

ria:

• abs

olute

neutr

ophil

coun

t <12

00

per m

l3 , pla

telet

coun

t <90

K pe

r ml3 ,

hgb <

12 g/

dL w

omen

or <

13 g/

dL

men

• sign

ifican

t live

r dise

ase

(e.g.

, can

cer,

deco

mpen

satio

n)

Patie

nt ch

arac

teris

tics:

Ag

e (me

an):

51 yr

s Ma

le: 69

%

Whit

e: 93

%

Blac

k: 5%

Hi

span

ic: 11

%

HCV

RNA

≥800

K IU

per m

l: 89%

HC

V ge

notyp

e 1a:

45%

HC

V ge

notyp

e 1b:

45%

HC

V ge

notyp

e 1c:

<1%

HC

V ge

notyp

e unk

: 10%

Ci

rrhos

is: 26

%

Bridg

ing fib

rosis

: 22%

Pr

eviou

s typ

e of r

espo

nse:

No r

espo

nse:

28%

P

artia

l: 19%

R

elaps

e: 53

%

Stra

tified

by ba

selin

e vira

l load

(HCV

RN

A <8

00K

or ≥

800K

IU pe

r mL)

and

type o

f pre

vious

resp

onse

to tr

eatm

ent

PR (n

o res

pons

e, pa

rtial re

spon

se, o

r

1. 26

6 2.

264

3. 13

2 mo

difi

ed

ITT

Prim

ary o

utcom

e as

sess

ed 24

wee

ks

after

end o

f tre

atmen

t (i.e

., wee

k 48

)

Susta

ined v

irolog

ical

resp

onse

: Pr

eviou

s rela

pse:

1. T1

2PR4

8: 83

% (p

<0.00

1)

2. lea

d-in

T12P

R48:

88%

(p

<0.00

1)

3. PR

48: 2

4%

No pr

eviou

s viro

logic

resp

onse

or pa

rtial re

spon

se:

1. T1

2PR4

8: 41

% (p

<0.00

1)

2. lea

d-in

T12P

R48:

41%

(p

<0.00

1)

3. PR

48: 9

%

Prev

ious p

artia

l resp

onse

: 1.

T12P

R48:

59%

(p<0

.001)

2.

lead-

in T1

2PR4

8: 54

%

(p<0

.001)

3.

PR48

: 15%

No

prev

ious v

irolog

ic re

spon

se:

1. T1

2PR4

8: 29

% (p

<0.00

1)

2. lea

d-in

T12P

R48:

33%

(p

<0.00

1)

3. PR

48: 5

%

Over

all:

1. T1

2PR4

8: 64

% (p

<0.00

1)

2. lea

d-in

T12P

R48:

66%

(p

<0.00

1)

3. PR

48: 1

7%

59%

/2 64

%/2

32%

/3 32

%/3

44%

/2 39

%/3

24%

/4 28

%/4

47%

/2 (C

I: 37–

57)

49%

/2 (C

I: 40–

60)

Rash

1.

T12P

R48:

37%

2.

Lead

-in T

12PR

48: 3

6%

3. PR

48: 1

9%

Prur

itus:

1. T1

2PR4

8: 52

%

2. Le

ad-in

T12

PR48

: 50%

3.

PR48

: 27%

An

emia:

1.

T12P

R48:

30%

2.

Lead

-in T

12PR

48: 3

6%

3. PR

48: 1

5%

All-d

rug d

iscon

tinua

tion

due t

o adv

erse

reac

tion:

1. T1

2PR4

8: 6%

2.

Lead

-in T

12PR

48: 4

%

3. PR

48: 3

%

18%

/ 6

17%

/ 6

25%

/ 4

23%

/ 4

15%

/ 7

21%

/ 5

3% / 3

1%

/ 10

0

Note:

The p

erce

ntag

es in

FDA

revie

w an

d RE

ALIZ

E su

pplem

ent fo

r eac

h stu

dy a

rm fo

r ea

ch su

bgro

up fo

r the

prim

ary e

ndpo

int a

re 1

or

2 po

ints h

igher

or lo

wer a

nd th

e SV

R for

null

resp

onde

rs on

PR4

8 ze

ro.

• Blin

ding c

ould

be co

mpro

mise

d by a

dver

se

reac

tion t

ype.

HCV

RNA

testin

g res

ults

unbli

nded

after

wee

k 24.

• Lev

el of

treatm

ent a

dher

ence

uncle

ar

• Exte

nsive

inclu

sion/e

xclus

ion cr

iteria

foun

d in

study

proto

col. M

ay im

pact

appli

catio

n and

re

sults

in ge

nera

l clin

ical s

etting

. • T

oo fe

w Af

rican

-Ame

rican

and H

ispan

ic pa

tients

to ad

equa

tely a

sses

s res

pons

e in t

hese

po

pulat

ions.

Race

and e

thnic

grou

ps w

ere s

elf-

repo

rted a

nd no

t mutu

ally e

xclus

ive (e

.g.,

Hisp

anic)

• D

iscon

tinua

tion d

ue to

adve

rse re

actio

ns in

TV

R gr

oup h

igh bu

t ove

rall d

iscon

tinua

tion

rates

high

er in

PR

grou

p due

to st

oppin

g ru

les: 1.

T12P

R48:

38%

2.

Lead

-in T

12PR

48: 3

0%

3. PR

: 62%

• G

uideli

ne de

finitio

ns of

null r

espo

nder

and

partia

l resp

onde

r use

an ev

aluati

on po

int of

24

week

s, wh

erea

s REA

LIZE

uses

12 w

eeks

. • O

vera

ll 73%

of vi

rolog

ic fai

lures

and r

elaps

es

due t

o eme

rgen

ce of

varia

nts w

ith re

duce

d se

nsitiv

ity to

TVR

. St

oppin

g rule

s: a.

TVR

stopp

ed if

HCV

RNA

>100

IU pe

r mL a

t we

eks 4

, 6, a

nd 8.

All t

reatm

ent D

/C if

patie

nt ha

d <2lo

g 10 d

ecre

ase i

n HCV

RNA

at w

eek 1

2 in

the T

12PR

48 gr

oup a

nd th

e con

trol g

roup

or

at we

ek 16

in th

e lea

d-in

grou

p or in

case

s of

detec

table

HCV

RNA

at we

ek 24

or 36

. (D/

C TV

R for

stop

ping r

ule =

trea

tmen

t failu

re.)

114 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

8 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

relap

se)

b. D/

C TV

R re

quire

d for

prog

ress

ing to

grad

e 2

and f

or gr

ade 3

rash

but P

R co

ntinu

ed. D

/C R

, wi

th or

with

out P

, if no

impr

ovem

ent in

rash

wi

thin 7

days

. c.

If dec

reas

e or D

/C R

IB du

e to a

nemi

a and

did

not im

prov

e ane

mia,

then d

/c TV

R.

ILLUM

INAT

E Fa

ir

Sher

man

74 ce

nters

Phas

e 3

Open

labe

l, ra

ndom

ized,

nonin

ferior

ity,

strati

fied,

DB

for re

sults

of

HCV

RNA

testin

g thr

ough

wee

k 24

1. T1

2PR2

4: T

(7

50 m

g q8h

) plu

s P (1

80 μ

g pe

r wee

k) an

d R

(100

0 mg q

d for

<7

5 kg o

r 120

0 mg

qd fo

r ≥75

mg

qd) f

or 12

wee

ks,

then P

R for

12

week

s 2.

T12 P

R48:

T plu

s PR

for 12

we

eks,

then P

R for

36 w

eeks

No

te: do

ses a

re

the sa

me fo

r ea

ch dr

ug in

all

arms

.

Inclu

sion

crite

ria:

• age

d 18–

70

• chr

onic

HCV

geno

type 1

• n

o pre

vious

trea

tmen

t • l

iver b

iopsy

Ex

clusio

n cr

iteria

: • H

IV or

HBV

posit

ive

• abs

olute

neutr

ophil

coun

t <15

00

per m

l3 , pla

telet

coun

t <90

K pe

r ml3 ,

hgb <

12 g/

dL w

omen

or <

13 g/

dL

men

• sign

ifican

t live

r dise

ase

Char

acte

ristic

s of r

ando

mly

assig

ne

patie

nts:

Ag

e (me

an):

51 yr

s Ma

le: 62

%

Whit

e: 83

%

Blac

k: 11

%

Hisp

anic:

9%

HCV

RNA

≥800

K IU

per m

l: 78%

HC

V ge

notyp

e 1a:

72%

HC

V ge

notyp

e 1b:

28%

HC

V ge

notyp

e unk

: <1%

Ci

rrhos

is: 9%

Br

idging

fibro

sis: 1

3%

Once

rand

omize

d, str

atifie

d by H

CV

geno

type s

ubtyp

e and

blac

k v. n

on-

black

1. 16

2 2.

160

eRVR

po

pul

ation

Prim

ary o

utcom

es

asse

ssed

24 w

eeks

aft

er en

d of tr

eatm

ent

(i.e., w

eek 4

8 or 7

2)

differ

ence

in S

VR be

twee

n pa

tients

who

had e

RVR

1. T1

2PR2

4: 92

%

2. T1

2PR4

8: 88

%

RR 1.

0

NS

Rash

: 1.

T12P

R24:

37%

2.

T12P

R48:

39%

Pr

uritu

s: 1.

T12P

R24:

59%

2.

T12P

R48:

52%

An

emia:

1.

T12P

R24:

42%

2.

T12P

R48:

41%

Al

l-dru

g disc

ontin

uatio

n du

e to a

dver

se

reac

tions

: 1.

T12P

R24:

1%

2. T1

2PR4

8: 12

%

NA

NA

NA

Note:

the

perce

ntag

es no

ninfe

riority

CI in

FDA

re

view

was –

4.3

to +

8.2%

and

SVR

rate

was

90

%, r

athe

r tha

n 88

% fo

r T12

PR48

• O

pen-

label

• Lev

el of

treatm

ent a

dher

ence

uncle

ar

• Tre

atmen

t unb

linde

d. On

ly HC

V RN

A tes

ting

resu

lts D

B thr

ough

wee

k 24

• Exte

nsive

inclu

sion/e

xclus

ion cr

iteria

foun

d in

study

proto

col. M

ay im

pact

appli

catio

n and

re

sults

in ge

nera

l clin

ical s

etting

. • O

vera

ll disc

ontin

uatio

n rate

s afte

r eRV

R ra

ndom

izatio

n: 1.

T12P

R24:

1%

2. T1

2PR4

8: 26

%

• Ove

rall d

iscon

tinua

tion r

ate pr

ior to

ra

ndom

izatio

n: 18

%

• Ran

domi

zatio

n to s

top P

R tre

atmen

t at w

eek

24 or

wee

k 48 o

ccur

red a

t wee

k 20 f

or pa

tients

wi

th eR

VR.

• Stop

ping r

ule: T

VR st

oppe

d in p

atien

ts wi

th HC

V RN

A >1

000 I

U/mL

at w

eek 4

. All s

tudy

drug

s stop

ped i

n pati

ents

with

virolo

gic fa

ilure

at

week

12 or

betw

een w

eeks

24 an

d 36 (

virolo

gic

failur

e = H

CV R

NA >

1000

IU/m

L at w

eek 4

, a

decli

ne fr

om ba

selin

e by <

2log 1

0 unit

s in l

evel

of de

tectab

le HC

V RN

A at

week

12, o

r a

detec

table

HCV

RNA

level

at an

y tim

e betw

een

week

s 24 a

nd 36

.) • N

oninf

erior

ity m

argin

–10.5

%. 8

0% po

wer t

o ru

le ou

t non

infer

iority

if ob

serve

d SVR

rate

was

90%

1 Stud

y de

sign

abb

revi

atio

ns: D

B =

doub

le-b

lind,

RCT

= r

ando

miz

ed tr

ial,

PC =

pla

cebo

-con

trol

led,

PG

= p

aral

lel -

grou

p, X

O =

cro

ssov

er.

2 Resu

lts

abbr

evia

tion

s: R

RR =

rel

ativ

e ri

sk r

educ

tion

, RR

=rel

ativ

e ri

sk, O

R= O

dds

Ratio

, HR

= H

azar

d Ra

tio,

ARR

= ab

solu

te r

isk

redu

ctio

n,

NN

T =

num

ber

need

ed to

trea

t, N

NH

= n

umbe

r ne

eded

to h

arm

, CI =

con

fiden

ce in

terv

al

3 NN

T/N

NH

are

rep

orte

d on

ly fo

r st

atis

tical

ly s

igni

fican

t res

ults

4 Q

ualit

y Ra

ting

: (G

ood-

like

ly v

alid

, Fai

r- li

kely

val

id/p

ossi

bly

valid

, Poo

r- fa

tal f

law

-not

val

id)

115 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

9 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

Clin

ical

Fin

ding

s Th

e FD

A re

view

ed s

ix p

hase

2 s

tudi

es a

nd th

ree

phas

e 3

stud

ies

in m

akin

g its

det

erm

inat

ion

for

appr

oval

of T

VR. T

hree

pha

se 2

and

thre

e ph

ase

3 st

udie

s ha

ve b

een

publ

ishe

d.

Phas

e 2

stud

ies

esta

blis

hed

that

dos

ing

TVR,

in c

ombi

natio

n w

ith P

R, fo

r mor

e th

an 1

2 w

eeks

hel

d no

adv

anta

ges

and

that

the

trea

tmen

t sho

uld

incl

ude

RIB

to m

itiga

te b

reak

thro

ugh

and

rela

pse

rate

s. R

esea

rche

rs a

lso

initi

ated

the

expl

orat

ion

of re

spon

se-g

uide

d th

erap

y (R

GT)

in p

hase

2

stud

ies

and

cont

inue

d th

e ev

alua

tion

in th

e ph

ase

3 st

udie

s AD

VAN

CE a

nd IL

LUM

INA

TE.3,

4,6,

9–11

Th

e AD

VAN

CE a

nd IL

LUM

INA

TE tr

ials

incl

uded

adu

lt tr

eatm

ent-

naïv

e su

bjec

ts w

ith H

CV-1

, whi

le th

e RE

ALI

ZE p

hase

3 tr

ial i

nclu

ded

adul

t sub

ject

s w

ith H

CV-1

who

had

bee

n pr

evio

usly

trea

ted.

The

pri

mar

y ef

ficac

y en

dpoi

nt in

all

thre

e tr

ials

was

the

prop

ortio

n of

pat

ient

s ac

hiev

ing

SVR.

“St

oppi

ng

rule

s” fo

r dis

cont

inui

ng T

VR o

r al

l tre

atm

ent w

ere

appl

ied

to e

ach

stud

y to

pre

vent

pat

ient

s w

ho d

id n

ot h

ave

adeq

uate

resp

onse

and

pat

ient

s w

ith

seri

ous

adve

rse

even

ts fr

om c

ontin

uing

trea

tmen

t. T

hese

pat

ient

s co

unte

d as

trea

tmen

t fai

lure

s.4–

6 A

DVA

NCE

test

ed tr

eatm

ent d

urat

ion:

whe

ther

8 o

r 12

wee

ks o

f TVR

in c

ombi

natio

n w

ith P

R (T

8PR

and

T12P

R, re

spec

tivel

y) w

as s

uper

ior t

o 48

w

eeks

of P

R. T

reat

men

t arm

s ha

d si

mila

r bas

elin

e ch

arac

teri

stic

s an

d de

mog

raph

ics.

Bot

h TV

R-co

ntai

ning

regi

men

s w

ere

stat

istic

ally

sup

erio

r to

PR. T

he S

VR r

ates

for t

he T

12PR

(n=3

63),

T8PR

(n=3

64),

and

PR (n

=361

) mod

ified

ITT

grou

ps w

ere

75%

, 69%

, and

44%

, res

pect

ivel

y, (p

<0.0

01

com

pari

ng e

ach

TVR

grou

p w

ith th

e PR

gro

up).

The

diff

eren

ce in

res

pons

es w

ere

31%

(CI:

18–3

2) fo

r T12

PR v

ersu

s PR

and

25%

for T

8PR

vers

us P

R,

givi

ng N

NTs

of 3

and

4, r

espe

ctiv

ely.

6 A

bout

60%

of p

atie

nts

rand

omiz

ed to

the

TVR

regi

men

s ac

hiev

ed e

RVR,

com

pare

d to

8%

in th

e PR

gro

up. A

mon

g pa

tient

s ac

hiev

ing

eRVR

, 89%

of

T12P

R an

d 83

% o

f T8P

R pa

tient

s ac

hiev

ed S

VR. T

hese

resu

lts in

dica

ted

tota

l tre

atm

ent d

urat

ion

of 2

4 w

eeks

wou

ld b

e su

ffic

ient

for p

atie

nts

achi

evin

g eR

VR, w

here

as a

long

er d

urat

ion

of P

R w

ould

be

pref

erre

d fo

r pat

ient

s w

ho d

id n

ot. R

elap

se o

ccur

red

in 9

%, 9

%, a

nd 2

8% o

f sub

ject

s re

ceiv

ing

T8PR

, T12

PR, a

nd P

R, r

espe

ctiv

ely.

6 A

ll pa

tient

s w

ith n

egat

ive

pred

ictiv

e fa

ctor

s (f

or s

ex, a

ge, r

ace,

eth

nici

ty, H

CV s

ubty

pe, b

asel

ine

HCV

RN

A, f

ibro

sis,

BM

I, di

abet

es) w

ho to

ok T

VR

had

high

er r

espo

nse

rate

s th

an th

ose

rand

omiz

ed to

PR

trea

tmen

t; h

owev

er, d

iffer

ence

s in

rate

of S

VR fo

r cir

rhos

is a

nd b

asel

ine

HCV

RN

A

<800

,000

IU/m

L di

d no

t rea

ch s

igni

fican

ce: ≈

0.3

(CI ≈

0.0

to 0

.6) a

nd ≈

0.1

(CI ≈

–0.

05 to

0.2

5), r

espe

ctiv

ely.

SVR

rat

es in

his

toric

ally

diff

icul

t-to

-tre

at

subg

roup

s (A

fric

an-A

mer

ican

s, H

ispa

nics

, and

cir

rhot

ic p

atie

nts)

rec

eivi

ng T

VR-c

onta

inin

g re

gim

ens

wer

e ab

out 3

0% a

bove

SVR

rat

es fo

r th

ose

taki

ng P

R al

one.

SVR

rat

es fo

r bla

ck p

atie

nts

wer

e 62

%, 5

8%, a

nd 2

5% fo

r T12

PR, T

8PR,

and

PR

grou

ps, r

espe

ctiv

ely,

and

for b

ridg

ing

fibro

sis

or

cirr

hotic

pat

ient

s w

ere

62%

, 53%

, and

33%

, res

pect

ivel

y. S

VR r

ates

for

His

pani

c pa

tient

s w

ere

74%

and

39%

for t

he T

12PR

and

PR

grou

ps,

resp

ectiv

ely.

6

116 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

10

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

ILLU

MIN

ATE

was

a s

uppo

rtiv

e, o

pen-

labe

l, no

n-in

ferio

rity

tria

l tha

t com

pare

d 12

-wee

ks o

f TVR

with

24-

to 4

8-w

eeks

of r

espo

nse

guid

ed th

erap

y (R

GT)

in tr

eatm

ent-

naïv

e su

bjec

ts (n

=540

) who

had

ach

ieve

d eR

VR. S

ubje

cts

achi

evin

g eR

VR w

ere

rand

omiz

ed to

rece

ive

24 w

eeks

or

48 w

eeks

of

ther

apy

with

PR

in c

ombi

natio

n w

ith T

VR (T

12PR

24 o

r T12

PR48

, res

pect

ivel

y). T

he p

rede

fined

non

-infe

riori

ty m

argi

n w

as –

10.5

%. O

vera

ll, 6

5%

(352

/540

) pat

ient

s ac

hiev

ed e

RVR.

Am

ong

subj

ects

who

ach

ieve

d eR

VR a

nd w

ere

rand

omly

ass

igne

d to

a s

tudy

gro

up (n

=322

), 92

% r

ecei

ving

T1

2PR2

4 co

mpa

red

to 8

8% r

ecei

ving

T12

PR48

had

SVR

. Non

infe

rior

ity w

as m

et w

ith a

two-

side

d CI

of –

2% to

11%

. The

SVR

rat

e fo

r ci

rrho

tic

subj

ects

ach

ievi

ng e

RVR

and

trea

ted

with

24-

wee

ks o

f TVR

-con

tain

ing

regi

men

was

67%

, whi

le th

e ra

te fo

r tho

se tr

eate

d fo

r 48

wee

ks w

as 9

2%.

Alth

ough

rep

rese

ntat

ion

of c

irrh

otic

pat

ient

s w

as li

mite

d, c

irrh

otic

pat

ient

s m

ay b

enef

it fr

om 4

8 w

eeks

PR

with

12-

wee

ks o

f TVR

.3,4

The

REA

LIZE

tria

l exa

min

ed th

e ef

ficac

y an

d sa

fety

of T

VR g

iven

for

12 w

eeks

in c

ombi

natio

n w

ith P

R fo

r 48

wee

ks in

662

pre

viou

sly

trea

ted

HCV

1 su

bjec

ts w

ho w

ere

rela

pser

s (5

3%),

part

ial r

espo

nder

s (1

9%),

or n

ull r

espo

nder

s (2

8%).

The

tria

l als

o ev

alua

ted

whe

ther

a 4

wee

k le

ad-in

of P

R pr

ior t

o tr

iple

ther

apy

wou

ld a

ffec

t rel

apse

and

resi

stan

ce. T

he b

asel

ine

char

acte

rist

ics

and

dem

ogra

phic

s of

the

trea

tmen

t arm

s w

ere

sim

ilar.

Be

caus

e th

is w

as a

stu

dy o

f sub

ject

s pr

evio

usly

trea

ted

with

PR,

the

stud

y ha

d m

ore

cirr

hotic

sub

ject

s (2

6%) c

ompa

red

to tr

ials

with

trea

tmen

t-na

ïve

patie

nts.

SVR

rat

es fo

r pre

viou

s re

laps

ers,

par

tial r

espo

nder

s, a

nd n

ull r

espo

nder

s w

ere

high

er fo

r the

TVR

gro

ups

than

the

PR48

gro

up

(p<0

.001

for

all c

ompa

riso

ns).

Trea

tmen

t out

com

es w

ere

sim

ilar w

ith o

r w

ithou

t lea

d-in

.3,5

SVR

T1

2PR4

8 Le

ad-in

T12

PR48

PR

48

Rela

pser

s 83

% (1

21/1

45)

88%

(124

/141

) 24

% (1

6/68

) Pa

rtia

l res

pond

ers

59%

(29/

49)

54%

(26/

48)

15%

(4/2

7)

Nul

l res

pond

ers

29%

(21/

72)

33%

(25/

75)

5% (2

/37)

Ra

tes

of r

elap

se a

t 72

wee

ks w

ere

low

er in

the

two

TVR

grou

ps th

an th

e PR

gro

up a

mon

g pr

evio

us re

laps

ers,

par

tial r

espo

nder

s, o

r nu

ll re

spon

ders

. H

owev

er, t

he n

umbe

r of

par

tial a

nd n

ull r

espo

nder

s w

as s

mal

l. Re

laps

e ra

tes

T1

2PR4

8 Le

ad-in

T12

PR48

PR

48

Rela

pser

s 7%

(10/

135)

7%

(9/1

38)

65%

(30/

46)

Part

ial r

espo

nder

s 21

% (8

/39)

25

% (9

/36)

(0

) N

ull r

espo

nder

s 27

% (8

/30)

25

% (9

/36)

60

% (3

/5)

Ove

rall,

73%

of v

irolo

gic

failu

re a

nd re

laps

es w

ere

asso

ciat

ed w

ith tr

eatm

ent-

emer

gent

TVR

-res

ista

nce.

117 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

11

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Viro

logi

c fa

ilure

rat

es (h

avin

g vi

rolo

gic

failu

re, i

.e.,

≥1 lo

g 10 i

ncre

ase

in H

CV R

NA

nad

ir d

urin

g tr

eatm

ent o

r H

CV R

NA

leve

l >10

0 IU

/mL

whe

n vi

ral

load

had

pre

viou

sly

been

<25

IU/m

L du

ring

trea

tmen

t, o

r mee

ting

stop

ping

rul

es)

T1

2PR4

8 Le

ad-in

T12

PR48

PR

48

Rela

pser

s 1%

(2/1

45)

1% (1

/141

) 26

% (1

8/68

) Pa

rtia

l res

pond

ers

18%

(9/4

9)

19%

(9/4

8)

70%

(19/

27)

Nul

l res

pond

ers

57%

(41/

72)

47%

(35/

75)

84%

(31/

37)

Am

ong

cirr

hotic

sub

ject

s, S

VR w

as h

ighe

st fo

r rel

apse

rs (8

7% fo

r TVR

-con

tain

ing

regi

men

s v.

13%

for

PR a

lone

). SV

R w

as lo

w fo

r nul

l res

pond

ers

with

or w

ithou

t TVR

(14%

v. 1

0%, r

espe

ctiv

ely)

; how

ever

, the

num

ber

of n

ull r

espo

nder

s w

as s

mal

l.3

The

ADVA

NCE

tria

l est

ablis

hed

a tr

eatm

ent r

egim

en in

clud

ing

TVR

for

12 w

eeks

and

PR

for

24 w

eeks

is s

uper

ior t

o PR

alo

ne in

trea

tmen

t-na

ive

patie

nts

who

hav

e ac

hiev

ed e

RVR,

whi

le 4

8 w

eeks

of P

R w

ith 1

2 w

eeks

of T

VR is

rec

omm

ende

d in

pat

ient

s no

t ach

ievi

ng e

RVR.

The

ILLU

MIN

ATE

tr

ial e

stab

lishe

d tr

eatin

g pa

tient

s w

ho h

ad a

chie

ved

eRVR

with

mor

e th

an 2

4 w

eeks

of P

R in

com

bina

tion

with

TVR

pro

vide

d no

adv

anta

ge. T

he

REA

LIZE

tria

l sup

port

s th

e us

e of

TVR

-con

tain

ing

regi

men

s in

pat

ient

s pr

evio

usly

trea

ted

with

PR

alon

e. 3–

6 In

tern

al a

nd e

xter

nal v

alid

ity c

once

rns

with

pha

se 3

clin

ical

tria

ls in

clud

ed e

xten

sive

incl

usio

n an

d ex

clus

ion

crite

ria,

lim

ited

or n

o tr

acki

ng o

f ad

here

nce,

pro

babi

lity

of c

ompr

omis

ed b

lindi

ng, a

nd w

heth

er s

imila

r ef

ficac

y an

d sa

fety

res

ults

can

be

achi

eved

in a

gen

eral

clin

ical

set

ting,

as

trip

le th

erap

y re

quire

s st

rict

and

freq

uent

mon

itori

ng o

f ser

um H

CV R

NA

, adh

eren

ce b

y cl

inic

ians

to s

topp

ing

rule

s an

d tr

eatm

ent r

egim

ens,

m

anag

emen

t of a

n ex

tens

ive

list o

f pro

babl

e an

d ac

tual

dru

g-dr

ug in

tera

ctio

ns, a

nd c

lose

mon

itorin

g fo

r ad

vers

e re

actio

ns. T

he e

mer

genc

e of

dru

g re

sist

ance

, esp

ecia

lly in

pat

ient

s w

ho h

ave

had

a pr

ior n

on-r

espo

nse,

are

non

-adh

eren

t to

ther

apy,

or

are

into

lera

nt o

f opt

imal

PR

dose

s al

so is

a

conc

ern.

12

Des

pite

thes

e un

know

ns, t

riple

ther

apy

has

over

ridin

g be

nefit

s, in

clud

ing

impr

oved

SVR

rate

s fo

r pat

ient

s as

a w

hole

, im

prov

ed S

VR ra

tes

for

diff

icul

t-to

-tre

at p

atie

nts,

sho

rter

dur

atio

n of

ther

apy

for

trea

tmen

t-na

ïve

patie

nts

who

ach

ieve

SVR

, and

a r

e-tr

eatm

ent o

ptio

n fo

r pa

tient

s w

ho

have

faile

d pr

evio

us th

erap

y w

ith P

R.

DRU

G S

AFE

TY

Safe

ty is

sues

ari

sing

from

clin

ical

tria

ls p

rim

arily

focu

sed

on r

ash,

pru

ritus

, and

ane

mia

. Ras

h le

d to

dis

cont

inua

tion

of T

VR a

nd tr

iple

ther

apy

in 6

%

and

1% o

f sub

ject

s, re

spec

tivel

y, a

nd a

nem

ia le

d to

dis

cont

inua

tion

of T

VR a

nd tr

iple

ther

apy

in 4

% a

nd 1

% o

f pat

ient

s, re

spec

tivel

y. In

clin

ical

tr

ials

, sev

ere

cuta

neou

s ad

vers

e re

actio

ns w

ere

repo

rted

in <

1% o

f sub

ject

s tr

eate

d w

ith T

VR-c

onta

inin

g re

gim

ens

com

pare

d to

0%

of s

ubje

cts

trea

ted

with

PR

alon

e. W

heth

er th

e ra

tes

of s

ever

e ra

sh, i

nclu

ding

Dru

g Ra

sh w

ith E

osin

ophi

lia a

nd S

yste

mic

Sym

ptom

s (D

RESS

) and

Ste

ven-

John

son

Synd

rom

e (S

JS),

seen

in c

linic

al tr

ials

repr

esen

t the

rate

s in

a g

ener

al tr

eatm

ent p

opul

atio

n is

as

yet u

nkno

wn.

3

118 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

12

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Serio

us (R

EMS,

Bla

ck B

ox W

arni

ngs,

Con

trai

ndic

atio

ns): 1

Con

trai

ndic

atio

ns to

peg

inte

rfer

on a

lfa a

nd r

ibav

irin

als

o ap

ply.

Tr

iple

the

rapy

is

cont

rain

dica

ted

in w

omen

who

are

or

may

bec

ome

preg

nant

and

men

who

se f

emal

e pa

rtne

rs a

re p

regn

ant.

Bec

ause

RIB

is

asso

ciat

ed w

ith s

igni

fican

t te

rato

geni

c or

em

bryo

cida

l eff

ects

, fem

ale

patie

nts

and

fem

ale

part

ners

of

child

bear

ing

age

shou

ld u

se t

wo

effe

ctiv

e co

ntra

cept

ive

met

hods

dur

ing

and

for

6 m

onth

s fo

llow

ing

trea

tmen

t. F

emal

e pa

tient

s sh

ould

use

tw

o ef

fect

ive

non-

horm

onal

con

trac

eptiv

es.

Conc

omita

nt u

se o

f te

lapr

evir

with

med

icat

ions

tha

t ha

ve a

nar

row

the

rape

utic

ind

ex a

nd a

re h

ighl

y de

pend

ent

on C

YP3A

4 is

con

trai

ndic

ated

. Co

ncom

itant

use

of

tela

prev

ir w

ith m

edic

atio

ns t

hat

stro

ngly

indu

ce C

YP3A

4 an

d m

ay r

esul

t in

red

uced

eff

icac

y of

tel

apre

vir

is c

ontr

aind

icat

ed.

Seri

ous

adve

rse

reac

tions

req

uiri

ng d

isco

ntin

uatio

n of

tel

apre

vir

incl

ude:

(1)

skin

rea

ctio

ns, i

nclu

ding

DRE

SS a

nd S

JS; (

2) s

ever

e ra

sh o

r if

syst

emic

sy

mpt

oms

deve

lop

from

ras

h; (

3) a

nem

ia u

nres

olve

d by

RIB

dos

e re

duct

ion.

tel

apre

vir

is n

ot r

ecom

men

ded

in m

oder

ate

or s

ever

e he

patic

im

pair

men

t or

with

dec

ompe

nsat

ed l

iver

dis

ease

. te

lapr

evir

use

in

mon

othe

rapy

is

cont

rain

dica

ted,

and

its

dos

e m

ust

not

be r

educ

ed o

r be

re

star

ted

if di

scon

tinue

d. D

urin

g cl

inic

al t

rial

s, s

ever

e cu

tane

ous

adve

rse

reac

tions

wer

e re

port

ed in

<1%

of

subj

ects

tre

ated

with

TVR

-con

tain

ing

regi

men

s co

mpa

red

to 0

% o

f su

bjec

ts t

reat

ed w

ith P

R al

one.

Thr

ee c

ases

(1

poss

ible

, 1

prob

able

, 1

unlik

ely)

of

SJS

and

11 c

ases

(1

defin

ite,

2 pr

obab

le, 8

pos

sibl

e) o

f DRE

SS o

ccur

red.

Mon

itorin

g: 1

,3 M

onth

ly p

regn

ancy

tes

ts; h

emog

lobi

n be

fore

and

at l

east

eve

ry 4

wee

ks d

urin

g TV

R th

erap

y; H

CV-R

NA

leve

ls a

t w

eeks

4 a

nd 1

2 an

d as

clin

ical

ly in

dica

ted;

hem

atol

ogic

al a

nd b

lood

che

mis

try

eval

uatio

ns a

t wee

ks 2

, 4, 8

, and

12

or a

s cl

inic

ally

indi

cate

d th

erea

fter

.1

Tole

rabi

lity:

1,3 D

urin

g ph

ase

2 an

d 3

stud

ies,

8%

to 1

4% o

f pat

ient

s tr

eate

d w

ith T

VR-c

onta

inin

g re

gim

ens

disc

ontin

ued

TVR

due

to a

dver

se

reac

tions

com

pare

d to

abo

ut 3

% o

f tho

se tr

eate

d w

ith P

R. T

he m

ost f

requ

ent r

eact

ions

lead

ing

to d

isco

ntin

uatio

n of

TVR

wer

e ra

sh, p

rurit

us,

anem

ia, f

atig

ue, n

ause

a, a

nd v

omiti

ng (s

ee A

dver

se R

eact

ions

tabl

e be

low

). Th

ree

perc

ent o

f pat

ient

s re

ceiv

ing

TVR

had

serio

us a

dver

se re

actio

ns

com

pare

d to

non

e of

the

patie

nts

rece

ivin

g PR

. The

mos

t fre

quen

t ser

ious

adv

erse

reac

tions

for p

atie

nts

rece

ivin

g TV

R w

ere

skin

rea

ctio

ns (r

ash

and

prur

itus)

and

ane

mia

. Ras

h le

d to

dis

cont

inua

tion

of T

VR a

nd tr

iple

ther

apy

in 6

% a

nd 1

% o

f sub

ject

s, re

spec

tivel

y, a

nd a

nem

ia le

d to

di

scon

tinua

tion

of T

VR a

nd tr

iple

ther

apy

in 4

% a

nd 1

% o

f pat

ient

s, re

spec

tivel

y. In

cide

nce

of a

no-r

ecta

l dis

com

fort

(e.g

., he

mor

rhoi

ds, a

nore

ctal

di

scom

fort

, ana

l pru

ritu

s, a

nd r

ecta

l bur

ning

) com

bine

d w

ere

29%

for p

atie

nts

rece

ivin

g TV

R ve

rsus

7%

for t

hose

rece

ivin

g PR

. Mos

t of t

hese

re

actio

ns w

ere

mild

or

mod

erat

e an

d le

ad to

onl

y 1%

of p

atie

nts

disc

ontin

uing

ther

apy.

Uri

c ac

id le

vels

wer

e el

evat

ed in

73%

of p

atie

nts

rece

ivin

g TV

R co

mpa

red

to 2

9% o

f pat

ient

s re

ceiv

ing

PR. H

owev

er, l

ess

than

1%

of c

ases

res

ulte

d in

gou

t or g

outy

art

hriti

s, a

nd n

o pa

tient

s di

scon

tinue

d th

erap

y fo

r thi

s re

ason

. Pr

egna

ncy/

Lact

atio

n:1,

3 Alth

ough

the

preg

nanc

y ca

tego

ry o

f TVR

alo

ne is

B, t

he p

regn

ancy

cat

egor

y fo

r co

mbi

natio

n th

erap

y is

X, s

ince

RIB

has

ca

used

bir

th d

efec

ts o

r fe

tal d

eath

s in

all

anim

al s

peci

es s

tudi

ed a

nd P

EG is

abo

rtifa

cien

t in

anim

als.

Nur

sing

mus

t be

disc

ontin

ued

prio

r to

initi

atio

n of

trea

tmen

t, b

ecau

se o

f the

pot

entia

l for

adv

erse

rea

ctio

ns in

nur

sing

infa

nts.

119 of 187

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eric

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elap

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011

13

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Una

nsw

ered

saf

ety

ques

tions

:3 A c

once

rn is

the

man

agem

ent o

f ser

ious

ski

n re

actio

ns in

gen

eral

clin

ical

set

ting,

as

mis

man

agem

ent c

ould

lead

to

deat

h. T

here

’s a

lso

conc

ern

whe

ther

the

clin

ical

tria

ls a

ccur

atel

y pr

edic

t the

inci

denc

e of

SJS

and

DRE

SS.

Dos

e In

dex

(eff

icac

y/to

xic)

:1,3 T

he e

ffec

tive

dose

is 7

50 m

g ev

ery

8 ho

urs.

The

hig

hest

doc

umen

ted

dose

of T

VR a

dmin

iste

red

alon

e is

187

5 m

g ev

ery

8 ho

urs

for f

our d

ays

in h

ealth

y hu

man

sub

ject

s. A

dver

se e

vent

s re

port

ed m

ore

freq

uent

ly a

t tha

t dos

e in

com

pari

son

to 7

50 m

g ev

ery

8 ho

urs

wer

e na

usea

, hea

dach

e, d

iarr

hea,

dec

reas

ed a

ppet

ite, d

ysge

usia

, and

vom

iting

. Als

o, h

ighe

r dos

e ex

posu

re w

as s

igni

fican

tly a

ssoc

iate

d w

ith in

crea

sed

risk

of a

nem

ia o

r hem

oglo

bin

toxi

city

(hgb

<10

g/dL

or

a de

crea

se o

f 3.5

g/d

L fr

om b

asel

ine)

. Se

vera

l oth

er u

nans

wer

ed q

uest

ions

rem

ain

with

rega

rd to

trea

tmen

t and

saf

ety,

incl

udin

g:

How

do

non-

Cauc

asia

n, c

irrh

otic

, liv

er-t

rans

plan

t, o

r H

IV o

r HBV

co-

infe

cted

pat

ient

s re

spon

d to

TVR

ther

apy,

as

repr

esen

tatio

n of

his

tori

cally

di

ffic

ult-

to-t

reat

sub

ject

s w

as li

mite

d in

all

tria

ls?

Wha

t is

the

dosi

ng fo

r ped

iatr

ic p

atie

nts?

W

hat f

acto

rs, s

uch

as g

enet

ics,

are

ass

ocia

ted

with

sev

ere

skin

reac

tions

?

Wou

ld p

atie

nts

prev

ious

ly fa

iled

trea

tmen

t with

a T

VR-c

onta

inin

g re

gim

en re

spon

d to

a r

epea

t cou

rse

of th

erap

y?

Wha

t is

the

long

-ter

m c

linic

al im

pact

of e

mer

genc

e or

per

sist

ence

of T

VR-a

ssoc

iate

d re

sist

ance

am

ino

acid

sub

stitu

tions

? W

hat i

s th

e im

pact

of T

VR e

xpos

ure

or tr

eatm

ent f

ailu

re o

n th

e ef

ficac

y of

oth

er H

CV N

S3/4

pro

teas

e in

hibi

tors

, suc

h as

boc

epre

vir?

Res

earc

hers

ha

ve d

emon

stra

ted

NS3

am

ino

acid

sub

stitu

tions

(V36

, T54

, R15

5, A

156,

or

D16

8) d

etec

ted

in T

VR-t

reat

ed s

ubje

cts

who

did

not

ach

ieve

SVR

in

clin

ical

tria

ls r

educ

es th

e an

ti-H

CV a

ctiv

ity o

f boc

epre

vir a

nd o

ther

NS3

/4 p

rote

ase

inhi

bito

rs.3

Wha

t ant

i-HCV

act

ivity

doe

s TV

R ha

ve a

gain

st n

on-g

enot

ype

1 H

CVs?

3 Lo

ok-a

like

/ So

und-

alik

e (L

A/S

A) E

rror

Ris

k Po

tent

ial:

LA/S

A n

ames

are

ass

esse

d du

ring

the

PDL

sele

ctio

n of

dru

gs.

Base

d on

clin

ical

judg

men

t and

an

eval

uatio

n of

LA/

SA in

form

atio

n fr

om fo

ur d

ata

sour

ces

(Lex

icom

p, U

SP O

nlin

e LA

SA F

inde

r, a

nd IS

MP

Conf

used

Dru

g N

ame

List

), th

e fo

llow

ing

drug

nam

es m

ay c

ause

LA

SA c

onfu

sion

: N

ME

Dru

g N

ame

Lexi

com

p U

SP O

nlin

e IS

MP

Clin

ical

Judg

men

t LA

/SA

for t

elap

revi

r (g

ener

ic)

Non

e N

one

Non

e N

one

LA/S

A fo

r Tel

apre

vir™

(bra

nd)

Non

e

Non

e N

one

Non

e

120 of 187

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eric

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e: T

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ber 2

011

14

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

AD

VER

SE R

EACT

ION

S1

121 of 187

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eric

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e: T

elap

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iew

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e: N

ovem

ber 2

011

15

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

DO

SE &

AV

AIL

ABI

LITY

1

STRE

NG

TH

FORM

RO

UTE

FR

EQU

ENCY

RE

NA

L A

DJ

HEP

ATI

C A

DJ

Pedi

atri

c

Dos

e El

derl

y D

ose

375

mg

Ta

blet

O

ral

750

mg

thre

e tim

es

daily

(7-9

ho

ur a

part

)

Non

e

Non

e fo

r m

ild h

epat

ic

impa

irm

ent.

Not

re

com

men

ded

for

mod

erat

e or

sev

ere

hepa

tic

impa

irm

ent (

Child

-Pug

h B

or C

, sco

re ≥

7)

Safe

ty a

nd

effe

ctiv

enes

s no

t es

tabl

ishe

d

Resp

onse

to th

erap

y in

pat

ient

s >

65

year

s ol

d is

unc

erta

in; t

here

fore

, ca

utio

n sh

ould

be

exer

cise

d

OTH

ER D

OSI

NG

CO

NSI

DER

ATI

ON

S:

• A

dmin

iste

r w

ith fo

od (n

ot lo

w fa

t), o

ther

wis

e ex

posu

re m

ay b

e in

adeq

uate

•

Dur

atio

n of

ther

apy

for p

atie

nts

achi

evin

g eR

VR is

12

wee

ks o

f TVR

and

24

wee

ks o

f PR.

Pat

ient

s w

ithou

t eRV

R an

d pr

ior p

artia

l and

nul

l re

spon

ders

sho

uld

rece

ive

12 w

eeks

of T

VR p

lus

48 w

eeks

of P

R. T

reat

men

t-na

ïve

patie

nts

who

hav

e ci

rrho

sis

and

eRVR

may

ben

efit

from

48

wee

ks o

f PR.

(Not

e: a

hig

h pr

opor

tion

of p

revi

ous

null

resp

onde

rs, p

artic

ular

ly th

ose

with

cir

rhos

is, d

id n

ot a

chie

ve S

VR a

nd h

ad T

VR-

resi

stan

ce s

ubst

itutio

ns e

mer

ge.)

• Th

e do

se o

f tel

apre

vir m

ust n

ot b

e re

duce

d or

inte

rrup

ted.

•

App

licat

ion

of s

topp

ing

rule

s ar

e re

com

men

ded:

If H

CV R

NA

at w

eek

4 or

12

is ≥

1000

IU/m

L, d

/c te

lapr

evir

and

PR

(tel

apre

vir

trea

tmen

t co

mpl

ete

at 1

2 w

eeks

). If

HCV

RN

A is

det

ecta

ble

at w

eek

24, d

/c P

R.

• Th

e sa

fety

and

eff

icac

y of

tela

prev

ir h

ave

not b

een

esta

blis

hed

in p

atie

nts

co-in

fect

ed w

ith H

CV/H

IV o

r H

CV/H

BV a

nd in

sol

id o

rgan

tran

spla

nt

patie

nts.

•

See

pres

crib

ing

info

rmat

ion

for P

EG a

nd R

IB fo

r oth

er d

osin

g co

nsid

erat

ions

. PH

ARM

ACO

KIN

ETIC

S1,3

Para

met

er

Resu

lt

Ora

l Bio

avai

labi

lity

Vari

es w

ith s

peci

es (f

rom

<22

% in

rab

bits

to 7

0–95

% in

fed

dogs

)*

Prot

ein

Bind

ing

59%

to 7

6%

Elim

inat

ion

82%

in th

e fe

ces,

9%

in e

xhal

ed a

ir, 1

% in

uri

ne

Hal

f-Li

fe

9 to

11

hour

s at

ste

ady

stat

e M

etab

olis

m

CYP3

A4

(maj

or)

*Foo

d m

arke

dly

affe

cts

expo

sure

to

TVR,

with

up

to f

our-

fold

incr

ease

in e

xpos

ure

whe

n ad

min

iste

red

with

sta

ndar

d te

st b

reak

fast

. H

ighe

r fa

t co

nten

t inc

reas

es e

xpos

ure.

122 of 187

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eric

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revi

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iew

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e: N

ovem

ber 2

011

16

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

PHA

RMA

COG

ENET

ICS1

Retr

ospe

ctiv

e st

udie

s in

dica

te t

riple

the

rapy

incr

ease

d SV

R ra

tes

rega

rdle

ss o

f ge

noty

pe in

tre

atm

ent-

naïv

e an

d tr

eatm

ent-

expe

rien

ced

patie

nts.

H

owev

er, t

hese

res

ults

sho

uld

be v

iew

ed c

autio

usly

, bec

ause

the

sam

ple

size

was

sm

all a

nd t

he s

ubst

udy

popu

latio

ns m

ay n

ot r

epre

sent

the

ful

l tr

ial p

opul

atio

ns.

ALL

ERG

IES/

INTE

RACT

ION

S1

Dru

g-D

rug:

TVR

is a

sub

stra

te a

nd s

tron

g in

hibi

tor

of C

YP3A

4 an

d a

subs

trat

e an

d in

hibi

tor o

f P-g

lyco

prot

ein.

Dru

gs c

ontr

aind

icat

ed (

adve

rse

even

t):

alfu

zosi

n (h

ypot

ensi

on o

r ca

rdia

c ar

rhyt

hmia

), rif

ampi

n (r

educ

ed T

VR p

lasm

a co

ncen

trat

ion)

, er

got

deri

vativ

es (

acut

e er

got

toxi

city

), St

. Jo

hn’s

wor

t (r

educ

ed T

VR p

lasm

a co

ncen

trat

ion)

, at

orva

stat

in o

r lo

vast

atin

or

sim

vast

atin

(m

yopa

thy)

, pi

moz

ide

(car

diac

arr

hyth

mia

s),

sild

enaf

il or

tad

alaf

il do

sed

for

pulm

onar

y ar

teria

l hyp

erte

nsio

n (P

DE5

inhi

bito

r-as

soci

ated

adv

erse

eve

nts)

, or

al

mid

azol

am o

r tr

iazo

lam

(inc

reas

ed s

edat

ion

or r

espi

rato

ry d

epre

ssio

n), a

nd c

isap

ride

(car

diac

arr

hyth

mia

s).

Doz

ens

of o

ther

dru

g in

tera

ctio

ns w

ith T

VR a

re p

redi

cted

or

have

bee

n co

nfir

med

via

stu

dies

. Sev

eral

of

thes

e dr

ugs

requ

ire

dose

adj

ustm

ents

or

clin

ical

mon

itorin

g w

hen

used

con

com

itant

ly w

ith T

VR.

Food

-Dru

g:

No

food

-dru

g in

tera

ctio

ns h

ave

been

rep

orte

d.1

123 of 187

Gen

eric

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e: T

elap

revi

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iew

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e: N

ovem

ber 2

011

17

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

APP

END

IX 1

Su

gges

ted

PA C

rite

ria

Hep

ati

tis C

Ora

l P

rote

ase I

nh

ibit

ors

/Tri

ple

Th

era

py

C

ov

ere

d

Alt

ern

ati

ves

: Lis

ted a

t; h

ttp://w

ww

.ore

go

n.g

ov/D

HS

/hea

lth

pla

n/t

ools

_pro

v/p

dl.shtm

l

Ap

pro

val

Cri

teri

a

1. W

hat is

the d

iag

nosis

?

R

ecord

IC

D-9

code

2. Is

the

dia

gnosis

an O

HP

covere

d d

iag

nosis

?

Yes:

Go to #

3.

No

: P

ass to R

Ph

, D

en

y f

or

OH

P C

overa

ge.

3. Is

the

requ

est fo

r tr

eatm

ent of

Chro

nic

H

epatitis C

?

Docum

ent appro

pri

ate

IC

D9 c

ode:

Yes:

Go to #

4

No

: P

ass

to R

Ph, D

eny

For

Appr

opria

tene

ss

4. D

oes the p

atien

t ha

ve

do

cum

ente

d H

CV

gen

oty

pe 1

?

Record

Gen

oty

pe:

Yes:

Go to #

5

No

: P

ass

to R

Ph, D

eny

For

Appr

opria

tene

ss

5. D

oes the p

atien

t ha

ve

a p

re-t

reatm

ent viral lo

ad (

sin

ce d

iagnosis

)?

Yes:

Go to #

6

No

: P

ass to R

Ph;

Den

y F

or

Appro

pria

ten

ess; R

ecom

mend

vira

l lo

ad

6. Is

the

patie

nt a

lso b

ein

g p

rescribed p

eg

inte

rfero

n a

lfa

-2a o

r -2

b a

nd r

iba

virin

?

Yes:

Go to #

7

N

o:

Pas

s to

RPh

, Den

y Fo

r Ap

prop

riate

ness

7. H

as p

rior

auth

ori

zation b

een g

rante

d f

or

peg

inte

rfero

n a

lfa

-2a o

r -2

b a

nd r

iba

vir

in o

r does p

atient m

eet pri

or

auth

ori

zation

crite

ria f

or

peg

yla

ted inte

rfero

n-a

lfa?

Yes: G

o t

o #

8

No

: P

ass to

RP

h; D

en

y f

or

appro

priate

ness

8. Is th

e r

eq

uest fo

r contin

uation o

f th

era

py? (

Patien

t has b

een o

n t

riple

th

era

py w

ith

a o

ral antivira

l a

gen

t in

pre

cedin

g 6

weeks)

Yes:

Go to “

Continu

ation o

f T

hera

py”

. N

o:

Go to #

9

9. H

as t

he p

atient

pre

vio

usly

been t

reate

d w

ith b

ocepre

vir o

r te

lapre

vir

?

Yes: P

ass to R

Ph, D

en

y f

or

appro

priate

ness

No

: G

o to #

10

10. Is

th

e r

eq

uest fo

r te

lapre

vir 7

50m

g (

two t

abs)

TID

for

12 w

eeks?

Y

es:

Ap

pro

ve f

or

6 w

eeks to a

llow

for

4 w

eek v

iral lo

ad c

heck to c

ontinue

for

a m

axim

um

of

12 w

eeks

No

: G

o to #

11 (

If d

ose is

diffe

rent pass to R

Ph f

or

appro

priate

ness)

11. Is

th

e r

eq

uest fo

r boce

pre

vir 8

00m

g (

four

tabs)

TID

and t

he p

atien

t has c

om

ple

ted

4 w

eeks o

f le

ad-i

n tre

atm

ent

with r

iba

virin

and p

eg

inte

rfero

n?

Yes:

Appro

ve f

or

10 w

eeks to a

llow

for

8 w

eek v

iral lo

ad c

heck to c

ontinue

for

a m

axim

um

of

24, 32,

or

40

weeks

based o

n r

esp

onse

No

: P

ass to R

Ph;

Den

y f

or

appro

priate

ness

124 of 187


Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

18

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Co

nti

nu

ati

on

of

Th

era

py-

Te

lap

revir

1

. Is

th

e p

atie

nt

tre

atm

en

t-

na

ïve

or

a p

rio

r re

lap

se

p

atien

t an

d h

as u

nd

ete

cta

ble

H

CV

RN

A o

r m

easu

red

at 4

a

nd

12

we

eks?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 6

we

eks o

f tr

iple

th

era

py w

ith

te

lap

revir

, p

eg

inte

rfe

ron

, a

nd

rib

avir

in (

tota

l 1

2 w

ee

ks),

fo

llow

ed

by

co

ntin

ued

dua

l th

era

py w

ith

peg

inte

rfe

ron a

nd r

iba

va

rin

fo

r 1

2 w

ee

ks (

tota

l tr

eatm

en

t du

ratio

n o

f 2

4 w

ee

ks).

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

Pa

tie

nts

with

in

ad

eq

ua

te v

ira

l re

sp

on

se a

re u

nlik

ely

to

ach

ieve

SV

R,

an

d m

ay d

eve

lop

tre

atm

en

t-em

erg

en

t re

sis

tance

su

bstitu

tion

s.

Dis

con

tin

ua

tio

n o

f th

era

py is r

ecom

men

ded

in

all

pa

tie

nts

with

(1

) H

CV

-RN

A le

ve

ls o

f g

reate

r th

an

or

equ

al to

10

00

IU

/mL a

t T

rea

tme

nt

Week 4

or

12

; o

r (2

) co

nfirm

ed d

ete

cta

ble

HC

V-R

NA

le

ve

ls a

t T

rea

tme

nt W

eek 2

4.

2.

Is th

e p

atie

nt

tre

atm

en

t-

na

ïve

or

a p

rio

r re

lap

se

p

atien

t an

d h

as d

ete

cta

ble

(1

00

0 I

U/m

L o

r le

ss)

at W

eeks

4 a

nd

/or

12

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 6

we

eks o

f tr

iple

th

era

py w

ith

te

lap

revir

, p

eg

inte

rfe

ron

, a

nd

rib

avir

in (

tota

l 1

2 w

ee

ks),

fo

llow

ed

by

co

ntin

ued

dua

l th

era

py w

ith

peg

inte

rfe

ron a

nd r

iba

va

rin

fo

r a

dd

itio

na

l 36

we

eks (

tota

l tr

eatm

en

t d

ura

tio

n o

f 48

we

eks).

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

Pa

tie

nts

with

in

ad

eq

ua

te v

ira

l re

sp

on

se a

re u

nlik

ely

to

ach

ieve

SV

R,

an

d m

ay d

eve

lop

tre

atm

en

t-em

erg

en

t re

sis

tance

su

bstitu

tion

s.

Dis

con

tin

ua

tio

n o

f th

era

py is r

ecom

men

ded

in

all

pa

tie

nts

with

(1

) H

CV

-RN

A le

ve

ls o

f g

reate

r th

an

or

equ

al to

10

00

IU

/mL a

t T

rea

tme

nt

Week 4

or

12

; o

r (2

) co

nfirm

ed d

ete

cta

ble

HC

V-R

NA

le

ve

ls a

t T

rea

tme

nt W

eek 2

4.

3.

Is th

e p

atie

nt a

prio

r p

art

ial

or

nu

ll re

sp

on

de

r?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 6

we

eks o

f tr

iple

th

era

py w

ith

te

lap

revir

, p

eg

inte

rfe

ron

, a

nd

rib

avir

in (

tota

l 1

2 w

ee

ks),

fo

llow

ed

by

co

ntin

ued

dua

l th

era

py w

ith

peg

inte

rfe

ron a

nd r

iba

va

rin

fo

r a

dd

itio

na

l 36

we

eks (

tota

l tr

eatm

en

t d

ura

tio

n o

f 48

we

eks).

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

4.

Is th

e p

atie

nt

tre

atm

en

t-

na

ïve

with

docu

me

nte

d

cir

rhosis

wh

o h

as

un

de

tecta

ble

HC

V-R

NA

at

we

eks 4

an

d 1

2?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 6

we

eks o

f tr

iple

th

era

py w

ith

te

lap

revir

, p

eg

inte

rfe

ron

, a

nd

rib

avir

in (

tota

l 1

2 w

ee

ks),

fo

llow

ed

by

co

ntin

ued

dua

l th

era

py w

ith

peg

inte

rfe

ron a

nd r

iba

va

rin

fo

r a

dd

itio

na

l 36

we

eks (

tota

l tr

eatm

en

t d

ura

tio

n o

f 48

we

eks).

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

Pa

tie

nts

with

in

ad

eq

ua

te v

ira

l re

sp

on

se a

re u

nlik

ely

to

ach

ieve

SV

R,

an

d m

ay d

eve

lop

tre

atm

en

t-em

erg

en

t re

sis

tance

su

bstitu

tion

s.

Dis

con

tin

ua

tio

n o

f th

era

py is r

ecom

men

ded

in

all

pa

tie

nts

with

(1

) H

CV

-RN

A le

ve

ls o

f g

reate

r th

an

or

equ

al to

10

00

IU

/mL a

t T

rea

tme

nt

Week 4

or

12

; o

r (2

) co

nfirm

ed d

ete

cta

ble

HC

V-R

NA

le

ve

ls a

t T

rea

tme

nt W

eek 2

4.

*TR

EA

TM

EN

T F

UT

ILIT

Y R

UL

ES

Week 4

or

Week 1

2:

HC

V-R

NA

gre

ate

r th

an

100

0 I

U/m

L: D

iscon

tinu

e I

NC

IVE

K a

nd

pe

gin

terf

ero

n a

lfa

and

rib

avir

in (

INC

IVE

K t

rea

tme

nt com

ple

te a

t 1

2 w

ee

ks)

Week 2

4:

Dete

cta

ble

Dis

con

tin

ue

pe

gin

terf

ero

n a

nd

rib

avir

in.

If p

egin

terf

ero

n a

lfa

or

rib

avir

in is d

isco

ntin

ue

d fo

r a

ny r

ea

son,

INC

IVE

K m

ust

als

o b

e d

iscon

tin

ue

d

125 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

19

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Co

nti

nu

ati

on

of

Th

era

py-

Bo

ce

pre

vir

1

.Is th

e p

atie

nt

tre

atm

en

t-n

aïv

e a

nd

ha

ve

un

de

tecta

ble

HC

V R

NA

at

tre

atm

en

t w

ee

ks 8

an

d 2

4?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 1

4 w

ee

ks o

f b

oce

pre

vir

fo

r to

tal tr

ea

tme

nt d

ura

tio

n o

f 2

8 w

ee

ks (

4 w

ee

k lea

d-in

, 24

we

eks t

riple

th

era

py)

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

2.

Is th

e p

atie

nt

tre

atm

en

t-n

aïv

e a

nd

ha

ve

de

tecta

ble

HC

V R

NA

at

tre

atm

en

t w

ee

k 8

and

und

ete

cta

ble

a

t w

ee

k 2

4?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 2

2 w

ee

ks o

f b

oce

pre

vir

fo

llow

ed

by c

on

tinu

ed

du

al

the

rap

y w

ith

peg

inte

rfe

ron

and r

iba

vir

in f

or

16

we

eks f

or

tota

l tr

ea

tme

nt

du

ratio

n o

f 4

8 w

ee

ks (

4 w

ee

k le

ad

-in,

32 w

ee

ks t

rip

le t

he

rap

y,

12

we

eks

du

al th

era

py)

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

3.

Is th

e p

atie

nt a

pre

vio

us p

art

ial

resp

on

de

r o

r re

lapse

r an

d h

ave

u

nd

ete

cta

ble

HC

V R

NA

at

treatm

en

t w

ee

ks 8

an

d 2

4?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 2

2 w

ee

ks o

f b

oce

pre

vir

fo

r to

tal tr

ea

tme

nt

du

ratio

n o

f 3

6 w

ee

ks (

4 w

ee

k le

ad

-in,

32 w

ee

ks t

rip

le t

he

rap

y)

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

4.

Is th

e p

atie

nt a

pre

vio

us p

art

ial

resp

on

de

r o

r re

lapse

r an

d h

ave

d

ete

cta

ble

HC

V R

NA

at

tre

atm

en

t w

ee

k 8

an

d u

nde

tecta

ble

at

we

ek

24

?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 2

2 w

ee

ks o

f b

oce

pre

vir

fo

llow

ed

by c

on

tinu

ed

d

ua

l th

era

py w

ith

pe

gin

terf

ero

n a

nd

rib

avirin

fo

r 1

6 w

ee

ks f

or

tota

l tr

ea

tme

nt d

ura

tio

n o

f 48

we

eks (

4 w

ee

k le

ad

-in

, 3

2 w

ee

ks t

rip

le

the

rap

y,

12

we

eks d

ual th

era

py)

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

5.

Do

es t

he p

atie

nt h

ave

do

cum

ente

d c

irrh

osis

or

is

do

cum

ente

d a

s a

null

respo

nde

r a

nd

d

oe

s n

ot m

eet

the

fu

tilit

y r

ule

s a

t tr

ea

tme

nt

we

eks 8

,12

, a

nd

24?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• C

on

tin

ue

trip

le t

he

rap

y w

ith

boce

pre

vir

fo

r a

to

tal tr

ea

tme

nt

du

ratio

n o

f 4

8 w

ee

ks (

4 w

ee

k le

ad

-in,

44 w

ee

ks t

rip

le t

he

rap

y).

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

*TR

EA

TM

EN

T F

UT

ILIT

Y R

UL

ES

If t

he

pa

tie

nt h

as H

CV

-RN

A r

esu

lts g

rea

ter

tha

n o

r eq

ual to

10

0 I

U/m

L a

t T

W12,

then

dis

con

tin

ue

th

ree

-me

dic

ine

re

gim

en.

If t

he

pa

tie

nt h

as c

on

firm

ed

, de

tecta

ble

HC

V-R

NA

at

TW

24

, th

en

dis

co

ntin

ue

th

ree

-me

dic

ine

re

gim

en.

126 of 187

Gen

eric

Nam

e: T

elap

revi

r

Rev

iew

Dat

e: N

ovem

ber 2

011

20

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Refe

renc

es

1. In

cive

k pa

ckag

e in

sert

. Cam

brid

ge, M

A: V

erte

x Ph

arm

aceu

tical

s In

corp

orat

ed; 2

011

May

. 2.

Gha

ny M

G, N

elso

n D

R, S

trad

er D

B, T

hom

as D

L, e

t al.

An

upda

te o

n tr

eatm

ent o

f gen

otyp

e 1

chro

nic

hepa

titis

C v

irus

infe

ctio

n: 2

011

prac

tice

guid

elin

e by

the

Am

eric

an A

ssoc

iatio

n fo

r the

Stu

dy o

f Liv

er D

isea

ses.

Hep

atol

ogy.

201

1; 5

4(4)

:143

3-44

. 3.

Foo

d an

d D

rug

Adm

inis

trat

ion

Cent

er fo

r Dru

g Ev

alua

tion

and

Rese

arch

. App

licat

ion

num

ber:

201

917O

rig1

s000

sum

mar

y re

view

. ht

tp:/

/ww

w.a

cces

sdat

a.fd

a.go

v/dr

ugsa

tfda

_doc

s/nd

a/20

11/2

0191

7Ori

g1s0

00Su

mR.

pdf (

acce

ssed

201

1 Se

p. 2

6)

4. S

herm

an K

E, F

lam

m S

L, A

fdha

l NH

, et a

l. Re

spon

se-g

uide

d te

lapr

evir

com

bina

tion

trea

tmen

t for

hep

atiti

s C

viru

s in

fect

ion.

N E

ngl J

Med

. 201

1;

365(

11):1

014-

24. E

rrat

um in

: N E

ngl J

Med

. 201

1 O

ct 2

0;36

5(16

):155

1.

5. Z

euze

m S

, And

reon

e P,

Pol

S, e

t al.

Tela

prev

ir fo

r re

trea

tmen

t of H

CV in

fect

ion.

N E

ngl J

Med

. 201

1; 3

64(2

5):2

417-

28.

6. Ja

cobs

on IM

, McH

utch

ison

JG, D

ushe

iko

G, e

t al.

Tela

prev

ir fo

r pre

viou

sly

untr

eate

d ch

roni

c he

patit

is C

vir

us in

fect

ion.

N E

ngl J

Med

. 201

1;

364(

25):2

405-

16.

7. G

hany

MG

, Str

ader

DB,

Tho

mas

DL,

et a

l. A

mer

ican

Ass

ocia

tion

for t

he S

tudy

of L

iver

Dis

ease

s. D

iagn

osis

, man

agem

ent,

and

trea

tmen

t of

hepa

titis

C: a

n up

date

. Hep

atol

ogy.

200

9; 4

9(4)

:133

5-74

. 8.

Ros

en H

R. C

linic

al p

ract

ice.

Chr

onic

hep

atiti

s C

infe

ctio

n. N

Eng

l J M

ed. 2

011;

364

(25)

:242

9-38

. 9.

Héz

ode

C, F

ores

tier N

, Dus

heik

o G

, Fer

enci

P, P

ol S

, Goe

ser T

, Bro

now

icki

JP, B

ourl

ière

M, G

hara

khan

ian

S, B

engt

sson

L, M

cNai

r L,

Geo

rge

S,

Kief

fer

T, K

won

g A,

Kau

ffm

an R

S, A

lam

J, P

awlo

tsky

JM, Z

euze

m S

; PRO

VE2

Stud

y Te

am. T

elap

revi

r and

peg

inte

rfer

on w

ith o

r w

ithou

t rib

avir

in fo

r ch

roni

c H

CV in

fect

ion.

N E

ngl J

Med

. 200

9; 3

60(1

8):1

839-

50.

10. M

cHut

chis

on JG

, Man

ns M

P, M

uir

AJ,

Terr

ault

NA,

Jaco

bson

IM, A

fdha

l NH

, Hea

thco

te E

J, Ze

uzem

S, R

eesi

nk H

W, G

arg

J, Bs

hara

t M, G

eorg

e S,

Ka

uffm

an R

S, A

dda

N, D

i Bis

cegl

ie A

M; P

ROVE

3 St

udy

Team

. Tel

apre

vir f

or p

revi

ousl

y tr

eate

d ch

roni

c H

CV in

fect

ion.

N E

ngl J

Med

. 201

0 Ap

r 8;

362(

14):1

292-

303.

Err

atum

in: N

Eng

l J M

ed. 2

010;

362

(17)

:164

7.

11. M

cHut

chis

on JG

, Eve

rson

GT,

Gor

don

SC, J

acob

son

IM, S

ulko

wsk

i M, K

auff

man

R, M

cNai

r L,

Ala

m J,

Mui

r AJ;

PRO

VE1

Stud

y Te

am. T

elap

revi

r w

ith p

egin

terf

eron

and

rib

avir

in fo

r chr

onic

HCV

gen

otyp

e 1

infe

ctio

n. N

Eng

l J M

ed. 2

009;

360

(18)

:182

7-38

. Err

atum

in: N

Eng

l J M

ed. 2

009

Oct

8;

361(

15):1

516.

12

. Eur

opea

n A

ssoc

iatio

n fo

r the

Stu

dy o

f the

Liv

er. E

ASL

Clin

ical

Pra

ctic

e G

uide

lines

: man

agem

ent o

f hep

atiti

s C

viru

s in

fect

ion.

J H

epat

ol. 2

011;

55

(2):2

45-6

4.

127 of 187

D

rug

Use

Res

earc

h &

Man

agem

ent P

rogr

am

Ore

gon

Stat

e U

nive

rsity

, 500

Sum

mer

Stre

et N

E, E

35, S

alem

, Ore

gon

9730

1-10

79

Phon

e 50

3-94

5-52

20 |

Fax

503-

947-

1119

1 M

onth

/Yea

r of

Rev

iew

: N

ovem

ber 2

011

En

d da

te o

f lit

erat

ure

sear

ch:

4th Q

uart

er 2

011

Gen

eric

Nam

e: B

ocep

revi

r M

anuf

actu

rer:

Mer

ck &

Co.

, Inc

. Br

and

Nam

e: V

ictr

elis

™

D

ossi

er r

ecei

ved:

No

PDL

Clas

s: H

epat

itis

C An

tivir

als

Com

para

tor

Ther

apie

s: p

egin

terf

eron

alfa

-2b

plus

rib

avir

in (P

R)

al

one

FDA

App

rove

d In

dica

tion

s:1 B

ocep

revi

r is

indi

cate

d fo

r tre

atin

g ch

roni

c he

patit

is C

(CH

C) g

enot

ype

1 in

fect

ion,

onl

y in

com

bina

tion

with

pe

gint

erfe

ron

alfa

and

riba

viri

n (P

R), i

n pa

tient

s >1

8 ye

ars

of a

ge w

ith c

ompe

nsat

ed li

ver d

isea

se, i

nclu

ding

cirr

hosi

s, w

ho a

re p

revi

ousl

y un

trea

ted

or w

ho h

ave

faile

d pr

evio

us in

terf

eron

and

rib

aviri

n th

erap

y. T

he fo

llow

ing

shou

ld b

e co

nsid

ered

whe

n in

itiat

ing

ther

apy

with

boc

epre

vir:

•

Boce

prev

ir ef

ficac

y ha

s no

t bee

n st

udie

d in

pat

ient

s pr

evio

usly

faili

ng th

erap

y w

ith a

trea

tmen

t reg

imen

incl

udin

g bo

cepr

evir

or o

ther

pro

teas

e in

hibi

tors

for

the

trea

tmen

t of h

epat

itis

C vi

rus.

•

At t

his

time,

ther

e ar

e cu

rren

tly n

o pu

blis

hed

tria

ls th

at e

valu

ated

boc

epre

vir

in c

ombi

natio

n w

ith P

R in

pat

ient

s w

ith a

prio

r nu

ll re

spon

se (<

2-lo

g 10 H

CV-R

NA

decl

ine

by tr

eatm

ent w

eek

12) t

o PR

. The

cur

rent

clin

ical

stu

dies

incl

uded

sub

ject

s w

ho w

ere

poor

ly in

terf

eron

res

pons

ive.

Sub

ject

s w

ith <

0.5-

log1

0 H

CV-R

NA

dec

line

in v

iral

load

at t

reat

men

t wee

k 4

with

PR

alon

e ar

e pr

edic

ted

to h

ave

a nu

ll re

spon

se to

PR

ther

apy.

•

Poor

ly in

terf

eron

res

pons

ive

(as

dete

rmin

ed a

t tre

atm

ent w

eek

4) p

atie

nts

trea

ted

with

boc

epre

vir

in c

ombi

natio

n w

ith P

R ha

ve a

low

er

likel

ihoo

d of

ach

ievi

ng a

sus

tain

ed v

irolo

gic

resp

onse

(SVR

), an

d a

high

er ra

te o

f det

ectio

n of

resi

stan

ce-a

ssoc

iate

d su

bstit

utio

ns u

pon

trea

tmen

t fa

ilure

, com

pare

d to

pat

ient

s w

ith a

gre

ater

res

pons

e to

PR.

Su

mm

ary:

Am

eric

an A

ssoc

iatio

n fo

r the

Stu

dy o

f Liv

er D

isea

ses

(AA

SLD

) gui

delin

es re

com

men

d tr

iple

ther

apy

with

boc

epre

vir

(BO

C) in

com

bina

tion

with

PR

as a

firs

t-lin

e tr

eatm

ent f

or C

HC2 . E

vide

nce

for u

se o

f trip

le th

erap

y co

mes

from

two

phas

e 3

stud

ies3 . M

oder

ate

leve

l evi

denc

e sh

ows

dosi

ng B

OC

in c

ombi

natio

n w

ith P

R im

prov

ed S

VR r

ates

in tr

eatm

ent-

naïv

e4 and

in tr

eatm

ent-

expe

rien

ced

patie

nts5 , s

peci

fical

ly p

artia

l res

pond

ers

and

rela

pser

s. H

owev

er, s

ever

al u

nres

olve

d qu

estio

ns r

emai

n w

ith re

gard

to o

ptim

al tr

eatm

ent d

urat

ion

in c

irrh

otic

pat

ient

s, n

ull r

espo

nder

s, la

te

resp

onde

rs, a

nd b

lack

pat

ient

s. In

add

ition

, stu

dies

did

not

dir

ectly

com

pare

res

pons

e-gu

ided

ther

apy

to fi

xed-

dura

tion

ther

apy.

SP

RIN

T-2

rand

omiz

ed 1

099

subj

ects

1:1

:1 a

nd te

sted

whe

ther

24

wee

ks o

r 44

wee

ks o

f BO

C pl

us P

R (G

roup

2 a

nd G

roup

3, r

espe

ctiv

ely)

was

su

peri

or to

44

wee

ks o

f PR

alon

e (G

roup

1). E

ach

trea

tmen

t reg

imen

was

pre

cede

d by

4 w

eeks

of P

R th

erap

y (i.

e., l

ead-

in).

Gro

ups

1 an

d 3

ende

d

128 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

2 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

trea

tmen

t at w

eek

48, G

roup

2 e

arly

res

pond

ers

ende

d tr

eatm

ent a

t wee

k 28

, whi

le G

roup

2 la

te re

spon

ders

rece

ived

an

addi

tiona

l 20

wee

ks o

f PR

and

ende

d tr

eatm

ent a

t wee

k 48

. For

the

com

bine

d co

hort

s an

d fo

r the

bla

ck a

nd n

on-b

lack

coh

orts

, BO

C-co

ntai

ning

reg

imen

s w

ere

stat

istic

ally

su

peri

or to

PR.

The

abs

olut

e ri

sk r

educ

tions

(ARR

) in

SVR

rate

s fo

r the

com

bine

d co

hort

wer

e 25

% fo

r G

roup

2 v

. 1 (p

<0.0

01) a

nd 2

8% fo

r Gro

up 3

v.

1 (p

<0.0

01),

givi

ng N

NTs

of 4

for

each

com

pari

son,

res

pect

ivel

y.4 S

PRIN

T-2

rese

arch

ers

indi

cate

d th

at a

tota

l tre

atm

ent d

urat

ion

of 2

8 w

eeks

wou

ld

be s

uffic

ient

for

earl

y re

spon

ders

, whi

le 4

8 w

eeks

of t

hera

py (4

wee

ks o

f lea

d-in

, 24

wee

ks o

f tri

ple

ther

apy,

and

20

wee

ks o

f PR

alon

e) w

ould

be

pref

erre

d fo

r la

te re

spon

ders

. How

ever

, the

FD

A re

com

men

ded

4 w

eeks

of l

ead-

in, 3

2 w

eeks

of t

riple

ther

apy,

and

12

wee

ks o

f PR

for

late

re

spon

ders

bas

ed o

n a

rean

alys

is o

f the

SVR

rat

es o

f Gro

ups

2 an

d 3

and

a su

bgro

up a

naly

sis

of e

arly

and

late

res

pond

ers.

RE

SPO

ND

-2 r

ando

miz

ed 4

03 p

rior

par

tial r

espo

nder

s an

d re

laps

ers

1:2:

2 an

d te

sted

whe

ther

32

wee

ks o

r 44

wee

ks o

f BO

C pl

us P

R (G

roup

2 a

nd

Gro

up 3

, res

pect

ivel

y) w

as s

uper

ior t

o 44

wee

ks P

R al

one

(48

wee

ks in

clud

ing

lead

-in).

Gro

ups

1 an

d 3

ende

d tr

eatm

ent a

t wee

k 48

. Gro

up 2

ear

ly

resp

onde

rs e

nded

trea

tmen

t at w

eek

36, w

hile

Gro

up 2

late

res

pond

ers

rece

ived

an

addi

tiona

l 12

wee

ks o

f PR

and

ende

d tr

eatm

ent a

t wee

k 48

. Bo

th B

OC-

cont

aini

ng r

egim

ens

wer

e st

atis

tical

ly s

uper

ior t

o PR

. The

ARR

for

SVR

rate

s w

ere

38%

for

Gro

up 2

v. 1

(p<0

.001

) and

45%

for G

roup

3 v

. 1

(p<0

.001

), gi

ving

NN

Ts o

f 3 a

nd 2

, res

pect

ivel

y.5 E

ven

thou

gh n

ull r

espo

nder

s w

ere

excl

uded

from

this

tria

l, FD

A r

evie

wer

s re

com

men

ded

appr

oval

of t

ripl

e th

erap

y fo

r nul

l res

pond

ers

base

d on

pos

t-ho

c an

alys

is o

f tre

atm

ent-

naïv

e pa

tient

s fr

om S

PRIN

T-2

who

wer

e id

entif

ied

as n

ull

resp

onde

rs b

y H

CV le

vel m

easu

red

at tr

eatm

ent w

eek

4 w

ith a

low

cut

-off

: ≤0.

5 lo

g 10 d

eclin

e in

HCV

RN

A. P

atie

nts

who

wer

e nu

ll re

spon

ders

be

cam

e el

igib

le to

ent

er a

sub

sequ

ent t

rial

(the

PRO

VID

E tr

ial)

and

is o

ngoi

ng.

Post

-hoc

ana

lysi

s es

tabl

ishe

d a

44-w

eek

trip

le th

erap

y re

gim

en fo

r nu

ll re

spon

ders

as

wel

l as

for c

irrh

otic

pat

ient

s. A

ASL

D g

uide

lines

adv

ise

caut

ion

in u

sing

BO

C in

nul

l res

pond

ers.

D

ata

esta

blis

hes

the

supe

rior

ity o

f BO

C-co

ntai

ning

reg

imen

s ov

er P

R al

one,

in g

ener

al, d

espi

te s

ever

al in

tern

al a

nd e

xter

nal v

alid

ity c

once

rns

lead

ing

to “

fair

” qu

ality

ass

essm

ent r

atin

gs fo

r pha

se 3

stu

dies

. Als

o, q

uest

ions

are

out

stan

ding

with

reg

ard

to d

osin

g an

d re

spon

se in

trea

tmen

t-na

ïve

late

resp

onde

rs, t

reat

men

t-ex

perie

nced

nul

l res

pond

ers,

and

spe

cial

pop

ulat

ions

and

with

reg

ard

to m

anag

ing

ther

apy

in a

gen

eral

clin

ical

se

ttin

g an

d CH

C po

pula

tion,

giv

en th

e ca

refu

l mon

itorin

g fo

r res

pons

e, s

afet

y, a

nd tr

eatm

ent a

dher

ence

requ

ired

for t

hera

py.

The

inci

denc

e of

adv

erse

rea

ctio

ns w

ith tr

iple

ther

apy,

and

eve

n fo

r PR

alon

e, a

re q

uite

hig

h an

d la

rgel

y dr

iven

by

the

rate

s of

ane

mia

(45–

50%

), ne

utro

peni

a (1

4–25

%),

naus

ea (4

3–46

%),

dysg

eusi

a (3

5–44

%),

and

diar

rhea

(24–

25%

). T

here

was

an

abso

lute

ris

k in

crea

se fo

r de

velo

ping

ane

mia

of

20%

in S

PRIN

T-2

for G

roup

s 2

and

3 co

mpa

red

to th

e co

ntro

l gro

up a

nd a

n ab

solu

te r

isk

incr

ease

of 2

3% a

nd 2

6% in

Res

pond

-2 fo

r Gro

ups

2 an

d 3,

res

pect

ivel

y. I

ncre

ased

rat

es o

f ane

mia

req

uirin

g us

e of

an

eryt

hrop

oies

is s

timul

atin

g ag

ent (

ESA

) or

tran

sfus

ion

is th

e gr

eate

st s

afet

y co

ncer

n.

In a

dditi

on, t

reat

men

t is

com

plic

ated

req

uiri

ng p

atie

nt a

dher

ence

and

tim

ely

labo

rato

ry m

onito

ring

to g

uide

ther

apy.

Trip

le th

erap

y al

so is

ver

y ex

pens

ive

nece

ssita

ting

judi

ciou

s us

e of

thes

e ag

ents

in p

atie

nts.

129 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

3 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

PDL

Plac

emen

t Re

com

men

dati

on:

• Re

com

men

d BO

C re

quire

prio

r au

thor

izat

ion

to li

mit

its u

se to

trea

tmen

t in

geno

type

1 H

CV w

ith c

linic

al, d

ose,

and

dur

atio

n lim

its (A

ppen

dix

1).

• Co

nsid

er o

ther

con

side

ratio

ns s

uch

as d

urat

ion

of th

erap

y, c

ompl

exity

of d

osin

g re

gim

en, p

ill b

urde

n, s

ide

effe

ct p

rofil

e, a

nd e

vide

nce

in

prev

ious

nul

l res

pond

ers

whe

n ev

alua

ting

BOC

and

TVR.

•

Due

to h

igh

cost

of t

reat

men

t and

lack

of c

ompa

rativ

e ef

fect

iven

ess

evid

ence

, rec

omm

end

eval

uatin

g O

HA

cos

ts fo

r bot

h BO

C an

d TV

R fo

r co

nsid

erat

ion

of O

HA

man

agem

ent.

BA

CKG

ROU

ND

/CU

RREN

T LA

ND

SCA

PE

CHC

Trea

tmen

t res

pons

e is

def

ined

by

surr

ogat

e bi

oche

mic

al, h

isto

logi

cal,

and

viro

logi

cal p

aram

eter

s, r

athe

r tha

n cl

inic

al e

ndpo

ints

suc

h as

live

r di

seas

e an

d de

ath,

bec

ause

the

natu

ral h

isto

ry o

f CH

C ev

olve

s ov

er d

ecad

es.6 S

hort

-ter

m o

utco

mes

incl

ude

norm

aliz

atio

n of

ser

um A

LT le

vels

, 2

poin

t im

prov

emen

t in

necr

oinf

lam

mat

ory

scor

e w

ith n

o w

orse

ning

in fi

bros

is s

core

, and

cle

aran

ce o

f HCV

RN

A fr

om s

erum

as

mea

sure

d by

PCR

.6 Vi

rolo

gica

l par

amet

ers

are

divi

ded

into

the

follo

win

g: 6

–9

• su

stai

ned

viro

logi

cal r

espo

nse

(SVR

): th

e ab

senc

e of

HCV

RN

A fr

om s

erum

by

PCR

24 w

eeks

aft

er d

isco

ntin

uing

ther

apy;

•

end-

of-t

reat

men

t res

pons

e (E

TR):

unde

tect

able

viru

s at

the

end

of e

ither

a 2

4-w

eek

or 4

8-w

eek

cour

se o

f the

rapy

; •

rapi

d vi

rolo

gica

l res

pons

e (R

VR):

unde

tect

able

HCV

RN

A a

t wee

k 4

of tr

eatm

ent (

low

er li

mit

of d

etec

tion

50 IU

/mL

by P

CR);

• ex

tend

ed r

apid

viro

logi

cal r

espo

nse

(eRV

R): u

ndet

ecta

ble

HCV

RN

A at

wee

ks 4

and

12;

•

earl

y vi

rolo

gica

l res

pons

e (E

VR):

a ≥2

log

redu

ctio

n in

or c

ompl

ete

abse

nce

of s

erum

HCV

RN

A a

t wee

k 12

of t

hera

py c

ompa

red

with

the

base

line

leve

l; •

viro

logi

cal b

reak

thro

ugh:

the

reap

pear

ance

of H

CV R

NA

whi

le s

till o

n th

erap

y;

• vi

rolo

gica

l rel

apse

: the

reap

pear

ance

of H

CV R

NA

in s

erum

follo

win

g tr

eatm

ent d

isco

ntin

uatio

n an

d do

cum

ente

d ET

R;

• nu

ll re

spon

ders

: pat

ient

s w

ho fa

il to

sup

pres

s se

rum

HCV

RN

A by

at l

east

2 lo

gs a

fter

24

wee

ks o

f the

rapy

; •

earl

y re

spon

der:

und

etec

tabl

e H

CV R

NA

at w

eek

8 an

d 24

or

wee

ks 8

thro

ugh

24 o

f the

rapy

(SPR

INT-

2 an

d RE

SPO

ND

-2 tr

ials

); •

late

resp

onde

r: d

etec

tabl

e H

CV R

NA

at w

eek

8 bu

t und

etec

tabl

e H

CV R

NA

at w

eek

24 (S

PRIN

T-2

and

RESP

ON

D-2

tria

ls);

• pa

rtia

l res

pond

ers:

pat

ient

s w

hose

HCV

RN

A le

vels

dec

reas

ed b

y ≥2

log 1

0 IU

/mL

at w

eek

12 b

ut n

ever

bec

ame

unde

tect

able

; and

•

non-

resp

onde

rs: p

atie

nts

who

fail

to c

lear

HCV

RN

A a

fter

24

wee

ks o

f the

rapy

.

130 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

4 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

Are

as o

f foc

us fo

r the

rape

utic

dev

elop

men

t hav

e be

en o

n in

crea

sing

the

SVR

rate

s in

pat

ient

s w

ith H

CV-1

infe

ctio

n w

ho h

ave

a hi

gh v

iral l

oad,

A

fric

an a

nces

try,

or f

aile

d pr

evio

us th

erap

y an

d, b

ecau

se o

f the

sid

e ef

fect

s as

soci

atio

n w

ith P

R tr

eatm

ent,

dec

reas

ing

the

dura

tion

of th

erap

y.6,

7

The

mol

ecul

ar c

hara

cter

izat

ion

of H

CV a

nd it

s lif

e-cy

cle

has

led

to th

e de

velo

pmen

t of d

irec

tly a

ctin

g an

tivira

l age

nts

(DA

As)

, whi

ch ta

rget

enz

ymes

es

sent

ial f

or H

CV r

eplic

atio

n.7 Tw

o N

S3/4

A s

erin

e pr

otea

se in

hibi

tors

, tel

apre

vir

and

boce

prev

ir, w

ere

rece

ntly

app

rove

d by

the

Food

and

Dru

g A

dmin

istr

atio

n (F

DA

).10

Sinc

e th

e in

trod

uctio

n of

DA

As,

AA

SLD

gui

delin

es fr

om th

e ha

ve b

een

upda

ted

and

stat

e: 2

1.

The

opt

imal

ther

apy

for g

enot

ype

1, c

hron

ic H

CV in

fect

ion

is th

e us

e of

boc

epre

vir o

r tel

apre

vir i

n co

mbi

natio

n w

ith p

egin

terf

eron

alfa

and

rib

aviri

n. (C

lass

1, L

evel

A)

2. B

ocep

revi

r and

tela

prev

ir sh

ould

not

be

used

wit

hout

peg

inte

rfer

on a

lfa a

nd w

eigh

t-ba

sed

ribav

irin.

(Cla

ss 1

, Lev

el A

). A

ASL

D d

osin

g gu

idel

ines

are

as

follo

ws:

3.

The

reco

mm

ende

d do

se o

f boc

epre

vir i

s 80

0 m

g ad

min

iste

red

with

food

thre

e tim

es p

er d

ay (e

very

7-9

hou

rs) t

oget

her w

ith p

egin

terf

eron

alfa

an

d w

eigh

t-ba

sed

ribav

irin

for 2

4-44

wee

ks p

rece

ded

by 4

wee

ks o

f lea

d-in

trea

tmen

t with

peg

inte

rfer

on a

lfa a

nd ri

bavi

rin a

lone

(Cla

ss 1

, Lev

el A

). 4.

Pat

ient

s w

ithou

t cirr

hosi

s tr

eate

d w

ith b

ocep

revi

r, p

egin

terf

eron

, and

rib

aviri

n, p

rece

ded

by 4

wee

ks o

f lea

d-in

peg

inte

rfer

on a

nd ri

bavi

rin,

who

se

HCV

RN

A le

vel a

t wee

ks 8

and

24

is u

ndet

ecta

ble,

may

be

cons

ider

ed fo

r a s

hort

ened

dur

atio

n of

trea

tmen

t of 2

8 w

eeks

in to

tal (

4 w

eeks

lead

-in

with

peg

inte

rfer

on a

nd ri

bavi

rin fo

llow

ed b

y 24

wee

ks o

f trip

le th

erap

y) (C

lass

2a,

Lev

el B

). 8.

Pat

ient

s w

ith c

irrho

sis

trea

ted

with

eith

er b

ocep

revi

r or t

elap

revi

r in

com

bina

tion

with

peg

inte

rfer

on a

nd ri

bavi

rin

shou

ld re

ceiv

e th

erap

y fo

r a

dura

tion

of 4

8 w

eeks

(Cla

ss 2

b, L

evel

B).

10. R

e-tr

eatm

ent w

ith b

ocep

revi

r or t

elap

revi

r, to

geth

er w

ith p

egin

terf

eron

alfa

and

wei

ght-

base

d rib

aviri

n, c

an b

e re

com

men

ded

for p

atie

nts

who

ha

d vi

rolo

gica

l rel

apse

or

wer

e pa

rtia

l res

pond

ers

afte

r a p

rior c

ours

e of

trea

tmen

t with

sta

ndar

d in

terf

eron

alfa

or p

egin

terf

eron

alfa

and

/or

ribav

irin

(Cla

ss 1

, Lev

el A

). 12

. Res

pons

e-gu

ided

ther

apy

of tr

eatm

ent-

expe

rienc

ed p

atie

nts

usin

g ei

ther

a b

ocep

revi

r- o

r tel

apre

vir-

base

d re

gim

en c

an b

e co

nsid

ered

for

rela

pser

s (C

lass

2a,

Lev

el B

for b

ocep

revi

r; C

lass

2b,

Lev

el C

for t

elap

revi

r), m

ay b

e co

nsid

ered

for p

artia

l res

pond

ers

(Cla

ss 2

b, L

evel

B fo

r boc

epre

vir;

Cl

ass

3, L

evel

C fo

r tel

apre

vir)

, but

can

not b

e re

com

men

ded

for n

ull r

espo

nder

s (C

lass

3, L

evel

C).

AA

SLD

reco

mm

enda

tions

with

rega

rd to

sto

ppin

g tr

eatm

ent a

re a

s fo

llow

s:

5. T

reat

men

t with

all

thre

e dr

ugs

(boc

epre

vir,

peg

inte

rfer

on a

lfa, a

nd ri

bavi

rin) s

houl

d be

sto

pped

if th

e H

CV R

NA

leve

l is

>100

IU/m

L at

trea

tmen

t w

eek

12 o

r det

ecta

ble

at tr

eatm

ent w

eek

24 (C

lass

2a,

Lev

el B

). 13

. Pat

ient

s re

-tre

ated

with

boc

epre

vir p

lus

pegi

nter

fero

n al

fa a

nd ri

bavi

rin

who

con

tinue

to h

ave

dete

ctab

le H

CV R

NA

>10

0 IU

at w

eek

12

131 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

5 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

shou

ld b

e w

ithdr

awn

from

all

ther

apy

beca

use

of th

e hi

gh li

kelih

ood

of d

evel

opin

g an

tivira

l res

ista

nce

(Cla

ss 1

, Lev

el B

). 15

. Pat

ient

s w

ho d

evel

op a

nem

ia o

n pr

otea

se in

hibi

tor-

base

d th

erap

y fo

r chr

onic

hep

atiti

s C

shou

ld b

e m

anag

ed b

y re

duci

ng t

he ri

bavi

rin d

ose

(Cla

ss2a

, Lev

el A

). 16

. Pat

ient

s on

pro

teas

e in

hibi

tor-

base

d th

erap

y sh

ould

und

ergo

clo

se m

onito

ring

of H

CV R

NA

leve

ls a

nd th

e pr

otea

se in

hibi

tors

sho

uld

be

disc

ontin

ued

if bi

olog

ical

bre

akth

roug

h (>

1 lo

g in

crea

se in

ser

um H

CV R

NA

abo

ve n

adir

) is

obse

rved

(Cla

ss 1

,Lev

el A

). 17

. Pat

ient

s w

ho fa

il to

hav

e a

biol

ogic

al re

spon

se, w

ho e

xper

ienc

e bi

olog

ical

bre

akth

roug

h, o

r who

rel

apse

on

one

prot

ease

inhi

bito

r sho

uld

not b

e re

-tre

ated

with

the

othe

r pro

teas

e in

hibi

tor (

Clas

s 2a

, Lev

el C

). CL

INIC

AL

PHA

RMA

COLO

GY:

1 BO

C is

a r

ever

sibl

e, D

AA

aga

inst

HCV

. BO

C w

orks

by

sele

ctiv

ely

inhi

bitin

g th

e H

CV N

S3/4

A s

erin

e pr

otea

se, w

hich

is e

ssen

tial f

or th

e pr

oduc

tion

of

nons

truc

tura

l pro

tein

s N

S4A

, NS4

B, N

S5A

, and

NS5

B an

d fo

r vi

ral r

eplic

atio

n. S

ever

al N

S3 a

min

o ac

id s

ubst

itutio

ns c

onfe

r re

sist

ance

to B

OC.

Va

rian

ts e

mer

ging

mos

t fre

quen

tly in

pat

ient

s w

ho d

id n

ot a

chie

ve S

VR in

clud

e V3

6M, T

54S,

R15

5K fo

r H

CV g

enot

ype

1a a

nd T

54A

, T54

S, V

55A

, A

156S

, I/V

170A

for

gen

otyp

e 1b

. CO

MPA

RATI

VE

CLIN

ICA

L EF

FICA

CY4,

5, 1

0

Rele

vant

End

poin

ts:

1) S

usta

ined

vir

olog

ical

resp

onse

(SVR

)

2) R

elap

se ra

te

3

) With

draw

als

due

to a

dver

se e

ffec

ts

4

) Ane

mia

Prim

ary

Stud

y En

dpoi

nt:

1) S

usta

ined

viro

logi

cal r

espo

nse

132 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

6 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

Evid

ence

Tab

le

Ref./

Stud

y De

sign1

Drug

Reg

imen

s Pa

tient

Pop

ulat

ion

N Du

ratio

n (w

eeks

) Ef

ficac

y Res

ults

2 (C

I, p-v

alues

) AR

R/NN

T (C

I, p-v

alues

)3 Sa

fety

Res

ults

^

(CI, p

-valu

es)

ARR/

NN

H4 Qu

ality

Rat

ing/

Com

men

ts

SPRI

NT-2

Fa

ir

Poor

dad

(Abo

ut 20

0 ce

nters

pla

nned

)

Phas

e 3

Aug 2

008 t

o Ja

20

09

RCT,

PC,

DB

for B

OC/P

LA

only,

stra

tified

1. Gr

oup 1

(con

trol):

lea

d-in

with

pegin

terfer

on

alfa-

2b (P

) (1.5

μg/k

g sc

per w

eek)

plus r

ibavir

in (R

) (60

0–14

00 m

g dail

y, div

ided)

for 4

wee

ks, th

en

place

bo (P

LA) p

lus P

R for

44

wee

ks

2. Gr

oup 2

(RGT

): lea

d-in

with

PR fo

r 4

week

s, the

n boc

epre

vir

(B) (

800 m

g tid)

plus

PR

for 2

4 wee

ks. If

de

tectab

le HC

V RN

A at

any p

oint w

eeks

8–23

but n

ot we

ek 24

(la

te re

spon

se),

then

PR pl

us P

LA fo

r 20

week

s mor

e 3.

Grou

p 3 (f

ixed-

dura

tion t

hera

py):

lead-

in wi

th PR

for 4

we

eks,

then B

PR fo

r 44

wee

ks

Note:

dose

s are

the

same

for e

ach d

rug i

n all

arms

.

Inclu

sion

crite

ria:

• age

>18

• w

eight

40–1

25 kg

• c

hron

ic inf

ectio

n with

HCV

-1 • n

o pre

vious

trea

tmen

t • H

CV R

NA le

vel ≥

10K

IU/m

L Ex

clusio

n cr

iteria

: • H

IV or

HBV

posit

ive

• live

r dise

ase o

f othe

r cau

se

• dec

ompe

nsate

d cirr

hosis

• r

enal

insuff

icien

cy

• pre

gnan

t or b

reas

t feed

ing

• acti

ve ca

ncer

Pa

tient

char

acte

ristic

s:

Age (

mean

): 49

yrs

Male:

60%

W

hite:

82%

Bl

ack:

14%

W

eight

(mea

n): 8

1 kg

HCV

RNA

≥800

K IU

per m

l: 85

%

HCV

geno

type 1

a: 64

%

HCV

geno

type 1

b: 33

%

HCV

geno

type u

nk: 3

%

Metav

ir fibr

osis

scor

e 3 or

4:

9%

Stra

tified

by ba

selin

e HCV

RNA

lev

el (≤

400 K

v. >

400K

IU/m

L)

and H

CV-1

geno

type 1

a v. 1

b

1. 36

3 2.

368

3. 36

6 Mo

dified

IT

T

Trea

tmen

t dur

ation

28

or 48

wee

ks.

Prim

ary o

utcom

e as

sess

ed w

eek 7

2 (24

we

eks f

ollow

ing en

d of

thera

py fo

r Gro

ups 1

an

d 3 an

d Gro

up 2

with

detec

table

HCV

RNA

week

8–24

(late

resp

onde

rs) an

d 44

week

s foll

owing

ther

apy

for G

roup

2 wi

th un

detec

table

HCV

RNA

we

eks8

–24 (

early

re

spon

ders)

prop

ortio

n of tr

eatm

ent-n

aïve

patie

nts w

ho ha

d SVR

1.

Grou

p 1: 3

8%

2.

Grou

p 2: 6

3% (p

<0.00

1)

3.

Grou

p 3: 6

6% (p

<0.00

1)

Bl

ack c

ohor

t: 1.

Grou

p 1: 2

3%

2.

Grou

p 2: 4

2% (p

=0.04

)

3. Gr

oup 3

: 53%

(p=0

.004)

No

n-bla

ck co

hort:

1.

Grou

p 1: 4

0%

2.

Grou

p 2: 6

7% (p

<0.00

1)

3.

Grou

p 3: 6

8% (p

<0.00

1)

Othe

r: %

patie

nts w

ith S

VR w

ho ha

d un

detec

table

HCV

RNA

week

s 8–2

4 (ea

rly

resp

onde

rs):

1. Gr

oup 1

: 93%

(n=4

3)

2.

Grou

p 2: 9

6% (n

=162

)

3. Gr

oup 3

: 96%

(n=1

61)

% pa

tients

with

SVR

who

had

detec

table

HCV

RNA

week

s 8–

24 (la

te re

spon

ders)

: 1.

Grou

p 1: 6

6% (n

=131

)

2. Gr

oup 2

: 72%

(n=8

2)

25%

/ 4

28%

/ 4

19%

/ 5

30%

/ 3

27%

/4 28

%/4

NS

NS

NS

NS

Anem

ia 1.

Grou

p 1: 2

9%

2. Gr

oup 2

: 49%

(p

<0.00

1)

3. Gr

oup 3

: 49%

(p

<0.00

1)

Disc

ontin

uatio

n due

to

adve

rse re

actio

n: 1.

Grou

p 1: 1

6%

2.

Grou

p 2: 1

2%

3.

Grou

p 3: 1

6%

20%

/ 5

20%

/ 5

• Blin

ding c

ould

be co

mpro

mise

d bec

ause

PR

open

labe

l and

trea

tmen

t dur

ation

for g

roup

2 pa

tients

with

unde

tectab

le HC

V RN

A we

eks 8

–24

stop t

hera

py at

wee

k 28

• Pro

tocol

says

adhe

renc

e to b

e che

cked

, but

adhe

renc

e not

repo

rted i

n pub

licati

on

• Una

ble to

asce

rtain

appr

opria

te do

sing d

urati

on

for ea

rly v.

late

resp

onde

rs • S

ubgr

oup a

nalys

is (ra

ce, s

ex, v

iral lo

ad, a

ge,

weigh

t, BMI

, plat

elet c

ount,

fibro

sis, s

teatos

is,

cirrh

otics

, HCV

geno

type,

ALT,

coun

try) s

howe

d the

nume

rical

odds

of S

VR re

spon

se w

as gr

eater

, ac

ross

all s

ubgr

oups

, for e

ither

grou

p 2 or

3 tha

n gr

oup 1

, exc

ept fo

r cirr

hotic

patie

nts. A

dditio

nally

, a s

tatist

ically

sign

ifican

t diffe

renc

e was

not s

een

for vi

ral lo

ad >8

00K

IU/m

L, BM

I ≤25

kg/m

2 , pla

telet

coun

t >15

0K–2

00K

IU/µ

L, fib

rosis

scor

e 3

or 4

for gr

oup 2

v. 1;

and a

ge ≤

40, p

latele

ts <2

00K/

µL, a

nd fib

rosis

scor

e 3 or

4 for

grou

p 3 v.

1. • S

toppin

g rule

s:

a. d/c

trea

tmen

t for a

ll pati

ents

with

detec

table

HCV

RNA

at we

ek 24

b.

If viro

logic

brea

kthro

ugh o

r inco

mplet

e viro

logic

resp

onse

and r

ebou

nd, d

/c BO

C bu

t con

tinue

PR

for up

to 48

wee

ks

• Disc

ontin

uatio

n due

to st

oppin

g rule

1a ab

ove:

1. Gr

oup 1

: 30%

2.

Grou

p 2: 9

%

3. Gr

oup 3

: 10%

• C

arrie

d for

ward

HCV

RNA

mea

sure

ment

at 12

we

eks o

f follo

w-up

for p

atien

ts mi

ssing

HCV

RNA

me

asur

emen

t at th

e end

of fo

llow-

up

• Exte

nsive

inclu

sion/e

xclus

ion cr

iteria

foun

d in

study

proto

col. M

ay im

pact

appli

catio

n and

resu

lts

in ge

nera

l clin

ical s

etting

. • A

dditio

n of B

OC to

ther

apy s

ignific

antly

133 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

7 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

3. Gr

oup 3

: 75%

(n=7

3)

By F

DA an

alysis

exc

luding

14

patie

nts f

rom

Gro

up 2

: 2.

Gro

up 2:

66%

(n=6

8)

3. G

roup

3: 7

5% (n

=73)

Re

lapse

rate:

1.

Grou

p 1: 2

2%

2. Gr

oup 2

: 9%

3.

Grou

p 3: 9

%

13%

/ 8

13%

/ 8

incre

ased

the i

ncide

nce o

f ane

mia r

equir

ing

eryth

ropo

ietin

admi

nistra

tion o

r tra

nsfus

ion.

Eryth

ropo

ietin,

grou

ps 1,

2, an

d 3:

24%

, 43%

(p<0

.001)

, 43%

(p<0

.001)

Tr

ansfu

sion,

grou

ps 1,

2, an

d 3:

1%, 3

% (p

=0.02

), 2%

(NS)

No

sign

ifican

t diffe

renc

e in t

he ra

te of

serio

us

adve

rse re

actio

ns be

twee

n gro

ups 1

, 2, a

nd 3:

9%

, 11%

, 12%

• O

vera

ll BOC

-resis

tance

-ass

ociat

e var

iants:

17

% gr

oup 2

; 15%

grou

p 3

• Use

d step

-dow

n hyp

othes

is tes

ting:

Grou

p 3

first c

ompa

red w

ith gr

oup 1

. If p

≤0.05

, the

supe

riority

of fix

ed du

ratio

n the

rapy

over

sta

ndar

d the

rapy

supp

orted

, and

grou

p 2 th

en

comp

ared

with

grou

p 1. If

p≤0

.05, th

e su

perio

rity of

RGT

over

stan

dard

ther

apy

estab

lishe

d.

RESP

OND-

2 Fa

ir

Baco

n 80

cente

rs Ph

ase 3

Au

g–No

v 20

08

RCT,

PC,

DB

for B

OC,

strati

fied

1. Gr

oup 1

(co

ntrol)

: lea

d-in

with

P (1

.5 μg

/kg

per w

eek)

plus R

(6

00–1

400 m

g da

ily, d

ivide

d) fo

r 4 w

eeks

, then

PL

A plu

s PR

for

44 w

eeks

2.

Grou

p 2

(RGT

): lea

d-in

PR fo

r 4

week

s, the

n B

(800

mg t

id)

plus P

R for

32

week

s. If

detec

table

HCV

RNA

at 8

week

s (bu

t un

detec

table

at 12

wee

ks),

then P

R 12

we

eks m

ore

3. Gr

oup 3

:

Inclu

sion

crite

ria:

• pre

vious

ly tre

ated f

or H

CV-1

• d

emon

strate

d res

pons

ivene

ss to

PR

(12 w

eeks

min.

ther

apy)

•par

tial re

spon

der o

r rela

pser

Ex

clusio

n cr

iteria

: • H

BV or

HIV

posit

ive

• abs

olute

neutr

ophil

coun

t <15

00

per m

l3 for

non-

black

s <12

00 pe

r ml3

for bl

acks

, plat

elet c

ount

<100

K pe

r ml

3 , hg

b <12

g/dL

wom

en or

<13

g/dL

me

n • o

ther c

ause

s of s

ignific

ant li

ver

disea

se

• dec

ompe

nsate

d live

r dise

ase

•unc

ontro

lled d

iabete

s • s

ever

e psy

chiat

ric di

sord

er

• acti

ve su

bstan

ce ab

use

Patie

nt ch

arac

teris

tics:

Ag

e (me

an):

53 yr

s Ma

le: 67

%

Whit

e: 85

%

Blac

k: 12

%

1. 80

2.

162

3. 16

1 mo

difi

ed

ITT

Trea

tmen

t dur

ation

36

or 48

wee

ks.

Prim

ary o

utcom

e as

sess

ed at

wee

k 72

(24 w

eeks

after

the

end o

f trea

tmen

t for

grou

ps 1

and 2

and

24 or

36 w

eeks

after

the

end o

f trea

tmen

t for

grou

p 2)

Prop

ortio

n of

patie

nts w

ho ha

d SV

R

1. Gr

oup 1

: 21%

2.

Grou

p 2: 5

9%

3. Gr

oup 3

: 66%

Ot

her:

Prior

relap

se:

1. Gr

oup 1

: 29%

2.

Grou

p 2: 6

9%

3. Gr

oup 3

: 75%

Re

lapse

: Gr

oup 1

: 32%

Gr

oup 2

: 15%

Gr

oup 3

: 12%

38%

/ 3

(CI: 2

6 to 4

9, p<

0.001

) 45

% / 2

(C

I:34 t

o 57,

p<0.0

01)

40%

/ 3

46%

/ 2

17%

/ 6

20%

/ 5

Anem

ia 1.

Grou

p 1: 2

0%

2.

Grou

p 2: 4

3%

(p<0

.001)

3. Gr

oup 3

: 46%

(p

<0.00

1)

Disc

ontin

uatio

n due

to

adve

rse re

actio

n: 1.

Grou

p 1: 2

%

2. Gr

oup 2

: 8%

3.Gro

up 3:

12%

23%

/ 4

26%

/ 4 6%

/ 17

10

% /

10

Notes

: The

perce

ntage

for g

roup

1 S

VR ra

te in

FD

A re

view

was 2

3% an

d % re

lapse

for G

roup

1

28%

and

Grou

p 2 1

4%.B

acon

et a

l. use

the

term

“n

on-re

spon

se” f

or w

hat th

e FDA

and g

uideli

nes

defin

e as

partia

l resp

onse

, so

partia

l resp

onse

su

bstitu

ted fo

r non

-resp

onse

. • B

lindin

g com

prom

ised b

ecau

se P

R op

en la

bel

and g

roup

2 pa

tients

with

unde

tectab

le HC

V RN

A at

week

s 8 an

d 12 s

top th

erap

y at w

eek 3

6 • P

rotoc

ol sa

ys ad

here

nce t

o be c

heck

ed, b

ut ad

here

nce n

ot re

porte

d in p

ublic

ation

• G

roup

s 2 an

d 3 ha

d gre

ater p

erce

nt of

patie

nts

with

high v

iral lo

ad (>

800K

IU/m

L) th

an gr

oup 1

(co

ntrol)

: 91%

, 88%

, 81%

, res

pecti

vely

(p=0

.04

grou

p 2 v.

grou

p 1)

• Ove

rall,

treatm

ent d

iscon

tinua

tion:

1. Gr

oup 1

: 69%

2.

Grou

p 2: 3

2%

3. Gr

oup 3

: 34%

• S

toppin

g rule

s:

134 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

8 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

lead-

in wi

th PR

for 4

we

eks,

then

BPR

for 44

we

eks

Note:

dose

s ar

e the

same

for

each

drug

in

all ar

ms.

Weig

ht (m

ean)

: 85 k

g HC

V RN

A ≥8

00K

IU pe

r ml: 8

8%

HCV

geno

type 1

a: 59

%

HCV

geno

type 1

b: 40

%

HCV

geno

type u

nk: 1

%

Metav

ir fibr

osis

scor

e 3 or

4: 19

%

Cirrh

osis:

12%

Pr

eviou

s typ

e of r

espo

nse:

Prio

r par

tial re

spon

se: 3

6%

Prio

r rela

pse:

64%

St

ratifi

ed by

partia

l resp

onse

or re

lapse

an

d HCV

subty

pe 1a

or 1b

(unk

nown

ge

notyp

e ran

doml

y ass

igned

)

a. Fa

ilure

to ac

hieve

an un

detec

table

HCV

RNA

level

at we

ek 12

resu

lted i

n d/c

of all

trea

tmen

t b.

If a pa

tient

had v

irolog

ic br

eakth

roug

h or a

n inc

omple

te vir

ologic

resp

onse

and r

ebou

nd w

hile

rece

iving

ther

apy,

BOC

could

by d/

c but

PR

conti

nued

for u

p to 4

8 wee

ks.

• Exte

nsive

inclu

sion/e

xclus

ion cr

iteria

foun

d in

st udy

proto

col. M

ay im

pact

appli

catio

n and

resu

lts

in ge

nera

l clin

ical s

etting

. • T

oo fe

w Af

rican

-Ame

rican

patie

nts to

adeq

uatel

y as

sess

resp

onse

in th

is po

pulat

ion. R

ace a

nd

ethnic

grou

ps w

ere s

elf-re

porte

d. • S

ubgr

oup a

nalys

is: th

e num

erica

l odd

s of S

VR

resp

onse

was

grea

ter, a

cross

all s

ubgr

oups

, for

eithe

r gro

up 2

or 3

than g

roup

1, al

thoug

h sta

tistic

al sig

nifica

nce w

as no

t rea

ched

for w

eight

<75 k

g, pla

telet

coun

t ≤20

0/µL,

and f

ibros

is sc

ore

3 or 4

for g

roup

2 v.

grou

p 1. N

ot en

ough

cirrh

otic

patie

nts to

adeq

uatel

y per

form

subg

roup

analy

sis

in cir

rhoti

c pati

ents.

• A

dditio

n of B

OC to

ther

apy s

ignific

antly

inc

reas

ed th

e inc

idenc

e of a

nemi

a req

uiring

er

ythro

poiet

in ad

minis

tratio

n or t

rans

fusion

. Er

ythro

poiet

in, gr

oups

1, 2,

and 3

: 21

%, 4

1% (p

=0.00

3), 4

6% (p

<0.00

1)

Tran

sfusio

n, gr

oups

1, 2,

and 3

: 0%

, 2%

(NS)

, 9%

(p=0

.006)

Inc

idenc

e of s

eriou

s adv

erse

reac

tion s

ignific

antly

gr

eater

for g

roup

3:

5%, 1

0% (N

S), 1

4% (p

=0.03

) for

grou

ps 1,

2, an

d 3,

resp

ectiv

ely.

• Car

ried f

orwa

rd H

CV R

NA m

easu

reme

nt at

12

week

s of fo

llow-

up fo

r 13 p

atien

ts mi

ssing

HCV

RN

A me

asur

emen

t at th

e end

of fo

llow-

up

1 Stud

y de

sign

abb

revi

atio

ns: D

B =

doub

le-b

lind,

RCT

= r

ando

miz

ed tr

ial,

PC =

pla

cebo

-con

trol

led,

PG

= p

aral

lel -

grou

p, X

O =

cro

ssov

er.

2 Resu

lts

abbr

evia

tion

s: R

RR =

rel

ativ

e ri

sk r

educ

tion

, RR

=rel

ativ

e ri

sk, O

R= O

dds

Ratio

, HR

= H

azar

d Ra

tio,

ARR

= ab

solu

te r

isk

redu

ctio

n,

NN

T =

num

ber

need

ed to

trea

t, N

NH

= n

umbe

r ne

eded

to h

arm

, CI =

con

fiden

ce in

terv

al

3 NN

T/N

NH

are

rep

orte

d on

ly fo

r st

atis

tical

ly s

igni

fican

t res

ults

4 Q

ualit

y Ra

ting

: (G

ood-

like

ly v

alid

, Fai

r- li

kely

val

id/p

ossi

bly

valid

, Poo

r- fa

tal f

law

-not

val

id)

135 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

9 A

utho

r: Sh

erri

J. W

illar

d A

rgyr

es

Clin

ical

Fin

ding

s Th

e FD

A p

rim

arily

bas

ed th

eir e

ffic

acy

and

safe

ty re

view

of B

OC

on tw

o ph

ase

3 st

udie

s (S

PRIN

T-2

and

RESP

ON

D-2

), bo

th o

f whi

ch h

ave

been

pu

blis

hed.

5 , 4 an

open

-labe

l pha

se 2

stu

dy (S

PRIN

T-1)

als

o ha

s be

en p

ublis

hed.

11 B

oth

phas

e 3

stud

ies

com

pare

d re

spon

se-g

uide

d th

erap

y (G

roup

2)

and

fixed

-dur

atio

n th

erap

y (G

roup

3) t

o PR

alo

ne (G

roup

1).

SPRI

NT-

2 in

clud

ed a

dult

trea

tmen

t-na

ïve

subj

ects

with

HCV

-1, w

hile

the

RESP

ON

D-2

in

clud

ed a

dult

subj

ects

with

HCV

-1 w

ho h

ad b

een

prev

ious

ly tr

eate

d, s

peci

fical

ly p

artia

l res

pond

ers

and

rela

pser

s. T

he S

PRIN

T-2

tria

l als

o ha

d tw

o co

hort

s, o

ne b

lack

and

one

non

-bla

ck. T

he p

rim

ary

effic

acy

endp

oint

in b

oth

tria

ls w

as th

e pr

opor

tion

of p

atie

nts

achi

evin

g SV

R. “

Stop

ping

rul

es”

for d

isco

ntin

uing

BO

C or

all

trea

tmen

t wer

e ap

plie

d to

eac

h st

udy

to p

reve

nt p

atie

nts

who

did

not

hav

e ad

equa

te re

spon

se fr

om c

ontin

uing

tr

eatm

ent.

All

trea

tmen

t reg

imen

s in

clud

ed a

four

-wee

k “l

ead-

in”

peri

od o

f dos

ing

with

PR

alon

e, w

hich

was

sho

wn

in th

e ph

ase

2 st

udy

to c

onfe

r a

num

eric

al a

dvan

tage

in S

VR r

ates

. Ass

ume

the

four

-wee

k le

ad-in

for a

ll tr

eatm

ent r

egim

ens

belo

w, w

hen

tota

l dur

atio

n no

t giv

en.4,

5, 1

1, a

nd 1

2 SP

RIN

T-2

rand

omiz

ed 1

099

subj

ects

1:1

:1 a

nd te

sted

whe

ther

24

wee

ks o

r 44

wee

ks o

f BO

C pl

us P

R (G

roup

2 a

nd G

roup

3, r

espe

ctiv

ely)

was

su

peri

or to

44

wee

ks P

R al

one

(48

wee

ks in

clud

ing

lead

-in).

Gro

ups

1 an

d 3

ende

d tr

eatm

ent a

t wee

k 48

. Gro

up 2

ear

ly r

espo

nder

s en

ded

trea

tmen

t at w

eek

28, w

hile

Gro

up 2

late

res

pond

ers

rece

ived

an

addi

tiona

l 20

wee

ks o

f PR

and

ende

d tr

eatm

ent a

t wee

k 48

. Tre

atm

ent a

rms

had

sim

ilar

base

line

char

acte

rist

ics

and

dem

ogra

phic

s. F

or th

e co

mbi

ned

coho

rts

and

for t

he b

lack

and

non

-bla

ck c

ohor

ts, B

OC-

cont

aini

ng re

gim

ens

wer

e st

atis

tical

ly s

uper

ior

to P

R. T

he S

VR r

ates

for G

roup

s 1,

2, a

nd 3

, mod

ified

inte

nt to

trea

t, w

ere

38%

, 63%

, and

66%

, res

pect

ivel

y (p

<0.0

01

com

pari

ng e

ach

BOC

grou

p w

ith th

e PR

gro

up).

The

diff

eren

ces

in r

espo

nses

wer

e 25

% fo

r Gro

up 2

v. 1

and

28%

for

Gro

up 3

v. 1

, giv

ing

NN

Ts o

f 4

and

4, re

spec

tivel

y.4

For

the

blac

k co

hort

, SVR

rat

es w

ere

23%

, 42%

, and

53%

for G

roup

s 1,

2, a

nd 3

, res

pect

ivel

y, a

nd fo

r th

e no

n-bl

ack

coho

rt 4

0%, 6

7%, a

nd 6

9%,

resp

ectiv

ely.

Pos

t hoc

ana

lysi

s su

gges

ts m

ost o

f the

11

perc

enta

ge p

oint

diff

eren

ce b

etw

een

Gro

ups

2 an

d 3

of th

e bl

ack

coho

rt m

ay b

e at

trib

uted

to

imba

lanc

es in

the

num

ber o

f sub

ject

s di

scon

tinui

ng th

erap

y du

ring

the

PR le

ad-in

pha

se a

nd p

oor

resp

onse

from

cir

rhot

ic s

ubje

cts.

4, 1

0 A

bout

44%

of p

atie

nts

rand

omiz

ed to

the

BOC

regi

men

s w

ere

earl

y re

spon

ders

, com

pare

d to

12%

in th

e PR

gro

up. A

mon

g pa

tient

s w

ith a

n ea

rly

resp

onse

, 96%

of G

roup

2 a

nd 3

sub

ject

s an

d 93

% o

f Gro

up 1

sub

ject

s ac

hiev

ed S

VR. S

PRIN

T-2

rese

arch

ers

indi

cate

d a

tota

l tre

atm

ent d

urat

ion

of

28 w

eeks

wou

ld b

e su

ffic

ient

for

earl

y re

spon

ders

, whi

le 4

8 w

eeks

of t

hera

py (4

wee

ks o

f lea

d-in

, 24

wee

ks o

f trip

le th

erap

y, a

nd 2

0 w

eeks

of P

R al

one)

wou

ld b

e pr

efer

red

for

late

resp

onde

rs. H

owev

er, t

he F

DA

rec

omm

ende

d a

tota

l tre

atm

ent d

urat

ion

of 4

8 w

eeks

(4 w

eeks

of l

ead-

in, 3

2 w

eeks

of t

ripl

e th

erap

y, 1

2 w

eeks

of P

R) fo

r la

te re

spon

ders

bas

ed o

n a

rean

alys

is o

f the

SVR

rat

es o

f Gro

ups

2 an

d 3

and

a su

bgro

up a

naly

sis

of

earl

y an

d la

te re

spon

ders

. Whi

le S

PRIN

T-2

tria

l res

earc

hers

, ide

ntifi

ed a

3%

diff

eren

ce in

SVR

rat

e be

twee

n G

roup

s 2

and

3 la

te re

spon

ders

, the

FD

A c

alcu

late

d a

9% d

iffer

ence

upo

n ex

clud

ing

14 s

ubje

cts

its re

sear

cher

s be

lieve

d w

ere

likel

y ea

rly r

espo

nder

s, r

athe

r tha

n la

te r

espo

nder

s.

Furt

herm

ore,

the

FDA

note

d th

at (1

) the

diff

eren

ce b

etw

een

Gro

ups

2 an

d 3

prim

arily

was

due

to v

irolo

gic

brea

kthr

ough

sho

rtly

aft

er s

topp

ing

BOC

and

(2) R

ESPO

ND

-2 tr

ial’s

trea

tmen

t-ex

peri

ence

d pa

tient

s ha

d re

ceiv

ed a

long

er d

urat

ion

of B

OC

ther

apy

and

had

few

er v

irol

ogic

bre

akth

roug

hs

136 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

10

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

afte

r end

of B

OC

ther

apy

(the

FD

A re

ason

ed S

PRIN

T-2’

s la

te r

espo

nder

s w

ere

sim

ilar t

o tr

eatm

ent-

expe

rien

ced

patie

nts

whe

n on

e lo

oks

at

inte

rfer

on re

spon

sive

ness

wee

k 4)

. The

refo

re, a

long

er d

urat

ion

of tr

iple

ther

apy

was

war

rant

ed fo

r la

te r

espo

nder

s.4,

12

Subg

roup

ana

lysi

s po

sitiv

e an

d ne

gativ

e pr

edic

tive

fact

ors

for

SVR

(rac

e, s

ex, v

iral

load

, age

, wei

ght,

BM

I, pl

atel

et c

ount

, fib

rosi

s, s

teat

osis

, cir

rhot

ics,

H

CV g

enot

ype,

ALT

, cou

ntry

) sho

wed

the

num

eric

al o

dds

of S

VR r

espo

nse

was

gre

ater

, acr

oss

all s

ubgr

oups

, for

eith

er g

roup

2 o

r 3 th

an g

roup

1,

exce

pt fo

r ci

rrho

tic p

atie

nts.

How

ever

, the

num

ber

of c

irrh

otic

pat

ient

s in

eac

h gr

oup

was

sm

all (

n=13

, 16,

and

24

for

Gro

ups

1, 2

, and

3,

resp

ectiv

ely)

. Add

ition

ally

, a s

tatis

tical

ly s

igni

fican

t diff

eren

ce w

as n

ot s

een

for

vira

l loa

d >8

00K

IU/m

L, B

MI

≤25

kg/m

2 , pla

tele

t cou

nt >

150K

–200

K IU

/µL,

fibr

osis

sco

re 3

or 4

for

Gro

up 2

v. 1

; and

age

≤40

, pla

tele

ts >

200K

/µL,

and

fibr

osis

sco

re 3

or

4 fo

r G

roup

3 v

. 1.4,

12

RESP

ON

D-2

ran

dom

ized

403

pri

or p

artia

l res

pond

ers

and

rela

pser

s 1:

2:2

and

test

ed w

heth

er 3

2 w

eeks

or

44 w

eeks

of B

OC

plus

PR

(Gro

up 2

and

G

roup

3, r

espe

ctiv

ely)

was

sup

erio

r to

44 w

eeks

PR

alon

e (4

8 w

eeks

incl

udin

g le

ad-in

). G

roup

s 1

and

3 en

ded

trea

tmen

t at w

eek

48. G

roup

2 e

arly

re

spon

ders

end

ed tr

eatm

ent a

t wee

k 36

, whi

le G

roup

2 la

te r

espo

nder

s re

ceiv

ed a

n ad

ditio

nal 1

2 w

eeks

of P

R an

d en

ded

trea

tmen

t at w

eek

48.

Trea

tmen

t arm

s ha

d si

mila

r ba

selin

e ch

arac

teri

stic

s, e

xcep

t tha

t Gro

ups

2 an

d 3

had

grea

ter p

erce

nt o

f pat

ient

s w

ith h

igh

vira

l loa

d (>

800K

IU/m

L)

than

Gro

up 1

: 91%

, 88%

, and

81%

, res

pect

ivel

y (p

=0.0

4 gr

oup

2 v.

gro

up 1

). Bo

th B

OC-

cont

aini

ng re

gim

ens

wer

e st

atis

tical

ly s

uper

ior t

o PR

. The

SVR

ra

tes

for G

roup

s 1,

2, a

nd 3

, mod

ified

inte

nt to

trea

t, w

ere

21%

, 59%

, and

66%

, res

pect

ivel

y. T

he d

iffer

ence

in re

spon

ses

wer

e 38

% (C

I: 26

to 4

9,

p<0.

001)

for

Gro

up 2

v. 1

and

45%

(CI:

34 to

57,

p<0

.001

) for

Gro

up 3

v. 1

, giv

ing

NN

Ts o

f 3 a

nd 2

, res

pect

ivel

y.5

RESP

ON

D-2

exc

lude

d pr

ior

null

resp

onde

rs fr

om th

e tr

ial b

ecau

se, a

ccor

ding

to th

e FD

A, “

the

phas

e 2

tria

l in

trea

tmen

t-ex

peri

ence

d pa

tient

s w

as

not i

nter

pret

able

.”12

Eve

n th

ough

nul

l res

pond

ers

had

been

exc

lude

d, F

DA

revi

ewer

s re

com

men

ded

appr

oval

of t

riple

ther

apy

for n

ull r

espo

nder

s ba

sed

on p

ost-

hoc

anal

ysis

of t

reat

men

t-na

ïve

patie

nts

from

SPR

INT-

2 w

ho w

ere

iden

tifie

d as

like

ly n

ull r

espo

nder

s by

HCV

leve

l mea

sure

d at

tr

eatm

ent w

eek

4 w

ith a

low

cut

-off

: ≤0.

5 lo

g 10 d

eclin

e in

HCV

RN

A. E

ight

y-ei

ght p

erce

nt o

f sub

ject

s m

eetin

g th

is c

rite

rion

wer

e nu

ll re

spon

ders

(<2

log 1

0 dec

line

at tr

eatm

ent w

eek

12 a

nd n

o SV

R) to

PR.

SVR

rat

es a

mon

g nu

ll re

spon

ders

(ide

ntifi

ed b

y th

e m

ore

low

cut

off

at w

eek

4) w

ere

30%

for

Gro

up 2

and

28%

for G

roup

3.5,

10 A

ASL

D g

uide

lines

adv

ise

caut

ion

in u

sing

BO

C in

nul

l res

pond

ers

until

furt

her

evid

ence

is a

vaila

ble.

2 Th

e FD

A a

lso

has

appr

oved

trip

le th

erap

y fo

r ci

rrho

tic p

atie

nts,

bec

ause

FD

A a

naly

sis

and

post

-hoc

ana

lysi

s by

RES

PON

D-2

rese

arch

ers

has

attr

ibut

ed th

e 7%

num

eric

al d

iffer

ence

in tr

eatm

ent r

espo

nse

betw

een

Gro

ups

2 an

d 3

to c

irrh

otic

pat

ient

s. T

here

fore

, dru

g-la

belin

g re

com

men

ds

resp

onse

-gui

ded

regi

men

(i.e

., 32

wee

ks o

f BO

C th

erap

y) fo

r non

-cir

rhot

ic, t

reat

men

t-ex

perie

nced

pat

ient

s an

d th

e fix

ed-d

ose

regi

men

(44

wee

ks

of B

OC

ther

apy)

for t

he c

irrh

otic

pat

ient

s.5,

12

The

SPRI

NT-

2 tr

ial a

nd F

DA

pos

t-ho

c an

alys

es e

stab

lishe

d a

24-w

eek

trip

le th

erap

y re

gim

en fo

r tre

atm

ent-

naïv

e ea

rly

resp

onde

rs a

nd a

32-

wee

k tr

iple

ther

apy

regi

men

with

an

addi

tiona

l 12

wee

ks o

f PR

for l

ate

resp

onde

rs. T

he R

ESPO

ND

-2 tr

ial e

stab

lishe

d a

32-w

eek

trip

le th

erap

y re

gim

en fo

r tr

eatm

ent-

expe

rien

ced

earl

y re

spon

ders

and

a 3

2-w

eek

trip

le th

erap

y re

gim

en w

ith a

n ad

ditio

nal 1

2 w

eeks

of P

R fo

r tre

atm

ent-

expe

rienc

ed la

te

resp

onde

rs. P

ost-

hoc

anal

ysis

est

ablis

hed

a 44

-wee

k tr

iple

ther

apy

regi

men

for

all c

irrh

otic

pat

ient

s an

d nu

ll re

spon

ders

.

137 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

11

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Inte

rnal

and

ext

erna

l val

idity

con

cern

s w

ith p

hase

3 c

linic

al tr

ials

incl

uded

lim

ited

or n

o tr

acki

ng o

f adh

eren

ce, e

xten

sive

incl

usio

n an

d ex

clus

ion

crite

ria,

pro

babi

lity

of c

ompr

omis

ed b

lindi

ng, u

nres

olve

d tr

eatm

ent d

urat

ions

for

late

res

pond

ers,

cir

rhot

ic p

atie

nts,

nul

l res

pond

ers,

and

bla

ck

patie

nts;

and

whe

ther

sim

ilar

effic

acy

and

safe

ty re

sults

can

be

achi

eved

in a

gen

eral

clin

ical

set

ting,

as

trip

le th

erap

y re

quire

s st

rict

and

freq

uent

m

onito

ring

of s

erum

HCV

RN

A, a

dher

ence

by

clin

icia

ns to

sto

ppin

g ru

les

and

trea

tmen

t reg

imen

s, m

anag

emen

t of a

n ex

tens

ive

list o

f pro

babl

e an

d ac

tual

dru

g-dr

ug in

tera

ctio

ns, a

nd c

lose

mon

itorin

g fo

r ad

vers

e re

actio

ns. T

he e

mer

genc

e of

dru

g re

sist

ance

, esp

ecia

lly in

pat

ient

s w

ho h

ave

had

a pr

ior n

on-r

espo

nse,

are

non

-adh

eren

t to

ther

apy,

or

are

into

lera

nt o

f opt

imal

PR

dose

s al

so is

a c

once

rn.13

D

espi

te th

ese

unkn

owns

, trip

le th

erap

y ha

s th

e be

nefit

of i

mpr

oved

SVR

rate

s fo

r ad

ult p

atie

nts

who

are

trea

tmen

t-na

ïve

or w

ho a

re tr

eatm

ent-

expe

rien

ced,

par

ticul

arly

pri

or p

artia

l res

pond

ers

and

rela

pser

s.

DRU

G S

AFE

TY

Safe

ty is

sues

ari

sing

fro

m c

linic

al t

rial

s fo

cuse

d on

ane

mia

and

neu

trop

enia

. For

the

pha

se 2

stu

dy (

SPRI

NT-

1) a

nd t

wo

phas

e 3

tria

ls c

ombi

ned,

an

emia

was

the

mos

t co

mm

on a

dver

se e

vent

and

occ

urre

d at

a g

reat

er f

requ

ency

for

sub

ject

s ta

king

BO

C-co

ntai

ning

reg

imen

s (4

9%)

v. P

R al

one

(29%

).1 The

fre

quen

cy o

f th

rom

bocy

tope

nia

and

neut

rope

nia

also

wer

e gr

eate

r, b

ut le

ss s

o. T

he h

ighe

r fr

eque

ncy

of a

nem

ia in

tho

se t

akin

g BO

C-co

ntai

ning

reg

imen

s le

d to

a g

reat

er fr

eque

ncy

of R

IB d

ose

redu

ctio

ns a

nd e

ryth

ropo

ietin

use

. Ery

thro

poie

tin u

se in

HCV

is o

ff-la

bel.

1,4,

5,12

Fin

ally

, th

ree,

pos

sibl

y fo

ur, s

erio

us in

fect

ions

occ

urri

ng in

pro

xim

ity to

sev

ere

neut

rope

nia

are

of c

once

rn, a

s m

ore

infe

ctio

ns m

ay o

ccur

as

BOC-

cont

aini

ng

regi

men

s ar

e us

ed in

the

gen

eral

clin

ical

set

ting.

In c

linic

al t

rial

s, B

OC

was

not

ass

ocia

ted

with

a s

ubst

antia

l inc

iden

ce o

f der

mat

olog

ic e

ffec

ts s

uch

as r

ash

or p

rurit

us. T

he d

isco

ntin

uatio

n ra

tes

for

adve

rse

even

ts fo

r su

bjec

ts r

ecei

ving

BO

C-co

ntai

ning

reg

imen

s ve

rsus

PR

alon

e w

ere

sim

ilar,

13%

an

d 12

%, r

espe

ctiv

ely.

1,12

Serio

us (R

EMS,

Bla

ck B

ox W

arni

ngs,

and

Con

trai

ndic

atio

ns):1 C

ontr

aind

icat

ions

to p

egin

terf

eron

alfa

and

rib

avir

in a

lso

appl

y.

Trip

le t

hera

py i

s co

ntra

indi

cate

d in

wom

en w

ho a

re o

r m

ay b

ecom

e pr

egna

nt a

nd m

en w

hose

fem

ale

part

ners

are

pre

gnan

t. B

ecau

se R

IB i

s as

soci

ated

with

sig

nific

ant

tera

toge

nic

or e

mbr

yoci

dal e

ffec

ts, f

emal

e pa

tient

s an

d fe

mal

e pa

rtne

rs o

f ch

ildbe

arin

g ag

e sh

ould

obt

ain

a ne

gativ

e pr

egna

ncy

test

bef

ore

ther

apy

and

use

two

effe

ctiv

e co

ntra

cept

ive

met

hods

dur

ing

and

for

6 m

onth

s fo

llow

ing

trea

tmen

t. F

emal

e pa

tient

s sh

ould

us

e tw

o ef

fect

ive

non-

horm

onal

con

trac

eptiv

es.

Conc

omita

nt u

se o

f Bo

cepr

evir

with

med

icat

ions

tha

t ha

ve a

nar

row

the

rape

utic

inde

x an

d ar

e hi

ghly

dep

ende

nt o

n CY

P3A

4/5

is c

ontr

aind

icat

ed. C

onco

mita

nt u

se o

f Bo

cepr

evir

with

med

icat

ions

tha

t st

rong

ly in

duce

CYP

3A4/

5 an

d m

ay r

esul

t in

red

uced

eff

icac

y of

Boc

epre

vir

is c

ontr

aind

icat

ed.

Seri

ous

adve

rse

reac

tions

req

uirin

g di

scon

tinua

tion

of B

ocep

revi

r in

clud

e an

emia

and

ne

utro

peni

a.

Mon

itorin

g:1 M

onth

ly p

regn

ancy

tes

ts; C

BC p

retr

eatm

ent

and

wee

ks 4

, 8, a

nd 1

2, o

f BO

C th

erap

y an

d as

app

ropr

iate

; HCV

-RN

A le

vels

at

wee

ks 4

, 8,

12,

and

24,

at t

he e

nd o

f tre

atm

ent,

dur

ing

follo

w-u

p, a

nd a

s cl

inic

ally

indi

cate

d

138 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

12

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Tole

rabi

lity:

1,12

In p

hase

2 a

nd 3

stu

dies

, ser

ious

adv

erse

reac

tions

occ

urre

d in

11%

of s

ubje

cts

rece

ivin

g tr

iple

ther

apy

and

8% r

ecei

ving

PR

alon

e.

Dos

e m

odifi

catio

ns (g

ener

ally

of P

R) d

ue to

ane

mia

occ

urre

d tw

ice

as o

ften

in s

ubje

cts

trea

ted

with

trip

le th

erap

y (2

6%) c

ompa

red

to P

R al

one

(13%

). Th

e tr

eatm

ent d

isco

ntin

uatio

n ra

te d

ue to

ane

mia

was

1%

for b

oth

subj

ects

trea

ted

with

trip

le th

erap

y an

d su

bjec

ts tr

eate

d w

ith P

R. T

he

prop

ortio

n of

sub

ject

s w

ho r

ecei

ved

an E

SA w

as 4

3% fo

r sub

ject

s tr

eate

d w

ith tr

iple

ther

apy

v. 2

4% fo

r su

bjec

ts tr

eate

d w

ith P

R. T

he p

ropo

rtio

n of

su

bjec

ts r

ecei

ving

a tr

ansf

usio

n fo

r the

man

agem

ent o

f ane

mia

was

3%

for

subj

ects

rece

ivin

g tr

iple

ther

apy

com

pare

d to

<1%

for P

R al

one.

The

pr

opor

tion

of s

ubje

cts

with

neu

trop

hil c

ount

s <0

.5 x

109 /L

was

7%

for s

ubje

cts

rece

ivin

g tr

iple

ther

apy

v. 4

% o

f sub

ject

s re

ceiv

ing

PR a

lone

. Thr

ee

subj

ects

exp

erie

nced

sev

ere

or li

fe-t

hrea

teni

ng in

fect

ions

ass

ocia

ted

with

neu

trop

enia

, and

two

subj

ects

exp

erie

nced

life

-thr

eate

ning

neu

trop

enia

w

hile

rec

eivi

ng tr

iple

ther

apy.

Thr

ombo

embo

lic e

vent

s w

ere

repo

rted

am

ong

subj

ects

rec

eivi

ng tr

iple

ther

apy

and

amon

g th

ose

rece

ivin

g PR

alo

ne.

How

ever

, no

caus

ality

ass

essm

ent c

an b

e m

ade

as th

ese

even

ts a

re n

ot o

nly

know

n to

be

asso

ciat

ed w

ith E

SA u

se b

ut a

lso

PR u

se a

nd u

nder

lyin

g di

seas

e.

Preg

nanc

y/La

ctat

ion:

1 Alth

ough

the

preg

nanc

y ca

tego

ry o

f BO

C al

one

is B

, the

pre

gnan

cy c

ateg

ory

for

com

bina

tion

ther

apy

is X

, sin

ce R

IB h

as

caus

ed b

irth

def

ects

or

feta

l dea

ths

in a

ll an

imal

spe

cies

stu

died

and

PEG

is a

bort

ifaci

ent i

n an

imal

s. A

nim

al s

tudi

es in

dica

te n

ursi

ng in

fant

s co

uld

be e

xpos

ed to

BO

C; th

eref

ore,

the

bene

fits

mus

t be

wei

ghed

aga

inst

the

risks

of d

isco

ntin

uing

nur

sing

or d

isco

ntin

uing

trea

tmen

t with

BO

C.

Una

nsw

ered

saf

ety

ques

tions

:1 Wha

t will

be

the

inci

denc

e of

neu

trop

enia

-ass

ocia

ted

seve

re o

r life

-thr

eate

ning

infe

ctio

ns in

the

gene

ral c

linic

al

sett

ing?

Wha

t is

the

safe

ty o

f ESA

use

in p

atie

nts

rece

ivin

g tr

iple

ther

apy?

D

ose

Inde

x (e

ffic

acy/

toxi

c):1 T

he e

ffec

tive

dose

is 8

00 m

g ev

ery

7–9

hour

s. H

ealth

y hu

man

sub

ject

s ha

ve ta

ken

daily

dos

es o

f 360

0 m

g fo

r 5 d

ays

with

out i

ll ef

fect

. Se

vera

l oth

er u

nans

wer

ed q

uest

ions

rem

ain

with

rega

rd to

trea

tmen

t and

saf

ety,

incl

udin

g:

Wha

t is

the

com

para

tive

effic

acy

of R

GT

vers

us fi

xed-

dose

ther

apy?

H

ow d

o liv

er-t

rans

plan

t or

HIV

or H

BV c

o-in

fect

ed p

atie

nts

resp

ond

to T

PR th

erap

y?

Wha

t is

the

dosi

ng fo

r ped

iatr

ic p

atie

nts?

W

ould

pat

ient

s w

ho p

revi

ousl

y fa

iled

trea

tmen

t with

a B

OC-

cont

aini

ng re

gim

en re

spon

d to

a r

epea

t cou

rse

of th

erap

y?

Wha

t is

the

long

-ter

m c

linic

al im

pact

of e

mer

genc

e or

per

sist

ence

of B

OC-

asso

ciat

ed r

esis

tanc

e am

ino

acid

sub

stitu

tions

? W

hat i

s th

e im

pact

of B

OC

expo

sure

or t

reat

men

t fai

lure

on

the

effic

acy

of o

ther

HCV

NS3

/4 p

rote

ase

inhi

bito

rs, s

uch

as te

lapr

evir

? W

hat a

nti-H

CV a

ctiv

ity d

oes

BOC

have

aga

inst

non

-gen

otyp

e 1

HCV

s?

139 of 187

Gen

eric

Nam

e: B

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embe

r 201

1

13

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Look

-alik

e /

Soun

d-al

ike

(LA

/SA

) Err

or R

isk

Pote

ntia

l: LA

/SA

nam

es a

re a

sses

sed

duri

ng th

e PD

L se

lect

ion

of d

rugs

. Ba

sed

on c

linic

al ju

dgm

ent a

nd a

n ev

alua

tion

of L

A/SA

info

rmat

ion

from

four

dat

a so

urce

s (L

exic

omp,

USP

Onl

ine

LASA

Fin

der,

and

ISM

P Co

nfus

ed D

rug

Nam

e Li

st),

the

follo

win

g dr

ug n

ames

may

cau

se L

ASA

con

fusi

on:

NM

E D

rug

Nam

e Le

xico

mp

USP

Onl

ine

ISM

P Cl

inic

al Ju

dgm

ent

LA/S

A fo

r bo

cepr

evir

(gen

eric

) or V

ictr

elis

™(b

rand

) N

one

Non

e N

one

Non

e

140 of 187

Gen

eric

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e: B

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embe

r 201

1

14

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

AD

VER

SE R

EACT

ION

S1

141 of 187

Gen

eric

Nam

e: B

ocep

revi

r

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w D

ate:

Nov

embe

r 201

1

15

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

DO

SE &

AV

AIL

ABI

LITY

1

STRE

NG

TH

FORM

RO

UTE

FR

EQU

ENCY

RE

NA

L A

DJ

HEP

ATI

C A

DJ

Pedi

atri

c

Dos

e El

derl

y D

ose

200

mg

Caps

ule

Ora

l

800

mg

thre

e tim

es

daily

(7-9

ho

ur a

part

)

Non

e

Non

e fo

r m

ild, m

oder

ate,

or

seve

re h

epat

ic im

pair

men

t.

Effic

acy

and

safe

ty n

ot

esta

blis

hed

in

deco

mpe

nsat

ed c

irrh

osis

.

Safe

ty a

nd

effe

ctiv

enes

s no

t es

tabl

ishe

d

Resp

onse

to th

erap

y in

pat

ient

s >

65

year

s ol

d is

unc

erta

in; t

here

fore

, ca

utio

n sh

ould

be

exer

cise

d

OTH

ER D

OSI

NG

CO

NSI

DER

ATI

ON

S:

• A

dmin

iste

r w

ith a

mea

l or

light

sna

ck.

• Pa

tien

ts w

itho

ut c

irrh

osis

who

are

tre

atm

ent-

naïv

e or

pre

viou

s pa

rtia

l res

pond

ers

or r

elap

sers

to in

terf

eron

and

rib

avir

in th

erap

y sh

ould

in

itiat

e th

erap

y w

ith P

R fo

r 4

wee

ks (i

.e.,

from

wee

k 1

thro

ugh

wee

k 4)

, the

n tr

iple

ther

apy

as fo

llow

s:

• Tr

eatm

ent-

naïv

e pa

tient

s w

ith u

ndet

ecta

ble

HCV

-RN

A a

t wee

ks 8

and

24

shou

ld c

ompl

ete

trip

le th

erap

y at

wee

k 28

, and

thos

e w

ith

dete

ctab

le H

CV-R

NA

at w

eek

8 an

d un

dete

ctab

le H

CV-R

NA

at w

eek

24 s

houl

d co

mpl

ete

trip

le th

erap

y at

wee

k 36

and

con

tinue

with

PR

only

th

roug

h w

eek

48.

• Pr

evio

us p

artia

l res

pond

ers

or re

laps

ers

with

und

etec

tabl

e H

CV-R

NA

at w

eeks

8 a

nd 2

4 sh

ould

com

plet

e tr

iple

ther

apy

at w

eek

36, a

nd

thos

e w

ith d

etec

tabl

e H

CV-R

NA

at w

eek

8 an

d un

dete

ctab

le H

CV-R

NA

at w

eek

24 s

houl

d co

mpl

ete

trip

le th

erap

y at

wee

k 36

and

con

tinue

PR

alo

ne th

roug

h w

eek

48.

• Pa

tient

s w

ith c

ompe

nsat

ed c

irrh

osis

sho

uld

rece

ive

4 w

eeks

PR

follo

wed

by

44 w

eeks

trip

le th

erap

y pl

us P

R.

• Re

spon

se-g

uide

d th

erap

y w

as n

ot s

tudi

ed in

pat

ient

s pr

evio

usly

trea

ted

with

PR

who

had

<2-

log 1

0 dec

reas

e in

HCV

-RN

A by

trea

tmen

t wee

k 12

. If t

reat

ed, t

hese

pat

ient

s sh

ould

rece

ive

4 w

eeks

PR

follo

wed

by

44 w

eeks

trip

le th

erap

y. A

lso,

con

side

r gi

ving

trea

tmen

t-na

ïve

patie

nts

who

wer

e po

orly

resp

onsi

ve to

inte

rfer

on a

t tre

atm

ent w

eek

4 w

ith 4

wee

ks o

f PR

follo

wed

by

44 w

eeks

trip

le th

erap

y.

• D

ose

redu

ctio

n of

Boc

epre

vir

is n

ot r

ecom

men

ded.

•

Dis

cont

inue

trip

le th

erap

y fo

r al

l pat

ient

s w

ith H

CV-R

NA

≥10

0 IU

/mL

at w

eek

12 o

r co

nfir

med

, det

ecta

ble

HCV

-RN

A a

t wee

k 24

. •

See

pres

crib

ing

info

rmat

ion

for P

EG a

nd R

IB fo

r oth

er d

osin

g co

nsid

erat

ions

. •

Alth

ough

cur

rent

ly u

nder

way

; at t

his

time

ther

e ar

e no

pub

lishe

d st

udie

s es

tabl

ishi

ng th

e ef

ficac

y an

d sa

fety

of B

ocep

revi

r in

patie

nts

co-

infe

cted

with

HCV

and

HIV

or h

epat

itis

B or

in o

rgan

tran

spla

nt p

atie

nts.

•

Not

e: T

reat

men

t dur

atio

n re

com

men

datio

ns d

iffer

for

som

e su

bgro

ups

from

dur

atio

ns in

the

phas

e 3

tria

ls.

142 of 187

Gen

eric

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revi

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Nov

embe

r 201

1

16

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

PHA

RMA

COKI

NET

ICS1

Para

met

er

Resu

lt

Ora

l Bio

avai

labi

lity

Not

rep

orte

d Pr

otei

n Bi

ndin

g 75

%

Elim

inat

ion

79%

in th

e fe

ces,

9%

in u

rine

H

alf-

Life

3.

4 ho

urs

Met

abol

ism

A

ldok

etor

educ

tase

(pri

mar

y) a

nd C

YP3A

4/5

*Foo

d, r

egar

dles

s of

mea

l typ

e, a

ffec

ts e

xpos

ure

to B

OC,

with

65%

incr

ease

in e

xpos

ure

rela

tive

to fa

stin

g st

ate.

PHA

RMA

COG

ENET

ICS1

Retr

ospe

ctiv

e st

udie

s in

dica

te t

ripl

e th

erap

y in

crea

sed

SVR

rate

s re

gard

less

of

inte

rleu

kin-

28B

geno

type

in

trea

tmen

t-na

ïve

and

trea

tmen

t-ex

peri

ence

d pa

tient

s. H

owev

er, t

hese

res

ults

sho

uld

be v

iew

ed c

autio

usly

, bec

ause

the

sam

ple

size

was

sm

all a

nd t

he s

ubst

udy

popu

latio

ns m

ay

not r

epre

sent

the

full

tria

l pop

ulat

ions

.

ALL

ERG

IES/

INTE

RACT

ION

S1,12

Dru

g-D

rug:

BOC

is a

sub

stra

te a

nd s

tron

g in

hibi

tor

of C

YP3A

4/5

and

a su

bstr

ate

and

pote

ntia

l inh

ibito

r of P

-gly

copr

otei

n. A

lthou

gh B

OC

is p

rim

arily

m

etab

oliz

ed b

y al

doke

tore

duct

ase

(AKR

), BO

C m

ay b

e co

-adm

inis

tere

d w

ith A

KR in

hibi

tors

. Co-

adm

inis

trat

ion

of B

OC

with

dru

gs th

at in

duce

or

inhi

bit C

YP3A

4/5

coul

d de

crea

se o

r inc

reas

e BO

C ex

posu

re.

Dru

gs c

ontr

aind

icat

ed (

adve

rse

reac

tion)

: al

fuzo

sin

(hyp

oten

sion

), rif

ampi

n (lo

ss o

f vi

rolo

gic

resp

onse

to

BOC)

, er

got

deri

vativ

es (

acut

e er

got

toxi

city

), St

. Jo

hn’s

wor

t (lo

ss o

f vi

rolo

gic

resp

onse

to

BOC)

, lo

vast

atin

or

sim

vast

atin

(m

yopa

thy)

, pi

moz

ide

(car

diac

arr

hyth

mia

s),

sild

enaf

il or

ta

dala

fil d

osed

for

pulm

onar

y ar

teri

al h

yper

tens

ion

(PD

E5 in

hibi

tor-

asso

ciat

ed a

dver

se e

vent

s), t

riazo

lam

or

oral

mid

azol

am (i

ncre

ased

sed

atio

n or

re

spir

ator

y de

pres

sion

), ci

sapr

ide

(car

diac

arr

hyth

mia

s),

carb

amaz

epin

e or

phe

noba

rbita

l or

phe

nyto

in (

loss

of

viro

logi

c re

spon

se t

o BO

C),

and

dros

peri

none

(hyp

erka

lem

ia).

Doz

ens

of o

ther

dru

g in

tera

ctio

ns w

ith B

OC

are

pred

icte

d or

hav

e be

en c

onfir

med

via

stu

dies

. Sev

eral

of

thes

e dr

ugs

requ

ire

dose

adj

ustm

ents

or

clin

ical

mon

itorin

g w

hen

used

con

com

itant

ly w

ith B

OC.

Dru

g in

tera

ctio

n tr

ials

hav

e ye

t to

be

cond

ucte

d, o

r w

ere

flaw

ed, f

or s

ome

key

drug

s or

dr

ug c

lass

es: a

sen

sitiv

e P-

glyc

opro

tein

sub

stra

te s

uch

as d

igox

in, m

etha

done

, ora

l con

trac

eptiv

es, a

nd a

ntid

epre

ssan

ts.

Food

-Dru

g:

No

food

-dru

g in

tera

ctio

ns h

ave

been

rep

orte

d.1

143 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

17

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

APP

END

IX 1

Su

gges

ted

PA C

rite

ria

Hep

ati

tis C

Ora

l P

rote

ase I

nh

ibit

ors

/Tri

ple

Th

era

py

C

ov

ere

d

Alt

ern

ati

ves

: Lis

ted a

t; h

ttp://w

ww

.ore

go

n.g

ov/D

HS

/hea

lth

pla

n/t

ools

_pro

v/p

dl.shtm

l

Ap

pro

val

Cri

teri

a

1. W

hat is

the d

iag

nosis

?

R

ecord

IC

D-9

code

2. Is

the

dia

gnosis

an O

HP

covere

d d

iag

nosis

?

Yes:

Go to #

3.

No

: P

ass to R

Ph

, D

en

y f

or

OH

P C

overa

ge.

3. Is

the

requ

est fo

r tr

eatm

ent of

Chro

nic

H

epatitis C

?

Docum

ent appro

pri

ate

IC

D9 c

ode:

Yes:

Go to #

4

No

: P

ass

to R

Ph, D

eny

For

Appr

opria

tene

ss

4. D

oes the p

atien

t ha

ve

do

cum

ente

d H

CV

gen

oty

pe 1

?

Record

Gen

oty

pe:

Yes:

Go to #

5

No

: P

ass

to R

Ph, D

eny

For

Appr

opria

tene

ss

5. D

oes the p

atien

t ha

ve

a p

re-t

reatm

ent viral lo

ad (

sin

ce d

iagnosis

)?

Yes:

Go to #

6

No

: P

ass to R

Ph;

Den

y F

or

Appro

pria

ten

ess; R

ecom

mend

vira

l lo

ad

6. Is

the

patie

nt a

lso b

ein

g p

rescribed p

eg

inte

rfero

n a

lfa

-2a o

r -2

b a

nd r

iba

virin

?

Yes:

Go to #

7

N

o:

Pas

s to

RPh

, Den

y Fo

r Ap

prop

riate

ness

7. H

as p

rior

auth

ori

zation b

een g

rante

d f

or

peg

inte

rfero

n a

lfa

-2a o

r -2

b a

nd r

iba

vir

in o

r does p

atient m

eet pri

or

auth

ori

zation

crite

ria f

or

peg

yla

ted inte

rfero

n-a

lfa?

Yes: G

o t

o #

8

No

: P

ass to

RP

h; D

en

y f

or

appro

priate

ness

8. Is th

e r

eq

uest fo

r contin

uation o

f th

era

py? (

Patien

t has b

een o

n tri

ple

th

era

py w

ith

a o

ral antivira

l a

gen

t in

pre

cedin

g 6

weeks)

Yes:

Go to “

Continu

ation o

f T

hera

py”

. N

o:

Go to #

9

9. H

as t

he p

atient

pre

vio

usly

been t

reate

d w

ith b

ocepre

vir o

r te

lapre

vir

?

Yes: P

ass to R

Ph, D

en

y f

or

appro

priate

ness

No

: G

o to #

10

10. Is

th

e r

eq

uest fo

r te

lapre

vir 7

50m

g (

two t

abs)

TID

for

12 w

eeks?

Yes:

Ap

pro

ve f

or

6 w

eeks to a

llow

for

4 w

eek v

iral lo

ad c

heck to c

ontinue

for

a m

axim

um

of

12 w

eeks

No

: G

o to #

11 (

If d

ose is

diffe

rent pass to R

Ph f

or

appro

priate

ness)

11. Is

th

e r

eq

uest fo

r boce

pre

vir 8

00m

g (

four

tabs)

TID

and t

he p

atien

t has c

om

ple

ted

4 w

eeks o

f le

ad-i

n tre

atm

ent

with r

iba

virin

and p

eg

inte

rfero

n?

Yes:

Appro

ve f

or

10 w

eeks to a

llow

for

8 w

eek v

iral lo

ad c

heck to c

ontinue

for

a m

axim

um

of

24, 32,

or

40

weeks

based o

n r

esp

onse

No

: P

ass to R

Ph;

Den

y f

or

appro

priate

ness

144 of 187


Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

18

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Co

nti

nu

ati

on

of

Th

era

py-

Te

lap

revir

1

. Is

th

e p

atie

nt

tre

atm

en

t-

na

ïve

or

a p

rio

r re

lap

se

p

atien

t an

d h

as u

nd

ete

cta

ble

H

CV

RN

A o

r m

easu

red

at 4

a

nd

12

we

eks?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 6

we

eks o

f tr

iple

th

era

py w

ith

te

lap

revir

, p

eg

inte

rfe

ron

, a

nd

rib

avir

in (

tota

l 1

2 w

ee

ks),

fo

llow

ed

by

co

ntin

ued

dua

l th

era

py w

ith

peg

inte

rfe

ron a

nd r

iba

va

rin

fo

r 1

2 w

ee

ks (

tota

l tr

eatm

en

t du

ratio

n o

f 2

4 w

ee

ks).

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

Pa

tie

nts

with

in

ad

eq

ua

te v

ira

l re

sp

on

se a

re u

nlik

ely

to

ach

ieve

SV

R,

an

d m

ay d

eve

lop

tre

atm

en

t-em

erg

en

t re

sis

tance

su

bstitu

tion

s.

Dis

con

tin

ua

tio

n o

f th

era

py is r

ecom

men

ded

in

all

pa

tie

nts

with

(1

) H

CV

-RN

A le

ve

ls o

f g

reate

r th

an

or

equ

al to

10

00

IU

/mL a

t T

rea

tme

nt

Week 4

or

12

; o

r (2

) co

nfirm

ed d

ete

cta

ble

HC

V-R

NA

le

ve

ls a

t T

rea

tme

nt W

eek 2

4.

2.

Is th

e p

atie

nt

tre

atm

en

t-

na

ïve

or

a p

rio

r re

lap

se

p

atien

t an

d h

as d

ete

cta

ble

(1

00

0 I

U/m

L o

r le

ss)

at W

eeks

4 a

nd

/or

12

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 6

we

eks o

f tr

iple

th

era

py w

ith

te

lap

revir

, p

eg

inte

rfe

ron

, a

nd

rib

avir

in (

tota

l 1

2 w

ee

ks),

fo

llow

ed

by

co

ntin

ued

dua

l th

era

py w

ith

peg

inte

rfe

ron a

nd r

iba

va

rin

fo

r a

dd

itio

na

l 36

we

eks (

tota

l tr

eatm

en

t d

ura

tio

n o

f 48

we

eks).

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

Pa

tie

nts

with

in

ad

eq

ua

te v

ira

l re

sp

on

se a

re u

nlik

ely

to

ach

ieve

SV

R,

an

d m

ay d

eve

lop

tre

atm

en

t-em

erg

en

t re

sis

tance

su

bstitu

tion

s.

Dis

con

tin

ua

tio

n o

f th

era

py is r

ecom

men

ded

in

all

pa

tie

nts

with

(1

) H

CV

-RN

A le

ve

ls o

f g

reate

r th

an

or

equ

al to

10

00

IU

/mL a

t T

rea

tme

nt

Week 4

or

12

; o

r (2

) co

nfirm

ed d

ete

cta

ble

HC

V-R

NA

le

ve

ls a

t T

rea

tme

nt W

eek 2

4.

3.

Is th

e p

atie

nt a

prio

r p

art

ial

or

nu

ll re

sp

on

de

r?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 6

we

eks o

f tr

iple

th

era

py w

ith

te

lap

revir

, p

eg

inte

rfe

ron

, a

nd

rib

avir

in (

tota

l 1

2 w

ee

ks),

fo

llow

ed

by

co

ntin

ued

dua

l th

era

py w

ith

peg

inte

rfe

ron a

nd r

iba

va

rin

fo

r a

dd

itio

na

l 36

we

eks (

tota

l tr

eatm

en

t d

ura

tio

n o

f 48

we

eks).

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

4.

Is th

e p

atie

nt

tre

atm

en

t-

na

ïve

with

docu

me

nte

d

cir

rhosis

tha

t ha

s

un

de

tecta

ble

HC

V-R

NA

at

we

eks 4

an

d 1

2?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 6

we

eks o

f tr

iple

th

era

py w

ith

te

lap

revir

, p

eg

inte

rfe

ron

, a

nd

rib

avir

in (

tota

l 1

2 w

ee

ks),

fo

llow

ed

by

co

ntin

ued

dua

l th

era

py w

ith

peg

inte

rfe

ron a

nd r

iba

va

rin

fo

r a

dd

itio

na

l 36

we

eks (

tota

l tr

eatm

en

t d

ura

tio

n o

f 48

we

eks).

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

Pa

tie

nts

with

in

ad

eq

ua

te v

ira

l re

sp

on

se a

re u

nlik

ely

to

ach

ieve

SV

R,

an

d m

ay d

eve

lop

tre

atm

en

t-em

erg

en

t re

sis

tance

su

bstitu

tion

s.

Dis

con

tin

ua

tio

n o

f th

era

py is r

ecom

men

ded

in

all

pa

tie

nts

with

(1

) H

CV

-RN

A le

ve

ls o

f g

reate

r th

an

or

equ

al to

10

00

IU

/mL a

t T

rea

tme

nt

Week 4

or

12

; o

r (2

) co

nfirm

ed d

ete

cta

ble

HC

V-R

NA

le

ve

ls a

t T

rea

tme

nt W

eek 2

4.

*TR

EA

TM

EN

T F

UT

ILIT

Y R

UL

ES

Week 4

or

Week 1

2:

HC

V-R

NA

gre

ate

r th

an

100

0 I

U/m

L: D

iscon

tinu

e I

NC

IVE

K a

nd

pe

gin

terf

ero

n a

lfa

and

rib

avir

in (

INC

IVE

K t

rea

tme

nt com

ple

te a

t 1

2 w

ee

ks)

Week 2

4:

Dete

cta

ble

Dis

con

tin

ue

pe

gin

terf

ero

n a

nd

rib

avir

in.

If p

egin

terf

ero

n a

lfa

or

rib

avir

in is d

isco

ntin

ue

d fo

r a

ny r

ea

son,

INC

IVE

K m

ust

als

o b

e d

iscon

tin

ue

d

145 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

19

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Co

nti

nu

ati

on

of

Th

era

py-

Bo

ce

pre

vir

1

.Is th

e p

atie

nt

tre

atm

en

t-n

aïv

e a

nd

ha

ve

un

de

tecta

ble

HC

V R

NA

at

tre

atm

en

t w

ee

ks 8

an

d 2

4?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 1

4 w

ee

ks o

f b

oce

pre

vir

fo

r to

tal tr

ea

tme

nt d

ura

tio

n o

f 2

8 w

ee

ks (

4 w

ee

k lea

d-in

, 24

we

eks t

riple

th

era

py)

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

2.

Is th

e p

atie

nt

tre

atm

en

t-n

aïv

e a

nd

ha

ve

de

tecta

ble

HC

V R

NA

at

tre

atm

en

t w

ee

k 8

and

und

ete

cta

ble

a

t w

ee

k 2

4?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 2

2 w

ee

ks o

f b

oce

pre

vir

fo

llow

ed

by c

on

tinu

ed

du

al

the

rap

y w

ith

peg

inte

rfe

ron

and r

iba

vir

in f

or

16

we

eks f

or

tota

l tr

ea

tme

nt

du

ratio

n o

f 4

8 w

ee

ks (

4 w

ee

k le

ad

-in,

32 w

ee

ks t

rip

le t

he

rap

y,

12

we

eks

du

al th

era

py)

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

3.

Is th

e p

atie

nt a

pre

vio

us p

art

ial

resp

on

de

r o

r re

lapse

r an

d h

as

un

de

tecta

ble

HC

V R

NA

at

treatm

en

t w

ee

ks 8

an

d 2

4?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 2

2 w

ee

ks o

f b

oce

pre

vir

fo

r to

tal tr

ea

tme

nt

du

ratio

n o

f 3

6 w

ee

ks (

4 w

ee

k le

ad

-in,

32 w

ee

ks t

rip

le t

he

rap

y)

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

4.

Is th

e p

atie

nt a

pre

vio

us p

art

ial

resp

on

de

r o

r re

lapse

r an

d h

as

de

tecta

ble

HC

V R

NA

at

tre

atm

en

t w

ee

k 8

an

d u

nde

tecta

ble

at

we

ek

24

?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• A

pp

rove

add

itio

nal 2

2 w

ee

ks o

f b

oce

pre

vir

fo

llow

ed

by c

on

tinu

ed

d

ua

l th

era

py w

ith

pe

gin

terf

ero

n a

nd

rib

avirin

fo

r 1

6 w

ee

ks f

or

tota

l tr

ea

tme

nt d

ura

tio

n o

f 48

we

eks (

4 w

ee

k le

ad

-in

, 3

2 w

ee

ks t

rip

le

the

rap

y,

12

we

eks d

ual th

era

py)

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

5.

Do

es t

he p

atie

nt h

ave

do

cum

ente

d c

irrh

osis

or

is

do

cum

ente

d a

s a

null

respo

nde

r a

nd

d

oe

s n

ot m

eet

the

fu

tilit

y r

ule

s a

t tr

ea

tme

nt

we

eks 8

,12

, a

nd

24?

Ye

s:

Ap

pro

ve

as fo

llow

s:

• C

on

tin

ue

trip

le t

he

rap

y w

ith

boce

pre

vir

fo

r a

to

tal tr

ea

tme

nt

du

ratio

n o

f 4

8 w

ee

ks (

4 w

ee

k le

ad

-in,

44 w

ee

ks t

rip

le t

he

rap

y).

No

: D

EN

Y

(Me

dic

al A

pp

rop

ria

tene

ss)

*TR

EA

TM

EN

T F

UT

ILIT

Y R

UL

ES

If t

he

pa

tie

nt h

as H

CV

-RN

A r

esu

lts g

rea

ter

tha

n o

r eq

ual to

10

0 I

U/m

L a

t T

W12,

then

dis

con

tin

ue

th

ree

-me

dic

ine

re

gim

en.

If t

he

pa

tie

nt h

as c

on

firm

ed

, de

tecta

ble

HC

V-R

NA

at

TW

24

, th

en

dis

co

ntin

ue

th

ree

-me

dic

ine

re

gim

en.

146 of 187

Gen

eric

Nam

e: B

ocep

revi

r

R

evie

w D

ate:

Nov

embe

r 201

1

20

Aut

hor:

Sher

ri J.

Will

ard

Arg

yres

Ref

eren

ces:

1.

Vic

trel

is p

acka

ge in

sert

. Ava

ilabl

e at

: htt

p://

ww

w.m

erck

.com

/pro

duct

/usa

/pi_c

ircu

lars

/v/v

ictr

elis

/vic

trel

is_p

i.pdf

.

2. G

hany

MG,

Nel

son

DR, S

trad

er D

B, T

hom

as D

L, S

eeff

LB. A

n up

date

on

trea

tmen

t of g

enot

ype

1 ch

roni

c hep

atiti

s C v

irus

infe

ctio

n: 2

011

prac

tice

guid

elin

e by

the

Amer

ican

Ass

ocia

tion

for t

he S

tudy

of L

iver

Dis

ease

s. H

epat

olog

y. 20

11;5

4(4)

:143

3-14

44.

3. F

ood

and

Drug

Adm

inis

trat

ion

Cent

er fo

r Dru

g Ev

alua

tion

and

Rese

arch

. App

licat

ion

Num

ber:

202

258O

rig1

s000

sum

mar

y re

view

. Ava

ilabl

e at

: ht

tp:/

/ww

w.a

cces

sdat

a.fd

a.go

v/dr

ugsa

tfda_

docs

/nda

/201

1/20

2258

Orig

1s00

0Sum

R.pd

f. Ac

cess

ed S

epte

mbe

r 26,

201

1.

4. P

oord

ad F

, McC

one

JR, B

acon

BR,

et a

l. Bo

cepr

evir

for u

ntre

ated

chro

nic H

CV g

enot

ype

1 in

fect

ion.

N. E

ngl.

J. M

ed. 2

011;

364(

13)L

1195

-206

5. B

acon

BR,

Gor

don

SC, L

awitz

, et a

l. Bo

cepr

evir

for P

revi

ousl

y Tr

eate

d Ch

roni

c HCV

Gen

otyp

e 1

Infe

ctio

n. N

. Eng

l. J.

Med

. 201

1;36

4(13

):120

7-17

.

6. G

hany

MG,

Str

ader

DB,

Tho

mas

DL,

See

ff LB

. Dia

gnos

is, m

anag

emen

t, an

d tr

eatm

ent o

f hep

atiti

s C: a

n up

date

. Hep

atol

ogy.

200

9;49

(4):1

335-

1374

.

7. R

osen

, HR.

Chr

onic

Hep

atiti

s C In

fect

ion.

N. E

ngl.

J. M

ed. 2

011;

364(

25):2

429-

38.

8. Ja

cobs

on IM

, McH

utch

ison

JG, D

ushe

iko

G, e

t al.

Tela

prev

ir fo

r pre

viou

sly

untr

eate

d ch

roni

c hep

atiti

s C v

irus

infe

ctio

n. N

. Eng

l. J.

Med

. 20

11;3

64(2

5):2

405-

2416

.

9. Z

euze

m S

, Bug

gisc

h P,

Aga

rwal

K, e

t al.

The

prot

ease

inhi

bito

r GS-

9256

and

non

-nuc

leos

ide

poly

mer

ase

inhi

bito

r teg

obuv

ir a

lone

, with

RBV

or

pegi

nter

fero

n pl

us R

BV in

hep

atiti

s C. H

epat

olog

y. 20

11 O

ct 1

7. d

oi: 1

0.10

02/h

ep.2

4744

.

10. F

ood

and

Drug

Adm

inis

trat

ion

Cent

er fo

r Dru

g Ev

alua

tion

and

Rese

arch

. App

licat

ion

Num

ber:

202

258O

rig1

s000

Cro

ss D

isci

line

Team

Lea

der

Revi

ew. A

vaila

ble

at: h

ttp:

//w

ww

.acc

essd

ata.

fda.

gov/

drug

satfd

a_do

cs/n

da/2

011/

2022

58Or

ig1s

000C

ross

R.pd

f. Ac

cess

ed N

ovem

ber 1

9, 2

011.

11. P

aul Y

Kw

o, E

ric J

Law

itz, J

onat

han

McC

one,

et a

l. Ef

ficac

y of

boc

epre

vir,

an N

S3 p

rote

ase

inhi

bito

r, in

com

bina

tion

with

peg

inte

rfer

on a

lfa-2

b an

d ri

bavi

rin

in tr

eatm

ent-

naiv

e pa

tient

s with

gen

otyp

e 1

hepa

titis

C in

fect

ion

(SPR

INT-

1): a

n op

en-la

bel,

rand

omis

ed, m

ultic

entr

e ph

ase

2 tr

ial.

12. F

ood

and

Drug

Adm

inis

trat

ion

Cent

er fo

r Dru

g Ev

alua

tion

and

Rese

arch

. App

licat

ion

num

ber:

202

258O

rig1

s000

sum

mar

y re

view

. Ava

ilabl

e at

: ht

tp:/

/ww

w.a

cces

sdat

a.fd

a.go

v/dr

ugsa

tfda_

docs

/nda

/201

1/20

2258

Orig

1s00

0Sum

R.pd

f.

13. E

ASL

Clin

ical

Pra

ctic

e Gu

idel

ines

: Man

agem

ent o

f hep

atiti

s C v

irus

infe

ctio

n. Jo

urna

l of H

epat

olog

y. 20

11;5

5(2)

:245

-264

.

147 of 187

D

rug

Use

Res

earc

h &

Man

agem

ent P

rogr

am

Ore

gon

Stat

e U

nive

rsity

, 500

Sum

mer

Stre

et N

E, E

35, S

alem

, Ore

gon

9730

1-10

79

Phon

e 50

3-94

5-52

20 |

Fax

503-

947-

1119

Cl

ass

Upd

ate:

Ang

iote

nsin

-Con

vert

ing

Enzy

me

Inhi

bito

rs (A

CEIs

), A

ngio

tens

in II

Rec

epto

r Bl

ocke

rs (A

RBs)

, and

Dir

ect R

enin

Inhi

bito

rs (D

RIs)

EX

ECU

TIV

E SU

MM

ARY

: M

onth

/Yea

r of

Rev

iew

: Jan

uary

201

2 N

ew P

rodu

ct fo

r re

view

: azi

lsar

tan

(Eda

rbi)

D

ossi

er r

ecei

ved:

Yes

Man

ufac

ture

r: T

aked

a Ph

arm

aceu

tical

s

La

st O

rego

n Re

view

: Feb

201

0

So

urce

Doc

umen

t: D

ERP

Ava

ilabl

e A

ltern

ativ

es

Cu

rren

t Pre

ferr

ed A

gent

s:

Curr

ent

Non

-Pre

ferr

ed A

gent

s:

ACE

Is

bena

zepr

il ca

ptop

ril

enal

apri

l fo

sino

pril

lisin

opri

l m

oexi

pril

quin

apri

l ra

mip

ril

tran

dola

pril

Thia

zide

Com

bo:

bena

zepr

il-H

ydro

chlo

roth

iazi

de

Beni

car

HCT

(olm

esar

tan-

hydr

ochl

orot

hiaz

ide)

ca

ptop

ril/

hydr

ochl

orot

hiaz

ide

enal

apri

l-Hyd

roch

loro

thia

zide

fo

sino

pril-

Hyd

roch

loro

thia

zide

lis

inop

ril-H

ydro

chlo

roth

iazi

de

losa

rtan

-Hyd

roch

loro

thia

zide

M

icar

dis

HCT

(tel

mis

arta

n-hy

droc

hlor

othi

azid

e)

moe

xipr

il-H

ydro

chlo

roth

iazi

de

quin

apri

l-Hyd

roch

loro

thia

zide

ACE

Is

Ace

on (p

erin

dopr

il)

ARB

s A

taca

nd (c

ande

sart

an)

Teve

ten

(epr

osar

tan)

A

vapr

o (ir

besa

rtan

) D

iova

n (v

alsa

rtan

) D

RIs

Tekt

urna

(alis

kire

n)

Com

bo P

rodu

cts:

A

zor

(am

lodi

pine

/olm

esar

tan)

Ex

forg

e (a

mlo

dipi

ne/v

alsa

rtan

) Tw

ynst

a (t

elm

isar

tan/

amlo

dipi

ne)

Valtu

rna

(alis

kire

n/va

lsar

tan)

A

mtu

rnid

e (a

liski

ren/

amlo

dipi

ne/h

ctz)

Te

kam

lo (a

liski

ren/

amlo

dipi

ne)

Lotr

el (a

mlo

dipi

ne/b

enaz

epri

l) Ta

rka

(tra

ndol

apri

l/ve

rapa

mil)

Te

ktur

na H

CT

A

RBs

Beni

car

(olm

esar

tan)

lo

sart

an

Mic

ardi

s (t

elm

isar

tan)

148 of 187

Pr

evio

us C

oncl

usio

ns b

y H

RC:

1.

Ther

e ar

e no

clin

ical

ly s

igni

fican

t diff

eren

ces

amon

g A

CE-Is

or

ARB

s.

2.

Com

bina

tion

ther

apy

with

an

ACE

-I an

d an

ARB

pro

duce

s a

redu

ctio

n in

pro

tein

uria

in n

ondi

abet

ic p

rote

inur

ia o

r ch

roni

c ki

dney

dis

ease

but

pr

oduc

ed n

o cl

inic

ally

sig

nific

ant d

iffer

ence

in o

ther

mea

sure

s of

rena

l fun

ctio

n.

3.

Rate

s of

cou

gh w

ere

low

er w

ith A

RBs

than

ACE

-Is h

owev

er o

vera

ll ra

tes

of w

ithdr

awal

wer

e th

e sa

me.

4.

Th

ere

wer

e no

incl

uded

stu

dies

that

eva

luat

ed c

ompa

rativ

e ef

fect

iven

ess/

eff

icac

y an

d ha

rms

betw

een

alis

kiri

n as

mon

othe

rapy

or f

or

com

bina

tion

ther

apy

with

ACE

-I an

d A

RB.

5.

Ther

e w

as n

o si

gnifi

cant

diff

eren

ce fo

und

betw

een

ARB

S an

d A

CEIs

for

subg

roup

s ba

sed

on a

ge, e

ject

ion

frac

tion,

or N

YHA

func

tiona

l cla

ss

Reas

on fo

r Re

view

: Si

nce

the

last

OR

revi

ew in

201

0 a

high

qua

lity

syst

emat

ic r

evie

w w

as p

erfo

rmed

for t

he A

genc

y fo

r H

ealth

care

Res

earc

h an

d Q

ualit

y (A

HRQ

) to

upda

te th

eir p

revi

ous

com

para

tive

effe

ctiv

enes

s re

view

to e

valu

ate

the

long

-ter

m b

enef

its a

nd h

arm

s of

ACE

Is, A

RBs,

and

DRI

s fo

r tre

atin

g es

sent

ial h

yper

tens

ion

in a

dults

1 . Th

is r

evie

w lo

oked

at a

vaila

ble

com

para

tive

effe

ctiv

enes

s re

sear

ch o

f DRI

s w

hile

the

prev

ious

DER

P re

view

onl

y ha

d pl

aceb

o-co

ntro

lled

stud

ies

for t

he D

RIs.

Sin

ce th

is s

yste

mat

ic r

evie

w, a

new

ARB

was

add

ed to

the

mar

ket.

Azi

lsar

tan

was

app

rove

d by

the

FDA

in F

ebru

ary

2011

for t

reat

men

t of h

yper

tens

ion2 .

Ther

e is

als

o ne

w e

vide

nce

show

ing

no a

dvan

tage

of c

ombi

natio

n th

erap

y w

ith a

n A

CEI a

nd

ARB

on

clin

ical

out

com

es a

nd m

ore

adve

rse

effe

cts

asso

ciat

ed w

ith th

e co

mbi

natio

n.3 I

n D

ecem

ber,

the

ALT

ITU

DE

stud

y w

ith a

liski

ren

was

te

rmin

ated

due

to th

e un

likel

y be

nefit

from

trea

tmen

t and

the

high

er in

cide

nce

of a

dver

se e

vent

s id

entif

ied

in th

is s

tudy

. In

the

trea

tmen

t arm

th

ere

was

an

incr

ease

d in

cide

nce

of n

on-f

atal

str

oke,

ren

al c

ompl

icat

ions

, hyp

erka

lem

ia a

nd h

ypot

ensi

on.

This

was

the

first

tria

l tha

t eva

luat

ed th

e D

RI a

liski

ren

for l

onge

r th

an o

ne y

ear

in h

igh

risk

car

diov

ascu

lar

and

rena

l pat

ient

s.

Issu

es:

• Is

ther

e an

y ne

w e

vide

nce

that

ther

e is

a m

eani

ngfu

l diff

eren

ce in

ACE

Is, A

RBS,

and

DRI

s in

long

term

clin

ical

out

com

es o

r saf

ety

that

wou

ld

prec

ipita

te c

hang

es to

pre

viou

s re

com

men

datio

ns?

• Is

ther

e an

y ev

iden

ce th

at a

zils

arta

n is

mor

e ef

fect

ive

than

cur

rent

ly a

vaila

ble

med

icat

ions

in th

e PD

L dr

ug c

lass

? •

Shou

ld a

zils

arta

n be

add

ed a

s a

pref

erre

d ag

ent o

n th

e O

HA

PD

L cl

ass?

Co

nclu

sion

s:

The

AH

RQ s

yste

mat

ic r

evie

w c

oncl

uded

that

the

stre

ngth

of e

vide

nce

rem

ains

hig

h fo

r equ

ival

ence

bet

wee

n A

CEIs

and

ARB

s fo

r blo

od p

ress

ure

low

erin

g an

d us

e of

a s

ingl

e an

tihyp

erte

nsiv

e ag

ent,

and

a m

eani

ngfu

l diff

eren

ce b

etw

een

ARB

s an

d A

CEIs

onl

y fo

r sh

ort-

term

adv

erse

eve

nts

due

to c

ough

. The

ove

rall

inci

denc

e of

cou

gh v

arie

s w

idel

y in

clin

ical

tria

ls a

nd h

as b

een

repo

rted

to b

e in

the

rang

e of

5 to

35%

and

a m

uch

low

er

inci

denc

e ha

s be

en d

escr

ibed

in s

tudi

es o

f pat

ient

s pr

esen

ting

for t

he e

valu

atio

n of

chr

onic

cou

gh4 . T

he e

vide

nce

look

ed a

t sin

ce th

e in

itial

rev

iew

di

d no

t cha

nge

any

conc

lusi

ons

mad

e re

gard

ing

long

term

car

diov

ascu

lar o

utco

mes

, qua

lity

of li

fe, p

rogr

essi

on o

f ren

al d

isea

se, m

edic

atio

n ad

here

nce,

or p

ersi

sten

ce r

ates

of a

ngio

edem

a, o

r di

ffer

ence

s in

key

pat

ient

sub

grou

ps a

nd th

e st

reng

th o

f evi

denc

e re

mai

ns lo

w to

mod

erat

e.

Ther

e w

as in

suff

icie

nt e

vide

nce

to r

each

con

clus

ion

for t

he D

RIs

for a

ny o

utco

mes

of i

nter

est.

149 of 187

A

zils

arta

n is

the

eigh

th A

RB in

dica

ted

for t

he tr

eatm

ent o

f hyp

erte

nsio

n to

low

er b

lood

pre

ssur

e ei

ther

alo

ne o

r in

com

bina

tion

with

oth

er a

gent

s.

Alth

ough

rec

ent s

tudi

es h

ave

dem

onst

rate

d th

at a

zils

arta

n is

mor

e ef

fect

ive

than

olm

esar

tan,

val

sart

an, a

nd r

amip

ril a

t low

erin

g sy

stol

ic B

P5-8 ,

ther

e is

no

evid

ence

sho

win

g an

impa

ct in

clin

ical

car

diov

ascu

lar o

utco

mes

, pre

vent

ing

mor

talit

y, o

r sh

owin

g re

duct

ion

in c

ardi

ovas

cula

r ris

k in

pa

tient

s w

ith h

yper

tens

ion.

In

addi

tion,

oth

er e

stab

lishe

d A

RBs

have

evi

denc

e fo

r m

ultip

le in

dica

tions

incl

udin

g CH

F, d

iabe

tic n

ephr

opat

hy, s

trok

e pr

even

tion,

and

trea

tmen

t of h

yper

tens

ion

in p

edia

tric

pat

ient

s w

hile

azi

lsar

tan

is o

nly

indi

cate

d fo

r bl

ood

pres

sure

low

erin

g. In

sho

rt te

rm s

tudi

es,

azils

arta

n se

ems

to b

e w

ell t

oler

ated

with

the

mos

t com

mon

sid

e ef

fect

s be

ing

diar

rhea

and

hea

dach

e. S

till,

long

term

saf

ety

is u

ncle

ar a

s a

very

lim

ited

num

ber

of p

atie

nts

have

rec

eive

d th

e dr

ug fo

r at l

east

one

yea

r. L

osar

tan

is c

urre

ntly

the

only

ARB

ava

ilabl

e in

gen

eric

form

. U

se o

f azi

lsar

tan

in S

peci

fic S

ubpo

pula

tion

s:

Pedi

atri

c U

se: S

afet

y an

d ef

fect

iven

ess

in p

atie

nts

unde

r 18

year

s of

age

hav

e no

t bee

n es

tabl

ishe

d.

Ger

iatr

ics:

No

dose

adj

ustm

ent n

eces

sary

. Ab

norm

ally

hig

h se

rum

cre

atin

ine

valu

es w

ere

mor

e lik

ely

to b

e re

port

ed fo

r pat

ient

s ag

e 75

or o

lder

. G

ende

r, r

ace,

and

eth

nici

ty:

Azi

lsar

tan

was

eff

ectiv

e in

redu

cing

blo

od p

ress

ure

rega

rdle

ss o

f the

age

, gen

der,

or

race

of p

atie

nts,

but

the

effe

ct

was

sm

alle

r in

bla

ck p

atie

nts,

app

roxi

mat

ely

half,

who

tend

to h

ave

low

er re

nin

leve

ls.

This

is s

imila

r to

oth

er d

rugs

in th

is c

lass

. Pl

ace

in th

erap

y:

The

valu

e of

azi

lsar

tan

rem

ains

unc

lear

unt

il lo

nger

term

stu

dies

eva

luat

ing

clin

ical

out

com

es a

nd a

dditi

onal

indi

catio

ns a

re c

ondu

cted

.

Reco

mm

enda

tion

s:

1.

Due

to la

ck o

f com

para

tive

effe

ctiv

enes

s re

sear

ch fo

r an

y cl

inic

al o

utco

mes

, rec

omm

end

mai

ntai

ning

all

DRI

’s a

nd p

rodu

cts

cont

aini

ng a

DRI

as

non-

pref

erre

d on

the

curr

ent P

DL.

2.

D

ue to

lack

of l

ong

term

stu

dies

dem

onst

ratin

g re

duct

ion

of c

ardi

ovas

cula

r ev

ents

and

mor

talit

y or

long

-ter

m s

afet

y da

ta c

ompa

red

to m

ultip

le

alte

rnat

ives

, rec

omm

ende

d m

akin

g az

ilsar

tan

a no

npre

ferr

ed A

RB.

3.

No

sign

ifica

nt e

vide

nce

exis

ts s

ince

last

OH

A c

lass

revi

ew th

at w

ould

man

date

cha

nges

to P

DL

med

icat

ions

bas

ed o

n co

mpa

rativ

e ef

fect

iven

ess

rese

arch

. Re

com

men

d co

mpa

ring

cost

s of

age

nts

for a

ny fu

rthe

r ad

ditio

ns o

r el

imin

atio

ns to

pre

ferr

ed p

rodu

cts.

150 of 187

I. Ba

ckgr

ound

An

estim

ated

80

mill

ion

Am

eric

ans

have

car

diov

ascu

lar

dise

ase

and

73.6

mill

ion

of t

hese

peo

ple

have

hyp

erte

nsio

n.9

The

reni

n-an

giot

ensi

n-al

dost

eron

e sy

stem

(RA

AS)

has

long

bee

n co

nsid

ered

a s

igni

fican

t co

ntrib

utor

to

CVD

thr

ough

incr

ease

s in

blo

od v

olum

e, a

rter

ial p

ress

ure,

and

va

scul

ar le

sion

s. A

gent

s us

ed t

o m

odul

ate

the

RAA

S in

clud

e A

CEIs

, ARB

S, a

nd D

RIs.

8 The

str

engt

h of

the

evi

denc

e in

sup

port

of r

enin

-ang

iote

nsin

sy

stem

blo

ckad

e ha

s le

d to

inc

orpo

ratio

n of

ACE

-Is a

nd A

RBs

into

im

port

ant

clin

ical

gui

delin

es i

n th

e tr

eatm

ent

of s

ever

al m

edic

al c

ondi

tions

in

clud

ing

hype

rten

sion

, con

gest

ive

hear

t fa

ilure

, and

ren

al d

isea

se.

The

rece

ntly

upd

ated

gui

delin

es p

ublis

hed

by t

he N

atio

nal I

nstit

ute

for

Hea

lth

and

Clin

ical

Exc

elle

nce

(NIC

E) r

ecom

men

d tr

eatin

g hy

pert

ensi

on w

ith a

n A

CE o

r a

low

cos

t A

RB if

an

ACE

is n

ot t

oler

ated

as

step

1 t

reat

men

t in

pa

tient

s un

der

55 y

ears

old

sec

onda

ry to

evi

denc

e sh

owin

g no

mea

ning

ful d

iffer

ence

bet

wee

n A

CEIs

and

ARB

s on

maj

or c

linic

al o

utco

mes

incl

udin

g de

ath,

car

diov

ascu

lar

even

ts, s

trok

e, a

nd d

iabe

tes.

The

y al

so r

ecom

men

d no

t co

mbi

ning

an

ACE

and

an

ARB

for

trea

tmen

t of

hyp

erte

nsio

n du

e to

ev

iden

ce s

how

ing

no a

dvan

tage

on

clin

ical

out

com

es a

nd m

ore

asso

ciat

ed a

dver

se e

ffec

ts w

hen

usin

g th

e co

mbi

natio

n3 . A

lthou

gh o

utda

ted,

the

Jo

int

Nat

iona

l Co

mm

ittee

on

Prev

entio

n, D

etec

tion,

Eva

luat

ion

and

Trea

tmen

t of

Hig

h Bl

ood

Pres

sure

(JN

C-7)

rec

omm

ends

an

ACE

I or

ARB

for

pa

tient

s w

ith h

yper

tens

ion

who

hav

e he

art

failu

re, d

iabe

tes,

or

chro

nic

kidn

ey d

isea

se.10

The

Kid

ney

Dis

ease

Out

com

e Q

ualit

y In

itiat

ive

guid

elin

es

reco

mm

end

ACE

Is o

r A

RBs

for

patie

nts

with

dia

betic

or

non-

diab

etic

pro

tein

uric

ren

al d

isea

se11

. A

CEIs

are

als

o re

com

men

ded

in a

ll pa

tient

s w

ith

sym

ptom

s of

hea

rt fa

ilure

and

red

uced

eje

ctio

n fr

actio

n an

d A

RB’s

are

reco

mm

ende

d as

alte

rnat

ives

12.

Hyp

erte

nsio

n is

a h

ighl

y pr

eval

ent

dise

ase

that

is

a m

ajor

ris

k fa

ctor

for

car

diov

ascu

lar

dise

ase.

The

re i

s gr

owin

g ev

iden

ce f

or i

ncre

ased

CV

com

plic

atio

ns a

nd m

orta

lity

asso

ciat

ed w

ith h

yper

tens

ion

and

high

er B

P le

vels

, inc

ludi

ng a

n in

crea

sed

rate

of

deat

h du

e to

str

oke

and

isch

emic

he

art

dise

ase.

Th

e Fr

amin

gham

Hea

rt S

tudy

fou

nd a

n as

soci

atio

n be

twee

n BP

cat

egor

y an

d in

cide

nce

of C

V di

seas

e an

d da

ta f

rom

the

Nat

iona

l, H

eart

, Lun

g, a

nd B

lood

Inst

itute

indi

cate

tha

t hy

pert

ensi

on is

ass

ocia

ted

with

a s

hort

er o

vera

ll lif

e ex

pect

ancy

. Th

erap

ies

aim

ed a

t th

e RA

AS

are

freq

uent

ly u

sed

for

the

low

erin

g of

blo

od p

ress

ure

as w

ell a

s in

oth

er in

dica

tions

suc

h as

hea

rt f

ailu

re, m

yoca

rdia

l inf

arct

ion,

dia

bete

s, a

nd r

enal

di

seas

e.

Curr

ent g

uide

lines

rec

omm

end

a st

ep-w

ise

appr

oach

from

life

styl

e m

odifi

catio

ns to

mon

othe

rapy

or

com

bina

tion

ther

apy,

as

man

y pa

tient

s ca

nnot

re

ach

goal

on

one

drug

and

will

req

uire

tw

o or

mor

e an

tihyp

erte

nsiv

e ag

ents

sel

ecte

d fr

om d

iffer

ent

clas

ses.

Th

e ta

rget

BP

for

patie

nts

with

hy

pert

ensi

on is

< 1

40/9

0 m

m H

g an

d <1

30/8

0 fo

r w

hose

with

dia

bete

s m

ellit

us, h

eart

dis

ease

, or

rena

l dis

ease

. D

espi

te t

he a

vaila

bilit

y of

a w

ide

sele

ctio

n of

ant

ihyp

erte

nsiv

e ag

ents

, opt

imal

BP

cont

rol r

emai

ns a

cha

lleng

e. A

lthou

gh A

CEIs

, ARB

S, a

nd D

RIs

all t

arge

t the

reni

n sy

stem

, the

y al

l do

so in

a s

light

ly d

iffer

ent

way

, tar

getin

g th

e pa

thw

ay a

t di

ffer

ent

poin

ts a

nd q

uest

ions

stil

l ari

se w

heth

er t

here

are

any

diff

eren

ces

in t

hese

cla

sses

ar

e in

fact

equ

ival

ent a

nd h

ow th

ey c

ompa

re in

eff

ectin

g cl

inic

al o

utco

mes

151 of 187

II.

Syst

emat

ic R

evie

ws:

A

HRQ

Rev

iew

1 : Pu

blis

hed

in Ju

ne 2

011

Com

pare

d th

e A

CEIs

, ARB

s, a

nd D

RIs

in b

oth

effic

acy

and

safe

ty in

adu

lt pa

tient

s w

ith h

yper

tens

ion.

Clin

ical

out

com

es o

f int

eres

t wer

e bl

ood

pres

sure

con

trol

, mor

talit

y, m

orbi

dity

, saf

ety,

per

sist

ence

/adh

eren

ce, c

ardi

ovas

cula

r ris

k re

duct

ion,

and

qua

lity

of li

fe. T

hey

also

ass

esse

d if

ther

e w

as a

ny e

vide

nce

show

ing

that

diff

eren

t sub

grou

ps o

f pat

ient

s to

lera

ted

the

diff

eren

t age

nts

bett

er.

The

revi

ew in

clud

ed o

nly

rele

vant

hea

d to

hea

d co

mpa

rato

r st

udie

s th

at h

ad a

min

imum

of 1

2 w

eeks

follo

w-u

p.

D

id n

ot in

clud

e st

udie

s co

mpa

ring

the

new

est A

RB, a

zils

arta

n.

Conc

lusi

ons:

1.

Th

ere

is h

igh

qual

ity e

vide

nce

that

ACE

Is a

nd A

RBs

appe

ar to

hav

e si

mila

r lo

ng-t

erm

eff

ects

on

bloo

d pr

essu

re.

Ther

e is

low

qua

lity

evid

ence

re

gard

ing

the

effe

cts

of D

RIs

on b

lood

pre

ssur

e an

d is

onl

y ba

sed

on th

ree

stud

ies.

2.

Th

ere

is lo

w q

ualit

y ev

iden

ce th

at s

how

s no

diff

eren

ce e

xist

s be

twee

n A

CEIs

and

ARB

s re

gard

ing

mor

talit

y an

d m

ajor

car

diov

ascu

lar

even

ts d

ue

to e

xtre

mel

y lo

w n

umbe

rs o

f the

out

com

es th

at w

ere

repo

rted

. Th

ere

is in

suff

icie

nt e

vide

nce

com

pari

ng D

RIs

to d

etec

t a d

iffer

ence

in th

ese

outc

omes

. 3.

Th

ere

is lo

w q

ualit

y ev

iden

ce th

at th

ere

are

diff

eren

ces

betw

een

ACE

Is a

nd A

RBs

in q

ualit

y of

life

and

insu

ffic

ient

evi

denc

e co

mpa

ring

DRI

s.

4.

Ther

e is

hig

h qu

ality

evi

denc

e th

at th

ere

is a

diff

eren

ce in

with

draw

als

due

to a

dver

se e

vent

s be

twee

n A

CEIs

and

ARB

s an

d th

is c

an b

e co

ntrib

uted

to a

n in

crea

sed

risk

of c

ough

ass

ocia

ted

with

the

ACE

Is th

an A

RBs.

Cou

gh is

the

only

adv

erse

eve

nt s

how

n to

hav

e ev

iden

ce o

f di

ffer

ence

acr

oss

trea

tmen

t rat

es.

5.

Ther

e is

low

qua

lity

evid

ence

sho

win

g no

sig

nific

ant d

iffer

ence

com

parin

g D

RIs

and

ACE

Is in

with

draw

als

due

to a

dver

se e

vent

s.

6.

Evid

ence

doe

s no

t sup

port

any

con

clus

ions

rega

rdin

g co

mpa

rativ

e ef

fect

iven

ess

or s

afet

y in

pat

ient

sub

grou

ps b

ased

on

age,

rac

e, e

thni

city

, se

x, c

omor

bidi

ties,

and

con

curr

ent u

se o

f oth

er m

edic

atio

ns.

Rem

aini

ng Is

sues

: Th

ere

is s

till l

ittle

com

para

tive

evid

ence

for

long

-ter

m b

enef

its o

r har

ms

of A

CEIs

and

ARB

s, a

nd D

RIs

in p

artic

ular

abo

ut d

eath

or

maj

or

card

iova

scul

ar e

vent

s. T

here

is v

ery

limite

d co

mpa

rativ

e ef

fect

iven

ess

rese

arch

for t

he D

RIs

vers

us A

CEIs

or

ARB

S w

ith o

nly

3 st

udie

s m

eetin

g th

e au

thor

s’ in

clus

ion

crite

ria fo

r eva

luat

ion

and

repo

rtin

g.

Furt

her

com

para

tive

stud

ies

are

need

ed to

em

phas

ize:

152 of 187

•

Subg

roup

s of

impo

rtan

ce

• O

utco

mes

ove

r se

vera

l yea

rs to

com

pare

car

diov

ascu

lar

and

cere

brov

ascu

lar

even

ts

• Ca

ncer

-rel

ated

out

com

es

• Br

oade

r re

pres

enta

tion

of g

roup

s to

incl

ude

the

elde

rly

and

ethn

ic m

inor

ities

•

Long

-ter

m c

ompa

riso

ns o

f DRI

s w

ith A

CEIs

and

ARB

s •

Eval

uatio

n of

diff

eren

tial e

ffec

ts o

f spe

cific

med

icat

ions

that

are

diff

eren

t tha

n ot

her a

gent

s w

ithin

the

clas

s A

lthou

gh th

is r

ecen

t AH

RQ s

yste

mat

ic r

evie

w o

nly

eval

uate

d ou

tcom

es in

pat

ient

s w

ith h

yper

tens

ion

the

mos

t rec

ent D

ERP

repo

rt fo

und

sim

ilar

resu

lts w

hen

com

parin

g A

CEIs

and

ARB

s in

clin

ical

out

com

es in

clud

ing

card

iova

scul

ar e

vent

s, m

orta

lity,

qua

lity

of li

fe, r

enal

func

tion,

and

sy

mpt

oms

in p

atie

nts

with

hea

rt d

isea

se, d

iabe

tic p

rote

inur

ia, n

ondi

abet

ic p

rote

inur

ia a

nd c

hron

ic k

idne

y di

seas

e. T

his

repo

rt a

lso

conc

lude

d th

at

ARB

s ar

e no

t diff

eren

t fro

m, n

or in

ferio

r to,

ACE

Is.12

153 of 187

III.

New

ARB

: Azi

lsar

tan

Clin

ical

Fin

ding

s –

Azi

lsar

tan

is a

n A

RB in

dica

ted

for

the

trea

tmen

t of h

yper

tens

ion,

eith

er a

lone

or

in c

ombi

natio

n w

ith o

ther

ant

ihyp

erte

nsiv

e ag

ents

. Az

ilsar

tan

was

ap

prov

ed b

ased

on

the

resu

lts o

f sev

en d

oubl

e-bl

ind,

rand

omiz

ed s

tudi

es in

volv

ing

a to

tal o

f 5,9

41 p

atie

nts

with

hyp

erte

nsio

n ra

ngin

g fr

om 6

w

eeks

to 6

mon

ths

in d

urat

ion;

two

of w

hich

hav

e be

en p

ublis

hed

and

peer

rev

iew

ed.

Thes

e st

udie

s on

ly e

valu

ated

azi

lsar

tan’

s ef

fect

s on

the

inte

rmed

iate

bio

mar

ker o

f blo

od p

ress

ure.

The

re is

no

evid

ence

with

long

term

clin

ical

out

com

es a

sses

sed.

Azi

lsar

tan

has

been

com

pare

d he

ad to

he

ad w

ith th

e ot

her

ARB

S ol

mes

arta

n an

d va

lsar

tan

as w

ell a

s w

ith th

e A

CEI r

amip

ril.2 T

he d

etai

ls o

f the

2 p

ublis

hed

full-

text

hea

d to

hea

d tr

ials

ar

e sh

own

in th

e ev

iden

ce ta

ble

foun

d in

App

endi

x 1.

One

dou

ble-

blin

d, p

lace

bo-c

ontr

olle

d, r

ando

miz

ed tr

ial c

ompa

red

azils

arta

n 40

mg

and

80m

g to

val

sart

an 3

20m

g, o

r ol

mes

arta

n 40

mg

daily

for 6

w

eeks

. Th

e pr

imar

y ef

ficac

y en

d po

int w

as th

e ch

ange

from

bas

elin

e in

24-

hour

mea

n SB

P. A

zils

arta

n 80

mg

show

ed a

sta

tistic

ally

sig

nific

ant

grea

ter c

hang

e in

bas

elin

e in

mea

n di

ffer

ence

com

pare

d to

bot

h va

lsar

tan

and

olm

esar

tan

(-4.

3 an

d -2

.5 re

spec

tivel

y) w

hile

azi

lsar

tan

40m

g ha

d a

stat

istic

ally

sig

nific

ant m

ean

diff

eren

ce in

BP

com

pare

d to

val

sart

an o

nly

-3.2

) and

was

non

infe

rior t

o ol

mes

arta

n. S

afet

y an

d to

lera

bilit

y w

ere

sim

ilar

amon

g th

e pl

aceb

o an

d al

l act

ive

trea

tmen

ts6 .

In a

noth

er d

oubl

e-bl

ind,

rand

omiz

ed, p

lace

bo-c

ontr

olle

d tr

ial,

patie

nts

wer

e ra

ndom

ized

to p

lace

bo, a

zils

arta

n 20

mg,

40m

g, o

r 80

mg

or

olm

esar

tan

40m

g da

ily fo

r 6

wee

ks.

The

chan

ge in

24-

hour

SBP

was

sig

nific

antly

gre

ater

with

azi

lsar

tan

80m

g co

mpa

red

to o

lmes

arta

n 40

mg

(mea

n di

ffer

ence

-2.1

), w

hile

azi

lsar

tan

40m

g w

as fo

und

to b

e no

ninf

erio

r8 .

Both

of t

hese

stu

dies

use

s si

mila

r in

clus

ion

and

excl

usio

n cr

iteri

a an

d w

ere

rate

d as

fair

qual

ity.

They

bot

h ha

d ex

tens

ive

excl

usio

n cr

iteri

a an

d ha

d un

clea

r inf

orm

atio

n re

gard

ing

thei

r ra

ndom

izat

ion

met

hods

. In

sub

grou

p an

alys

is, b

oth

stud

ies

saw

diff

eren

ces

only

in th

e bl

ack

popu

latio

n w

hich

is

con

sist

ent w

ith p

revi

ous

findi

ngs.

Ther

e ar

e ad

ditio

nal c

ompa

rativ

e ef

fect

iven

ess

stud

ies

cond

ucte

d ev

alua

ting

bloo

d pr

essu

re th

at h

ave

not b

een

publ

ishe

d. T

he a

bstr

acts

for t

hese

w

ere

pres

ente

d at

the

2010

Eur

opea

n M

eetin

g on

Hyp

erte

nsio

n an

d ca

n be

foun

d in

the

Jour

nal o

f Hyp

erte

nsio

n. P

relim

inar

y re

sults

from

a

rand

omiz

ed, d

oubl

e bl

ind

stud

y sh

owed

that

azi

lsar

tan

40m

g an

d 80

mg

redu

ced

both

clin

ic a

nd m

ean

24-h

our

syst

olic

BP

sign

ifica

ntly

mor

e th

an

did

ram

ipri

l 10m

g an

d th

ere

wer

e le

ss d

isco

ntin

uatio

ns d

ue to

adv

erse

eve

nts

and

coug

h w

ith b

oth

dose

s of

azi

lsar

tan.

14 I

n an

othe

r tri

al, a

zils

arta

n w

as c

ombi

ned

with

the

diur

etic

chl

orth

alid

one

and

prov

ided

furt

her

SBP

redu

ctio

n fr

om b

asel

ine

and

appe

ared

to b

e su

perio

r to

the

com

bina

tion

of o

lmes

arta

n an

d hy

droc

hlor

othi

azid

e15.

Addi

tive

effe

cts

on b

lood

pre

ssur

e of

am

lodi

pine

com

bine

d w

ith a

zils

arta

n ha

ve a

lso

been

de

mon

stra

ted.

16

The

shor

t dur

atio

n of

thes

e st

udie

s re

mai

ns a

n im

port

ant l

imita

tion

mak

ing

it di

ffic

ult t

o ev

alua

te th

e lo

ng-t

erm

ben

efit

and

side

eff

ects

of

azils

arta

n. T

here

is n

o ev

iden

ce o

n th

e po

ssib

le ro

le o

f azi

lsar

tan

in p

reve

ntin

g m

orta

lity

and

CV m

orbi

dity

.

154 of 187

Cl

inic

al p

harm

acol

ogy

17

Azi

lsar

tan

bloc

ks th

e va

soco

nstr

icto

r an

d al

dost

eron

e se

cret

ing

effe

cts

of a

ngio

tens

in II

by

sele

ctiv

ely

bloc

king

the

bind

ing

of a

ngio

tens

in II

to th

e A

T1 r

ecep

tor

in m

any

tissu

es.

Angi

oten

sin

II is

the

prin

cipa

l pre

ssor

age

nt o

f the

ren

in-a

ngio

tens

in s

yste

m, w

ith e

ffec

ts th

at in

clud

e va

soco

nstr

ictio

n, s

timul

atio

n of

syn

thes

is a

nd r

elea

se o

f ald

oste

rone

, car

diac

stim

ulat

ion,

and

rena

l rea

bsor

ptio

n of

sod

ium

. D

rug

safe

ty 17

Bl

ack

Box

War

ning

: Avo

id u

se in

pre

gnan

cy.

If pr

egna

ncy

is d

etec

ted,

azi

lsar

tan

shou

ld b

e di

scon

tinue

d as

soo

n as

pos

sibl

e to

avo

id s

erio

us in

jury

or

eve

n de

ath

to th

e de

velo

ping

fetu

s.

Preg

nanc

y/La

ctat

ion

ratin

g: P

regn

ancy

Cat

egor

y C

(fir

st tr

imes

ter)

and

D (s

econ

d an

d th

ird

trim

este

rs).

Dos

e In

dex

(eff

icac

y/to

xic)

: Lim

ited

data

are

ava

ilabl

e re

late

d to

ove

rdos

age

in h

uman

s. D

urin

g co

ntro

lled

clin

ical

tria

ls in

hea

lthy

subj

ects

, onc

e da

ily

dose

s up

to 3

20 m

g of

azi

lsar

tan

wer

e ad

min

iste

red

for 7

day

s an

d w

ere

wel

l tol

erat

ed.

Com

mon

Dru

g-Re

late

d A

dver

se E

vent

s17:

Trea

tmen

t with

azi

lsar

tan

was

wel

l-tol

erat

ed w

ith a

n ov

eral

l inc

iden

ce o

f adv

erse

reac

tions

sim

ilar t

o pl

aceb

o.

The

mos

t com

mon

adv

erse

eff

ect w

as d

iarr

hea

with

an

inci

dent

of 2

%.T

he ra

te o

f with

draw

als

due

to a

dver

se e

vent

s in

pla

cebo

-co

ntro

lled

mon

othe

rapy

and

com

bina

tion

ther

apy

tria

ls w

as 2

.4 %

for p

lace

bo, 2

.2%

for

azils

arta

n 40

mg,

and

2.7

% fo

r azi

lsar

tan

80 m

g. T

he m

ost

com

mon

adv

erse

eve

nt le

adin

g to

dis

cont

inua

tion,

hyp

oten

sion

/ort

host

atic

hyp

oten

sion

, was

rep

orte

d by

0.4

% (8

/214

6) p

atie

nts

rand

omiz

ed to

az

ilsar

tan

40 m

g or

80

mg

com

pare

d to

0%

(0/8

01) p

atie

nts

rand

omiz

ed to

pla

cebo

. Gen

eral

ly, a

dver

se r

eact

ions

wer

e m

ild, n

ot d

ose

rela

ted

and

sim

ilar

rega

rdle

ss o

f age

, gen

der

and

race

. O

ther

adv

erse

rea

ctio

ns th

at h

ave

been

rep

orte

d w

ith a

n in

cide

nce

of >

0.3%

and

gre

ater

than

pla

cebo

are

: G

astr

oint

estin

al D

isor

ders

: nau

sea

Gen

eral

Dis

orde

rs a

nd A

dmin

istr

atio

n Si

te C

ondi

tion

s: a

sthe

nia,

fatig

ue

Mus

culo

skel

etal

and

Con

nect

ive

Tiss

ue D

isor

ders

: mus

cle

spas

m

Ner

vous

Sys

tem

Dis

orde

rs: d

izzi

ness

, diz

zine

ss p

ostu

ral

Resp

irato

ry, T

hora

cic

and

Med

iast

inal

Dis

orde

rs: c

ough

155 of 187

A

ppen

dix

1:

COM

PARA

TIV

E CL

INIC

AL

EFFI

CACY

Rele

vant

End

poin

ts:

1)

Mor

talit

y

2) C

ardi

ovas

cula

r Mor

talit

y

3)

Car

diov

ascu

lar H

ospi

taliz

atio

ns

5) W

ithdr

awal

s du

e to

adv

erse

eve

nts

Prim

ary

Stud

y En

dpoi

nt:

1) C

hang

e fr

om b

asel

ine

in 2

4-ho

ur m

ean

SBP

by a

mbu

lato

ry b

lood

pre

ssur

e m

onito

ring.

156 of 187

Ev

iden

ce T

able

Re

f./

Stud

y D

esig

n1

Dru

g Re

gim

ens

Pati

ent

Popu

lati

on/

Dur

atio

n

N

Effic

acy

Resu

lts2

ARR

/ N

NT

Safe

ty R

esul

ts^

(CI,

p-va

lues

) A

RR/

NN

H3

Qua

lity

Rati

ng4 ; C

omm

ents

1.W

hite

et a

l RC

T, D

B6 49

1-01

9

1. a

zils

arta

n (A

Z)

40m

g 2.

Azi

lsar

tan

(AZ)

80

mg

3. V

alsa

rtan

(VAL

32

0mg

4. O

lmes

arta

n (O

LM) 4

0mg

5. p

lace

bo

Adul

ts w

hose

SBP

w

as b

etw

een

150

and

180

and

who

se m

ean

24-

hour

SBP

was

be

twee

n 13

0 an

d 18

0 M

ean

age

56

54%

men

D

urat

ion

= 6

w

eeks

1. 2

80

2. 2

85

3. 2

54

4. 2

90

5. 1

54

Chan

ge in

24

h m

ean

base

line

SBP

(mea

n tr

eatm

ent d

iffer

ence

in m

m H

g)

Vs.

Pla

cebo

A

Z 40

mg

-13.

2 P<

0.00

1 A

Z 80

mg

-14.

3 P<

0.00

1 VA

L 32

0mg

-9.9

P<

0.00

1 O

LM 4

0mg

-11.

7 P<

0.00

1 Vs

. Olm

esar

tan

AZ

40m

g

-1.4

95

% C

I (-3

.3,-0

.5)

P=0.

136

AZ 8

0mg

-2

.5

95%

CI (

-4.4

,-0.6

) P=

0.0

09

Vs.

Val

sart

an

AZ

40m

g -3

.2

P=0.

001

AZ

80m

g -4

.3

95%

CI (

-6.3

,-2.4

) P<

0.00

1

N/A

N

/A

N/A

N

/A

NS

N/A

N

/A

N/A

Dis

cont

inue

d du

e to

adv

erse

ev

ents

: 1.

7 (2

.5%

) 2.

9 (3

.2%

) 3.

8 (2

.8%

) 4.

6 (2

.1%

) 5.

4 (2

.6%

)

NS

Fair

: Si

gnifi

cant

car

diov

ascu

lar

excl

usio

n cr

iteri

a m

akin

g it

hard

to g

ener

aliz

e to

pop

ulat

ion

Elig

ible

pat

ient

s un

derw

ent a

3 t

o 4

wee

ks w

asho

ut

peri

od b

efor

e ra

ndom

izat

ion

Am

ong

all r

ando

miz

ed p

atie

nts,

96

% w

ere

incl

uded

in

the

data

ana

lysi

s U

ncle

ar if

allo

catio

n co

ncea

lmen

t or

app

ropr

iate

ra

ndom

izat

ion

took

pla

ce

Ther

e w

as a

mar

gina

lly s

tati

stic

ally

sig

nific

ant

trea

tmen

t di

ffer

ence

bet

wee

n bl

ack

and

whi

te

patie

nts

*Clin

ical

out

com

es o

f Mor

talit

y, C

ardi

ovas

cula

r M

orta

lity,

and

Car

diov

ascu

lar

Hos

pita

lizat

ions

not

re

port

ed

157 of 187

2.

Bakr

is, e

t al

8 RC

T, D

B 49

1-00

8

1. a

zils

arta

n (A

Z)20

mg

2. A

zils

arta

n (A

Z)

40m

g 3.

Azi

lsar

tan(

AZ)

80m

g 4.

Olm

esar

tan

(OLM

) 40m

g 5.

pla

cebo

Adul

ts w

hose

SBP

w

as b

etw

een

150

and

180

and

Who

se 2

4 hr

m

ean

SBP

was

be

twee

n 13

0 an

d 17

0 M

ean

age

58

Dur

atio

n =

6 w

eeks

1. 2

83

2. 2

83

3. 2

85

4. 2

82

5. 1

42

Chan

ge in

24

h m

ean

base

line

SBP

(mea

n tr

eatm

ent d

iffer

ence

in m

m H

g)

Vs.

Pla

cebo

A

Z 20

mg

-10.

8 95

%CI

(-13

.2,-8

.3)

P<0.

001

AZ 4

0mg

-12.

1 95

%CI

(-14

.5,-9

.7)

P<0.

001

AZ 8

0mg

-1

3.2

95%

CI (-

15.6

,-10.

8)

P<0.

001

OLM

-1

1.2

95%

CI (-

13.6

,-8.8

) P<

0.00

1 Vs

. Olm

esar

tan

AZ

20m

g -0

.4

95%

CI (-

1.6,

-2.4

) P=

0.68

7 AZ

40m

g -0

.92

95%

CI (-

2.9,

1.0)

P=

0.35

2 AZ

80m

g

-2.1

95

%CI

(-4.

0.-0

.1)

P=0.

038

N/A

N

/A

N/A

N

/A

NS

NS

N/A

Dis

cont

inue

d du

e to

adv

erse

ev

ents

: 1.

11(

3.9%

) 2.

3(1

.1%

) 3.

6(2

.1%

) 4.

4(1

.4%

) 5.

6(4

.2%

)

NS

Fair

; Si

gnifi

cant

car

diov

ascu

lar

excl

usio

n cr

iteri

a m

akin

g it

hard

to g

ener

aliz

e to

pop

ulat

ion

Unc

lear

if a

lloca

tion

conc

ealm

ent

or a

ppro

pria

te

rand

omiz

atio

n to

ok p

lace

Bl

ack

popu

latio

n su

bgro

up d

emon

stra

ted

a tr

end

for

less

BP

redu

ctio

n in

all

activ

e tr

eatm

ent

grou

ps

com

pare

d w

ith C

auca

sian

s, b

ut a

tren

d of

gre

ater

ef

ficac

y w

ith a

zils

arta

n 80

mg

com

pare

d w

ith

olm

esar

tan

40m

g Lo

w r

ates

of a

ttri

tion.

*C

linic

al o

utco

mes

of M

orta

lity,

Car

diov

ascu

lar

Mor

talit

y, a

nd C

ardi

ovas

cula

r H

ospi

taliz

atio

ns n

ot

repo

rted

1 Stud

y de

sign

: DB

= do

uble

-blin

d, R

CT =

ran

dom

ized

tria

l, PC

= p

lace

bo-c

ontr

olle

d, P

G =

par

alle

l -gr

oup,

XO

= c

ross

over

, DD

= d

oubl

e du

mm

y.

2 Resu

lts

abbr

evia

tion

s: R

RR =

rel

ativ

e ri

sk r

educ

tion

, RR

=rel

ativ

e ri

sk, O

R= O

dds

Ratio

, HR

= H

azar

d Ra

tio,

ARR

= ab

solu

te r

isk

redu

ctio

n, A

RI =

abs

olut

e ri

sk in

crea

se

NN

T =

num

ber

need

ed to

trea

t, N

NH

= n

umbe

r ne

eded

to h

arm

, CI =

con

fiden

ce in

terv

al, I

TT=

inte

ntio

n-to

-tre

at a

naly

sis,

mIT

T-m

odifi

ed in

tent

ion-

to-t

reat

ana

lysi

s 3 N

NT/

NN

H a

re r

epor

ted

only

for

stat

istic

ally

sig

nific

ant r

esul

ts

4 Qua

lity

Rati

ng: (

Goo

d- li

kely

val

id, F

air-

like

ly v

alid

/pos

sibl

y va

lid, P

oor-

fata

l fla

w-n

ot v

alid

) Cl

inic

al A

bbre

viat

ions

: TT

R= ti

me

in th

erap

eutic

ran

ge, S

Q-s

ubcu

tane

ous,

STE

MI –

ST-

segm

ent e

leva

tion

myo

card

ial i

nfar

ctio

n, N

STEM

I – n

on-S

T-se

gmen

t ele

vatio

n m

yoca

rdia

l inf

arct

ion

158 of 187

A

ppen

dix

2 : S

peci

fic D

rug

Info

rmat

ion

DO

SE &

AV

AIL

ABI

LITY

: ST

REN

GTH

FO

RM

ROU

TE

FREQ

UEN

CY

REN

AL

AD

J H

EPA

TIC

AD

J Pe

diat

ric

D

ose

Elde

rly

Dos

e O

THER

DO

SIN

G

CON

SID

ERA

TIO

NS

40m

g Ta

b PO

D

aily

N

one

Non

e N

ot E

stab

lishe

d N

one

Cau

tion

in p

atie

nts

with

Vol

ume

or S

alt-

depl

eted

Pat

ient

s.

Cons

ider

sta

rtin

g w

ith lo

wer

40

mg

dose

for t

hose

on

high

do

se d

iure

tics.

80m

g Ta

b PO

D

aily

N

one

Non

e N

ot E

stab

lishe

d N

one

Ph

arm

acok

inet

ics

Para

met

er

Resu

lt

Ora

l Bi

oava

ilabi

lity

60%

Cm

ax

1.5

-3 h

ours

Pr

otei

n Bi

ndin

g >

99%

Elim

inat

ion

Fece

s 55

%

Uri

ne 4

2%

Met

abol

ite 1

5%

Hal

f-Li

fe

11

hour

s M

etab

olis

m

O-d

ealk

ylat

ion

deca

rboy

latio

n

159 of 187

13

REFE

REN

CES

1. S

ande

rs G

, Coe

ytau

x R,

Dol

or R

, et a

l. An

giot

ensi

n-Co

nver

ting

Enzy

me

Inhi

bito

rs (A

CEIs

), An

giot

ensi

n II

Rece

ptor

Ant

agon

ists

(ARB

s), a

nd D

irec

t Ren

in In

hibi

tors

for

Trea

ting

Esse

ntia

l Hyp

erte

nsio

n:

An U

pdat

e. C

ompa

rativ

e Ef

fect

iven

ess

Revi

ew N

o. 3

4. (P

repa

red

by th

e D

uke

Evid

ence

-bas

ed P

ract

ice

Cent

er.)

AHRQ

Pub

licat

ion

No.

11-

EHC0

63-E

F. R

ockv

ille,

MD

: Age

ncy

for

Hea

lthca

re R

esea

rch

and

Qua

lity.

201

1. A

vaila

ble

at: w

ww

.eff

ectiv

ehea

lthca

re.a

hrq.

gov/

repo

rts/

final

.cfm

.

2. F

ood

and

Dru

g Ad

min

istr

atio

n Ce

nter

for

Dru

g Ev

alua

tion

and

Rese

arch

. A

pplic

atio

n N

umbe

r: 2

0079

6Ori

g1s0

00 s

umm

ary

revi

ew. A

vaila

ble

at:

http

://w

ww

.acc

essd

ata.

fda.

gov/

drug

satf

da_d

ocs/

nda/

2011

/200

796O

rig1

s000

Med

R.pd

f. A

cces

sed

Nov

embe

r 21

, 201

1.

3. K

raus

e T,

Lov

ibon

d K,

Cau

lfiel

d M

, McC

orm

ack

T, W

illia

ms

B. M

anag

emen

t of h

yper

tens

ion:

sum

mar

y of

NIC

E gu

idan

ce. B

MJ.

2011

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:d48

91.

4. D

icpi

niga

itis,

P. A

ngio

tens

in-c

onve

rtin

g en

zym

e in

hibi

tor-

indu

ced

coug

h: A

CCP

evid

ence

-bas

ed c

linic

al p

ract

ice

guid

elin

es. C

HES

T. 2

006;

129

(1 s

uppl

): 1

69s-

173s

. 5.

Bön

ner

G, B

akri

s G

, Sic

a D

, et a

l. Co

mpa

riso

n of

ant

ihyp

erte

nsiv

e ef

ficac

y of

the

new

ang

iote

nsin

rec

epto

r bl

ocke

r az

ilsar

tan

med

oxom

il w

ith r

amip

ril:

PP.1

6.11

2. Jo

urna

l of H

yper

tens

ion.

201

0;28

:1.

6. W

hite

WB,

Web

er M

A, S

ica

D, e

t al.

Effe

cts

of th

e An

giot

ensi

n Re

cept

or B

lock

er A

zils

arta

n M

edox

omil

Vers

us O

lmes

arta

n an

d Va

lsar

tan

on A

mbu

lato

ry a

nd C

linic

Blo

od P

ress

ure

in P

atie

nts

With

St

ages

1 a

nd 2

Hyp

erte

nsio

n. H

yper

tens

ion.

201

1;57

(3):

413

-420

.

7. S

ica

D, W

hite

W, W

eber

M, e

t al

. New

ang

iote

nsin

ii r

ecep

tor

bloc

ker

azils

arta

n m

edox

omil:

com

pari

son

to v

alsa

rtan

: PP.

16.8

8. Jo

urna

l of H

yper

tens

ion.

201

0;28

:1.

8. B

akri

s G

L, S

ica

D, W

eber

M, e

t al

. The

com

para

tive

effe

cts

of a

zils

arta

n m

edox

omil

and

olm

esar

tan

on a

mbu

lato

ry a

nd c

linic

blo

od p

ress

ure.

J Cl

in H

yper

tens

(Gre

enw

ich)

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1;13

(2):

81-8

8.

9. M

unge

r M

A. U

se o

f ang

iote

nsin

rec

epto

r bl

ocke

rs in

car

diov

ascu

lar

prot

ectio

n: C

urre

nt e

vide

nce

and

futu

re d

irec

tions

. P a

nd T

. 201

1;36

(1):

22-3

1+40

.

10. C

hoba

nian

AV,

Bak

ris

GL,

Bla

ck H

R, e

t al.

The

Seve

nth

Repo

rt o

f the

Join

t Nat

iona

l Com

mitt

ee o

n Pr

even

tion

, Det

ectio

n, E

valu

atio

n, a

nd T

reat

men

t of H

igh

Bloo

d Pr

essu

re: t

he JN

C 7

repo

rt. J

AM

A.

2003

;289

(19)

:256

0-25

72.

11. L

evey

AS,

Cor

esh

J, Ba

lk E

, et a

l. N

atio

nal K

idne

y Fo

unda

tion

pra

ctic

e gu

idel

ines

for

chro

nic

kidn

ey d

isea

se: e

valu

atio

n, c

lass

ifica

tion,

and

str

atifi

catio

n. A

nn. I

nter

n. M

ed. 2

003;

139(

2):1

37-1

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Oregon State University, 500 Summer Street NE, E35, Salem, Oregon 97301-1079

Phone 503-945-5220 | Fax 503-947-1119

Month/Year of Review: January 2012 Date of Last Review: September 2010 PDL Class: Antivirals: HSV Source Document: PS Report Current Preferred Agents: Current Non-Preferred Agents: Acyclovir, oral (capsule, tablet, oral suspension) Famciclovir, oral Valacyclovir, oral Acyclovir (Zovirax®), topical Penciclovir (Denavir®), topical Docosanol (Abreva®), topical Previous Conclusions and Recommendations: 1. The oral agents which are approved for herpes infections include acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex). Based on available data, all of the agents have similar efficacy and adverse effects. 2. The 2006 CDC STD recommendations for genital herpes indicate no preference for any one of these three

agents over another. Patients presenting with an initial or a recurrent episode of genital HSV infection should be treated with any one of the three agents. Chronic suppressive therapy for patients with frequent recurrences may include any one of the three agents.

3. All three agents have similar efficacy for the treatment of herpes zoster, and recent guidelines support the use of any of the three agents for first line therapy.

4. Both acyclovir and valacyclovir are approved for the treatment of varicella (chickenpox). 5. These drugs are primarily used for below the line conditions. 6. Recommend including one or more agents from this category on the PDL PA Criteria/QL: Patient must have an ICD9 diagnosis for uncomplicated herpes simplex AND documentation of a disease state or medication that causes immunosuppression. Oral acyclovir does not require PA. (Appendix B)

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Methods: Search Strategy A MEDLINE OVID search was conducted using the following search terms: Herpes Genitalis, Herpes Simplex, Herpesvirus 2, Herpesvirus 1, Herpes Labialis, Herpe$; antiviral, antiviral$, antiviral agents; RCT, randomized control trial, clinical trial, controlled trial The search was limited to studies conducted with humans in English language publications from 2008 to 2011. Results: The MEDLINE search retrieved 65 full citations. After a full review of citations and abstracts, one new head-to-head RCT was identified, but no new placebo-controlled RCTs were identified. Most of the citations identified centered on HSV antiviral effects in patient populations co-infected with HIV; of those, most were observational with an objective to see if HSV antivirals might decrease HIV transmission. The search of the Cochrane website identified a protocol proposed this month (10/2011) to review topical and oral interventions for HSV. The search of the AHRQ, DERP, and VA/DoD websites did not identify any relevant systematic reviews. The search on the FDA websites identified one new approved drug, but no new indications, or safety alerts for preexisting products. The citations and abstracts for all relevant studies are listed in Appendix A. New FDA-approved drugs: Acyclovir/hydrocortisone (Xerese®), topical Xerese was approved by the FDA in 2009 for recurrent herpes simplex labialis. This is a new combination product of 5% acyclovir and 1% hydrocortisone as the active ingredients. It was approved on the basis of one efficacy and two safety trials. The citation and abstract of the efficacy study is listed in Appendix A. This was a randomized, double-blind, placebo controlled trial comparing the combination of acyclovir and hydrocortisone versus acyclovir cream. Although the study shows Xerese to be statistically significant to acyclovir and placebo in preventing lesions from occurring, the clinical relevance is low. New FDA Indications: None identified. New FDA safety alerts: None identified. New Systematic Reviews: None identified.

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Appendix A: Hull, C.M., Harmenberg, J., Arlander, E., Aoki, F., Bring J, et al. Early Treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: A randomized, double-blind, placebo=controlled, patient initiated clinical trial (2011) J Am Acad Dermatol2011; 64 :696.e1-696.e11. Background: Prior pilot studies support the use of antiviral medications with topical corticosteroids for herpes simplex labialis (HSL). ME-609 (Xerese, Xerclear) is a combination of 5% acyclovir and 1% hydrocortisone developed for the topical treatment of HSL. Objectives: The primary study end point was the prevention of ulcerative HSL lesions. Methods: In all, 2437 patients with a history of HSL were randomized to self-initiate treatment with ME-609, 5% acyclovir in ME-609 vehicle, or ME-609 vehicle (placebo) at the earliest sign of a cold sore recurrence. Cream was applied 5 times/d for 5 days. A total of 1443 patients experienced a recurrence and initiated treatment with ME-609 (n = 601), acyclovir (n = 610), or placebo (n = 232). Results: Of patients receiving ME-609, 42% did not develop an ulcerative lesion compared with 35% of patients receiving acyclovir in ME-609 vehicle (P = .014) and 26% of patients receiving placebo (P\.0001). In patients with ulcerative lesions, healing times were reduced in the ME-609 and acyclovir groups compared with placebo (P\.01 for both). The cumulative lesion area for all lesions was reduced 50%in patients receiving ME-609 compared with the placebo group (P\.0001). There were no differences among groups in the number of patients with positive herpes simplex virus cultures. The side-effect profile was similar among treatments. Limitations: The study did not contain a group treated with a topical corticosteroid alone. Conclusions: ME-609 prevented progression of cold sores to ulcerative lesions and significantly reduced the cumulative lesion area compared with acyclovir and placebo. ME-609 treatment offers additional therapeutic benefit compared with therapy with topical acyclovir alone. (J Am Acad Dermatol 2011;64:696.e1-11.)

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Appendix B:

Antivirals, Oral and Topical – HSV Goal(s): Cover oral and/or topical anti-virals only for covered diagnoses. HSV infections are covered only when complicated by an immunocompromised host. Antivirals Length of Authorization: Criteria Specific – up to 1 year

Preferred Alternatives: Oral acyclovir DOES NOT require PA. See PDL list at: http://www.oregon.gov/DHS/healthplan/tools_prov/pdl.shtml.

Requires PA: HIC3 = Q5V

GENERIC BRAND ROUTE

Famciclovir Famvir Oral

Valacyclovir Valtrex Oral

Acyclovir Zovirax Topical

Penciclovir Denavir Topical

Docosanol Abreva Topical

Approval Criteria

1. What is the diagnosis being treated?

Record ICD9 code

2. Will the prescriber consider a change to a preferred product?

Message:

• Preferred products do not require a PA.

• Preferred products are evidence-based reviewed for comparative effectiveness and safety by the Health Resource Commission (HRC). Reports are available at: http://www.oregon.gov/OHPPR/HRC/Evidence_Based_Reports.shtml.

Yes: Inform provider of covered alternatives in class. http://www.oregon.gov/DHS/healthplan/tools_prov/dl.shtml.

No: Go to #3

3. Is the diagnosis uncomplicated herpes simplex ICD9: 054.2,

054.6, 054.73, 054.9?

Yes: Go to #4

No: Pass to RPh; Go to #7

4. Is the patient immune compromised? Document ICD9 code.

• Current (not history of) diagnosis of cancer AND is currently undergoing Chemotherapy or Radiation? Document therapy and length of treatment

• Diagnosis of HIV/AIDS?

Yes: Approve for the shorter of expected therapy duration or90 days (applies to both topical and oral antivirals) (Immunocompromised Client)

No: Go to #5

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http://www.oregon.gov/D�


5. Is client currently taking an immunosuppressive drug? Document drug:

(If drug not in list below, Pass to RPh for evaluation)

Immunosuppressive drugs include, but are not limited to:

Generic Names Brand Names

Azathioprine Basiliximab Cyclosporine Sirolimus Tacrolimus Methotrexate Hydroxychloroquine Etanercept Leflunomide

Imuran Simulect Sandimmune, Neoral Rapamune Prograf Rheumatrex Plaquenil Enbrel Arava

Yes: Approve for the shorter of expected therapy duration or: 90 days (applies to topical or oral antivirals ; Immunocompromised Client).

No: If Diabetes or Sickle-Cell disease-go to #6. All others go to #7.

6. Does client have Diabetes or Sickle-Cell disease?

Note: Diabetes and Sickle-Cell is not considered as immunocompromisng for antivirals as it is for antifungal

Yes: Pass to RPH; Deny, (Not Covered by the OHP).

No: Pass to RPH to evaluate for immunosuppression. If not

immunocompromised, Deny (Not Covered by the OHP).

If

immunocompromised, approve for 1 year.

7. RPH only All other indications need to be evaluated as to whether they are above the line or below the line diagnosis.

• If above, viral diagnoses can be approved for treatment course with “prn” renewals. If length of therapy is unknown, please approve for 3 months intervals only (This is an exception to above guidelines and should be discussed with Lead Pharmacist)

• If below, Deny, (Not Covered by the OHP).

• Deny Non-viral diagnoses (Medical Appropriateness).

• Deny Viral ICD-9 codes that do not appear on the OHP list pending a more specific diagnosis code. (Not Covered by the OHP)

If above the line and clinic provides supporting literature: approve for length of treatment.

If below the line: Deny, (Not Covered by the OHP).

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Phone 503-945-5220 | Fax 503-947-1119

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Drug Class Scan

Month/Year of Review: January 2012 Date of Last Review: September 2010 PDL Class: Antivirals: Influenza Source Document: PS Report Current Preferred Agents: Current Non-Preferred Agents: Amantadine Zanamivir (Relenza®) Rimantidine* Oseltamivir* (Tamiflu®) *with quantity limit Previous Conclusions and Recommendations: 1. Vaccination is the primary method of preventing influenza infection. 2. The CDC currently does not recommend the use of amantadine or rimantadine for the treatment or

prophylaxis of influenza A due to viral resistance. 3. The CDC recommends treatment of 2009 influenza A (H1N1) in ‘at risk’ adults and children with either

oseltamivir or zanamivir. 4. Zanamivir uses a complex administration device for inhalation and should not be used in patients with pre-existing respiratory disorders. 5. Recommend taking into account current public health recommendations for appropriate populations,

duration and dosing schedules. PA Criteria/QL: For treatment: Patient must have an OHP covered ICD9 diagnosis AND the antiviral is for the treatment of influenza For prophylaxis: Patient must have an OHP covered ICD9 diagnosis AND be considered at high risk for complications for influenza Quantity Limit: Oseltamivir requires PA for therapy exceeding five days

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Methods: Search Strategy An Ovid MEDLINE search was conducted using the following search terms: Influenza, human influenza, influenza A virus, influenza B virus, H1N1 subtype influenza A virus, flu, H5N1 subtype influenza A virus; antiviral, antiviral$, antiviral agents; RCT, randomized control trial, randomized control trials, trial$, clinical trial, controlled trial The search was limited to studies conducted with humans in English language publications from 2008 to present. Results: The MEDLINE search retrieved 139 full citations. After a full review of citations and abstracts, no new head-to-or placebo-controlled RCTs using FDA approved agents were identified. Most of the RCTs identified compared oseltamivir with either neuraminidase inhibitors not approved for use in the US, or herbal/naturopathic agents. Many RCTs were related to vaccination. This search produced numerous articles analyzing the 2009 h1N1 pandemic; prevention and treatment were examined in various formats: articles, case studies, reviews, observational studies. The search of the Cochrane website identified two new proposed protocols in regards to influenza: one to review treatment interventions (proposed 11/2010) and the other to review prevention interventions (5/2010). The current Cochrane review for treatment with neuraminidase inhibitors (last updated 2010) was not included due to lack of quality RCTs. Prior recommendation of oseltamivir over zanamivir has been removed pending more data; a new protocol for review was proposed 6/2011. The search of the AHRQ, DERP, and VA/DoD websites did not identify any relevant systematic reviews. The search on the FDA websites identified no new approved drugs, no new indications, and one new safety alert. New FDA-approved drugs: None identified. New FDA Indications: None identified. New FDA safety alerts: Medication Alert Date FDA Alert Oseltamivir (Tamiflu®) suspension

July 2011 Warnings and Precautions: ISSUE: Labeling changes are being made to Tamiflu oral suspension to reduce the possibility of prescribing and dosing confusion that can lead to medication errors. The changes to the product label include:

• A change in the concentration of Tamiflu from 12 mg/mL to 6 mg/mL. The lower concentration of Tamiflu is less likely to become frothy when shaken, which helps to ensure an accurate measurement. A change in the measurements of the oral dosing

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device from milligrams (mg = weight) to milliliters (mL = volume). • A change in the dosing table for Tamiflu to include a column for

the volume (mL) based on the new 6 mg/mL concentration. Revised container labels and carton packaging. Revised compounding instructions for pharmacies to prepare a 6 mg/mL oral suspension from Tamiflu capsules in an emergency situation only if the commercially manufactured Tamiflu for oral suspension is unavailable.

BACKGROUND: Tamiflu is in a class of medications called neuraminidase inhibitors. These drugs work by stopping the spread of the influenza (flu) virus in the body. Genentech, the manufacturer of Tamiflu for oral suspension, plans to begin distribution of the new 6 mg/mL product in July 2011. The company has instituted a voluntary Take Back Program for wholesale buyers, distributors and pharmacies to remove the 12 mg/mL product from the marketplace. The 12 mg/mL product will remain in the marketplace and in state or national stockpiles until current supplies expire. RECOMMENDATION: It is important for healthcare professionals to be aware that a patient may potentially receive either concentration (6 mg/mL or 12 mg/mL) from their pharmacy during the next influenza season (2011-2012). Steps should be taken to avoid the potential for a medication error due to confusion between the two concentrations. Prescribers should include the new concentration (6 mg/mL) and dose in milliliters on all prescriptions for Tamiflu for oral suspension.

New Systematic Reviews: None identified. Guidelines1:

Centers for Disease Control and Prevention: Antiviral agents for the treatment and chemoprophylaxis of influenza1.

• Antiviral treatment is recommended as soon as possible for patients with confirmed or suspected influenza who have severe, complicated, or progressive illness or who require hospitalization.

• Antiviral treatment is recommended as soon as possible for outpatients with confirmed or suspected influenza who are at higher risk for influenza complications on the basis of their age or underlying medical conditions; clinical judgment should be an important component of outpatient treatment decisions.

• Recommended antiviral medications include oseltamivir and zanamivir, on the basis of recent viral surveillance and resistance data indicating that >99% of currently circulating influenza virus strains are sensitive to these medications. Amantadine and rimantadine should not be used because of the high levels of resistance to these drugs among circulating influenza A viruses, but information about these drugs is provided for use if current recommendations change because of the reemergence of adamantane-susceptible strains.

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• Oseltamivir may be used for treatment or chemoprophylaxis of influenza among infants aged <1 year when indicated.

• Antiviral treatment also may be considered on the basis of clinical judgment for any outpatient with confirmed or suspected influenza who does not have known risk factors for severe illness if treatment can be initiated within 48 hours of illness onset.

Duration of Treatment or Chemoprophylaxis1

Treatment: Recommended duration for antiviral treatment is 5 days. Longer treatment courses for patients who remain severely ill after 5 days of treatment can be considered.

Recommended duration is 7 days after exposure.

Chemoprophylaxis: For control of outbreaks in long-term care facilities (e.g. elderly nursing homes) and hospitals, CDC recommends antiviral chemoprophylaxis for a minimum of 2 weeks, and continuing up to 1 week after the last known case was identified. Antiviral chemoprophylaxis should be considered, especially for elderly long-term care facilities, for all exposed residents, including those who have received influenza vaccination. References: 1. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM, Centers for Disease Control and Prevention

(CDC). Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Surveill Summ 2011 Jan 21;60(1):1-24

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Appendix A: PA Criteria Antivirals - Influenza

Goal(s): To ensure appropriate extended influenza drug use by authorizing utilization in specified patient population.

Length of Authorization: Date of service Preferred Alternatives: See PDL options at : http://www.oregon.gov/DHS/healthplan/tools_prov/pdl.shtml Requires PA:

Name of Drug Brand Quantity Limits Zanamivir Relenza NA Oseltamivir Tamiflu >5 days therapy

requires a PA Amantadine NA

Approval Criteria

1. What is the diagnosis being treated?

Record ICD9 code

2. Is this an OHP covered diagnosis?

Yes: Go to #3

No: Pass to RPh, DENY (Not covered by the OHP)

3. Is the anitiviral being used to treat influenza?

Yes: Go to #4.

No: Go to #5

4. Will the prescriber consider a change to

a preferred product?

Message: • Preferred products do not require a PA. • Preferred products are evidence-based

reviewed for comparative effectiveness and safety by the Health Resource Commission (HRC). Reports are available at: http://www.oregon.gov/OHPPR/HRC/Evidence_Based_Reports.shtml.

Yes: Inform provider of covered alternatives in class. http://www.oregon.gov/DHS/healthplan/tools_prov/dl.shtml. Current recommended treatment duration*:

- 5 days for the following: Relenza, Tamiflu,

- Amantadine: Continue for at least 10 days.

No: Approve for 5 days

5. Does the patient have any of the following putting them at increased risk for complications requiring prophylaxis?

Yes: Approve for duration of prophylaxis.

No: Pass to RPh; Deny, (Not Medically Appropriate)

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- High-risk persons during 2 weeks after

vaccination before adequate immunity develops

- Patients >1 years of age at high risk for complications for whom the vaccine is contraindicated, unavailable or expected to have low effectiveness

- Residents in institutions such as nursing homes or long-term care facilities that are experiencing an influenza outbreak

- Persons at high-risk of complications of influenza, such as transplant and immunocompromised patients

Current recommended duration of prophylaxis*; Relenza: 10 days for prophylaxis in a household setting, up to 28 days in a community outbreak setting. Tamiflu: at least 10 days following close contact with an infected individual; up to 6 weeks in a community outbreak setting. Amantadine: Up to 4 weeks.

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Month/Year of Review: January 2012 Date of Last Review: July 2009 PDL Class: Oral Beta Blockers Source Document: DERP Report Current Preferred Agents: Current Non-Preferred Agents: Acebutolol HCL Betaxolol Atenolol Bisoprolol Carvedilol Metoprolol Succinate Labetalol HCL Nebivolol, (Bystolic®) Metoprolol Tartrate Penbutolol, (Levabutol®) Nadolol Pindolol Propranolol HCL Timolol Previous Recommendations: 1. In patients with mild-moderate HF, bisoprolol, carvedilol or metoprolol succinate (ER) reduce mortality. 2. In patients with severe HF, carvedilol or metoprolol succinate (ER) reduce mortality. 3. In patients with recent MI, acebutolol, carvedilol, metoprolol tartrate (IR), propranolol, or timolol reduce

mortality. It is important that at least one of these drugs be included in the PDL. 4. All of the β-Blockers reviewed are effective in the treatment of hypertension, but there is no evidence of

differences between β-blockers for blood pressure control, survival, or quality of life. 5. All of the β-Blockers reviewed except carteolol reduced anginal attacks in patients in short-term studies

that did not allow mortality evaluation. 6. Because of their effectiveness in rate control for atrial fibrillation at least one of either atenolol, bisoprolol,

carvedilol, metoprolol succinate (ER), nadolol, pindolol, or propranolol should be included in the PDL. 7. The current evidence does not distinguish a difference among these beneficial β −Blockers that were tested

for preventing recurrence and diminishing the severity of migraine headaches: atenolol, bisoprolol, metoprolol tartrate (IR), metoprolol succinate (ER), propranolol, propranolol LA nadolol, or timolol.

8. The current evidence does not distinguish a difference among beneficial β −Blockers that were tested for reducing esophageal variceal re-bleeding: atenolol, nadolol, propranolol, or propranolol LA.

9. There is no evidence of significant differences among β-blockers in safety or adverse effects. 10. There is no evidence of significant differences found for one β-blocker being more effective or associated

with fewer adverse effects in subgroups of patients based on demographics (race, ethnicity, gender), use of other medications, or co-morbidities.

PA Criteria/QL: Patient must have a covered ICD9 diagnosis.

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Methods: Search Strategy A MEDLINE OVID search was conducted using the following search terms: Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carvedilol, Labetalol, Metoprolol, Nadolol, Nebivolol, Penbutolol, Pindolol, Propranolol, Timolol, heart failure, myocardial infarction, MI, atrial fibrillation, atrial arrhythmias, atrial flutter, esophageal and gastric varices, angina pectoris, chronic stable angina, migraines, migraine disorders, hypertension, portal hypertension, left ventricular dysfunction The following limitations were used for the search: All clinical trials, or clinical trial, or comparative study, or controlled clinical trial, or evaluation studies, or meta analysis, or multicenter study, or randomized controlled trial English language Humans 2009-present Results: The MEDLINE search retrieved 328 full citations. After a review of citations and abstracts, 48 studies were identified for assessment. Of those, four trials are included below, one placebo and three head-to head trials. A sub-analysis of the SENOIRS trial is a placebo controlled trial that looks at prevention of CV events in CAD patients over 70 on nebivolol. Three head-to-head trails with various beta blockers looked at the following outcomes: reversal of left ventricular dysfunction, prevention of AF in HF patients after post-op CABG, and improvement in symptoms in HF patients with non-selective beta-blockers. Although all of these studies had an outcome for the intervention group over the comparator group, none of these studies should impact current clinical practice. Citations and abstracts for the four included trails are listed in Appendix A. The search of the Cochrane, AHRQ, DERP, and VA/DoD websites did not identify any relevant new systematic reviews. Search of the FDA website found no new FDA-approved drugs, indications, or relevant safety alerts. New FDA-approved drugs: None identified. New FDA Indications: None identified. New FDA safety alerts: None identified. New Systematic Reviews: None identified.

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Appendix A: 1 Ambrosio G, Flather M.D, Böhm M, Cohen-Solal A, Murrone A, et al. β-blockade with nebivolol for prevention of acute ischaemic events in elderly patients with heart failure. Heart 2011;97 (3): 209-214. Objectives: This subanalysis of the Study of the Effects of Nebivolol Intervention on Outcomes and Hospitalisation in Seniors with Heart Failure (SENIORS) investigates whether treatment with nebivolol, a β-blocker with nitric oxide-releasing properties, can provide additional benefits besides its effects on heart failure (HF), by reducing cardiac ischaemic events in patients with HF of ischaemic aetiology. Design: A double-blind, randomised, placebo-controlled, multicentre trial of nebivolol in 2128 elderly patients. Patients and interventions: For this analysis, data were extracted for 2128 elderly (≥70 years) HF patients in whom coronary artery disease (CAD) was the underlying aetiology (68.2%; 717 placebo-treated patients and 735 assigned to nebivolol). Main outcome measures: The main endpoint was the composite of cardiac ischaemic events at 2 year follow-up: death/hospitalisation for myocardial infarction, unstable angina or sudden death, as originally identified in the case report form. Results: At follow-up, nebivolol treatment was associated with a one-third reduction in the risk of ischaemic events, the composite endpoint occurring in 15.9% of placebo and 10.7% of nebivolol-treated patients (HR 0.68; 95% CI 0.51 to 0.90; p=0.008). This effect was independent of age, gender and ejection fraction. No difference in this composite endpoint was observed in the subgroup of patients of non-ischaemic aetiology. Conclusions: Nebivolol was effective in reducing cardiac ischaemic events in patients with HF of ischaemic aetiology. The prevention of ischaemic events can be an additional beneficial effect of β-blockade in HF patients with underlying CAD

2 Vinereanu D, Gherghinescu C, Ciobanu AO, Magda S, Niculescu N, et al. Reversal of subclinical left ventricular dysfunction by antihypertensive treatment: A prospective trial of nebivolol against metoprolol. J Hypertens 2011;29(4):809-17.

Objectives: To assess the effects of antihypertensive treatment on subclinical left ventricular dysfunction and to compare the effects of nebivolol with metoprolol. Methods: This is a prospective, randomized, parallel, active-controlled, PROBE design study (ClinicalTrials.org: NCT00942487) in 60 patients (53 ± 9 years, 67% men) with arterial hypertension, left ventricular hypertrophy, normal ejection fraction, and no coronary heart disease, randomized to either a nebivolol-based or a metoprolol-based treatment, who had conventional and tissue Doppler echocardiography, at rest and during dobutamine stress, at baseline and after 6 months. Results: SBP and DBP, and resting heart rate decreased by 13, 13, and 12%, respectively, on nebivolol, and by 11, 13, and 7%, respectively, on metoprolol (all, P < 0.01). Mean longitudinal early diastolic velocity increased by 16% (P < 0.05) on nebivolol compared with 9% (P = not significant) on metoprolol (P = not significant for intergroup differences), whereas flow propagation velocity increased by 34% on nebivolol (P < 0.05) and did not change on metoprolol (P < 0.01 for intergroup differences). Mean longitudinal displacement increased by 10% on nebivolol (P < 0.05) and did not change on metoprolol (P < 0.05 for intergroup differences), whereas ejection time increased by 5% on nebivolol (P < 0.05) and did not change on metoprolol. All the other parameters of left ventricular function were not different between the two treatment arms.

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Conclusion: Patients with mild-to-moderate hypertension have a beneficial effect from 6-month antihypertensive treatment on diastolic longitudinal left ventricular function; effects are significant with nebivolol, but not with Metoprolol 3 Marazzi G, Iellamo F, Volterrani M, Caminiti G, Madonna M, et al. Comparison of effectiveness of carvedilol versus bisoprolol for prevention of postdischarge atrial fibrillation after coronary artery bypass grafting in patients with heart failure. Am J Cardiol 2011;107(2):215-9. Atrial fibrillation (AF) occurs frequently soon after coronary artery bypass grafting (CABG) and often results in increased mortality and morbidity, particularly in patients with heart failure. New-onset AF is also a common event in the early period after discharge from a cardiac surgery clinic. Current guidelines recommend β blockers as first-line medication for the prevention of AF after CABG. In this prospective study, we investigated the effectiveness of the highly selective β1 receptor antagonist bisoprolol compared to the less selective β blocker carvedilol in preventing postdischarge AF after CABG in patients with decreased left ventricular function. Three hundred twenty patients (231 men, 89 women, mean age 66 ± 10 years) with ejection fraction <40% who underwent CABG and were then referred to an in-hospital cardiac rehabilitation program were randomized to receive bisoprolol (n = 160) or carvedilol (n = 160) starting 4 to 5 days after surgery. Bisoprolol was started at 1.25 mg 1 time/day and carvedilol was started 3.125 mg 2 times/day. All patients underwent continuous telemetric electrocardiographic monitoring for 5 days after entry in the study and thereafter 2 times/day routinely up to hospital discharge. During follow-up, 23 patients (14.6%) in the bisoprolol group and 37 patients (23%) in the carvedilol group developed AF (relative risk 0.6, confidence interval 0.4 to 0.9, p = 0.032). Twenty-six percent of all AF episodes were asymptomatic. At the 4-week outpatient visit, those in the bisoprolol group showed a significantly greater decrease in heart rate, being in sinus rhythm or AF (-15.6 ± 3 vs -9.4 ± 3 beats/min, p = 0.021), whereas changes in systolic and diastolic blood pressures did not differ significantly. In conclusion, bisoprolol is more effective than carvedilol in decreasing the incidence of postdischarge AF after CABG in patients with decreased left ventricular function. 4 Marques F, De Castro RBP, Nobre F, Pintya AO, Gallo Jr. L, et al. Replacement of carvedilol for propranolol in patients with heart failure. Arq Bras Cardiol 2010;95(1):107-14. Background: Large clinical trials using the beta-blockers carvedilol, metoprolol, bisoprolol and nebivolol have demonstrated improvement of survival and symptoms in patients with heart failure. Despite the lack of scientific evidence, it is plausible that their beneficial effects are extensible to other beta-blockers. Objective: To evaluate the impact of the replacement of carvedilol for propranolol on left ventricular function, functional capacity, quality of life, pressure levels, and cardiac autonomic control in patients with heart failure. Methods: Twenty nine patients receiving optimized drug therapy including maximum tolerated doses of carvedilol were divided into two groups: replacement of carvedilol for propranolol (n = 15) and continued carvedilol (n = 14). At baseline and 6 months later, clinical and laboratorial assessments were carried out with radionuclide ventriculography, echocardiography, Minnesota questionnaire, walk test, APBM and Holter monitoring. Results: The clinical and demographic characteristics were similar in the two groups at baseline. Individualized propranolol dose adjustment ensured a similar degree of beta-blockade, as assessed by resting heart rate and chronotropic reserve. The mean propranolol dose used was 109 ± 43 mg/day. Only one patient presented with intolerance to propranolol, thus carvedilol was reintroduced. One death was recorded in group propranolol.

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Ejection fraction significantly increased in the propranolol group. No significant change was observed in the other cardiovascular variables after beta-blocker replacement. Conclusion: Our results indicate that replacement of carvedilol for propranolol in patients with heart failure is not associated with deterioration of the ejection fraction, functional capacity, quality of life, and other cardiovascular variables related to autonomic and blood pressure control.

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Appendix B

Medline search

n=328

48 citations identified for review

44 rejected citations

Wrong outcome 15

Wrong drug 20

Wrong design 5

Wrong publication type 4

Included citations:

1 placebo controlled trial

3 head-to-head trials

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Phone 503-945-5220 | Fax 503-947-1119

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Month/Year of Review: January 2012 Date of Last Review: 2005 PDL Class: Calcium Channel Blockers (CCB) Source Document: DERP Report Current Preferred Agents: Current Non-Preferred Agents: Dihydropyridines: amlodipine nicardipine nifedipine ER 24 nifedipine ER SA Non-dihydropyridines: diltiazem SR 24 HR diltiazem ER diltiazem HCL verapamil HCL verapamil HCL 24H

felodipine isradapine nisoldipine Nimotop (nimodipine)

Previous Recommendations: 1. The current evidence does not allow for comparisons of CCBs for the treatment of hypertension and does not differentiate amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nisoldipine, or verapamil SR for efficacy, adverse effects and in subgroups for the treatment of hypertension. There is no evidence for bepridil and felodipine. 2. The current evidence does not differentiate amlodipine, diltiazem, nicardipine, nifedipine, and nisoldipine for efficacy in the treatment of chronic stable angina. There is no evidence for felodipine and isradipine. No difference in efficacy was found between dihydropyridines and non-dihydropyridines for the treatment of angina. 3. The current evidence does not differentiate between diltiazem or verapamil for efficacy and adverse effects in the treatment of supraventricular arrhythmias and there is no evidence in subgroups of patients. 4. In the setting of CHF (defined as systolic dysfunction with a LVEF of < 45%) there is evidence that amlodipine and felodipine do not decrease survival or cause harm in this patient population, but neither do they improve survival nor decrease nonfatal cardiovascular events. In patients with systolic dysfunction the evidence does not demonstrate differences between amlodipine, felodipine nifedipine and nisoldipine on symptoms and exercise tolerance.

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PA Criteria/QL: Patient must have a covered ICD9 diagnosis. Background: Since the DERP report and OHP review of the CCB medications in 2005 there have been 3 DERP CCB class scans conducted in 2006, 2007, and 2009. Based on a defined search criteria a total of 40 potentially relevant trials were identified in those 3 scans (Appendix B - D). The majority of these were identified in the first year following the DERP report. New drugs, indications, and safety alerts found in these scans (2006-2009) since the 2005 report are summarized as follows: New drugs: 2006 scan Bepridil discontinued due to ventricular arrhythmias 2009 scan FDA approved a change in the formulation of extended-release nisoldipine to lower the strengths and replace all current tablets with new lower, bioequivalent strengths. New FDA Indications: 2006 scan Amlodipine indicated for use in patients with angiographically documented coronary artery disease– expanded population New FDA safety alerts: 2007 scan New information was added to the Precautions section for 4 CCBs: Cardizem LA (diltiazem hydrochloride) Extended Release Tablets

Drug interactions : Bispirone, Quinidine, Buspirone

Tiazac (diltiazem hcl) ER Drug Interactions: Bispirone , Quinidine Buspirone: Verelan PM (verapamil hydrochloride) Extended-Release Capsules Controlled Onset

Drug Drug Interactions : Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics

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Methods: Search Strategy A search was conducted to identify newly published high quality systematic reviews, new randomized controlled trials, new FDA approved drugs, indications, and safety alerts since the last DERP update scan (2009) was conducted. A MEDLINE OVID search was conducted using the following search terms: Amlodipine, diltiazem, felodipine, nicardipine, nisoldipine, verapamil, bepridil, isradipine, nifedipine, angina pectoris, supreventricular tachycardia, hypertension, heart failure. The following limitations were used for the search: All controlled clinical trials or randomized controlled trials English language Humans 2010-present Results: The MEDLINE search retrieved 217 full citations. These were reviewed for inclusion by evaluating citations and abstracts for head to head trials of CCB’s evaluating outcomes of interest. 6 new studies were included and are listed in Appendix A. This includes only 1 head to head trial that compared two CCB’s, Nifedipine CR and Diltiazem R in vasopastic angina. The search of the Cochrane, AHRQ, DERP, and VA/DoD websites did not identify any relevant new systematic reviews. The FDA website was reviewed for new FDA approved drugs, indications, and safety alerts. New FDA-approved drugs: Procardia XL (nifedipine gastrointestinal therapeutic system (GITS)) – once-a-day controlled-release tablet New FDA Indications: None identified. New FDA safety alerts: None identified. New Systematic Reviews: None identified.

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Appendix A: New literature from current scan

1. Ferdinand KC, Pool J, et al. Peripheral and central blood pressure responses of combination aliskiren/hydrochlorothiazide and amlodipine monotherapy in African American patients with stage 2 hypertension: the ATLAAST trial. J Clin Hypertens 2011 May;13(5):366-75

Objectives: Evaluate efficacy of antihypertneisve agents on central blood pressure in African Americans. Design: 8-week double-blind, randomized study of African American patients with stage 2 hypertension that compared brachial and central BP responses to combination aliskiren/HCTZ and amlodipine monotherapy. Results: Mean seated systolic BP reductions from baseline was similar with both treatments (-28.6 mm Hg with aliskiren/HCTZ vs -28.2 mm Hg with amlodipine). In the substudy, significantly greater reductions in central systolic BP was observed with aliskiren/HCTZ vs amlodipine (-30.1 mm Hg vs -21.2; P=.031), although 24-hour mean ambulatory BP reductions between the two groups were similar. Conclusions: Central pressure is considered an important risk factor in African Americans, and these findings may suggest a new treatment option for these patients.

2. Saruta, T., K. Hayashi, et al. (2009). "Effects of candesartan and amlodipine on cardiovascular events in hypertensive patients with chronic kidney disease: subanalysis of the CASE-J Study." Hypertension Research - Clinical & Experimental 32(6): 505-12.

Objectives: Examine the effects of candesartan and amlodipine on cardiovascular events in hypertensive patients with chronic kidney disease (CKD) using the data from the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial. Design: CKD was defined as proteinuria and/or decreased GFR (<60 ml per min per 1.73 m(2)) at enrollment. Among 2720 subjects with CKD, there were 1376 and 1344 patients in the candesartan and the amlodipine group, respectively. Results: During a 3.2-year follow-up, cardiovascular event rate did not differ in the two groups (7.2% for candesartan and 7.6% for amlodipine). In the subgroup analysis based on the CKD stage, there were no significant differences in the incidence rates of cardiovascular events between the two groups in stages 1+2 and 3 CKD. In stage 4 CKD, however, candesartan reduced the incidence of cardiovascular events (55% risk reduction), particularly of renal events (81% risk reduction), compared with amlodipine. Furthermore, composite cardiovascular events were increased as the CKD stage progressed, and this effect was exaggerated in the presence of proteinuria. Finally, the new onset of diabetes was less in the candesartan-based regimen in stage 3 CKD. Conclusions: candesartan protected hypertensive patients with CKD more potently against renal events, particularly in moderately-to-severely impaired CKD. Furthermore, candesartan prevented a new onset of diabetes in CKD, which would be favorable for the long-term management of CKD

3. Higuma, T., Oikawa, K., Kato, T., Mori, Y., Kudo, T., Yamamoto T., et al. (2010). Comparison of the effects of long-acting nifedipine CR and diltiazem R in patients with vasospastic angina: Aomori coronary spastic angina study. Journal of Cardiology, 56(3), 354-60.

Objectives: Compare the efficacy of once-daily administration of nifedipine CR 40 mg (N) with that of twice-daily diltiazem R 100mg (D) in patients with vasospastic angina (VSA) registered in 8 cardiovascular institutes in Aomori Prefecture.

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Design: VSA was diagnosed by the ischemic ST segment changes during chest pain attacks at rest and/or acetylcholine induction test done during coronary angiography. Thirty-seven patients were randomly allocated to either the N (n=20) or D group (n=17). The number of symptomatic attacks and amount of short-acting nitrate use were examined based on data in diaries written by the patients. Results: There were no significant differences in the baseline characteristics between the two groups. The mean number (median number) of attacks per week was significantly decreased in the N group from 2.56 (2.0) at baseline to 0.41 (0.0) after 4 weeks of treatment, to 0.24 (0.0) after 8 weeks, and to 0.36 (0.0) after 12 weeks (all p<0.05 vs. baseline). It was also decreased in D group from 2.71 (2.0) at baseline to 0.55 (0.0) after 4 weeks, to 0.32 (0.0) after 8 weeks, and to 0.27 (0.0) after 12 weeks (all p<0.05 vs. baseline). The numbers of attacks before and after treatment were comparable between N and D groups. In one patient in each of the N and D groups, the allocated drug was crossed over to the other due to recurrence of the attacks. One patient in each group experienced adverse effects and the drug was changed to the other. Conclusions: Once-daily administration of nifedipine CR was as effective as twice-daily diltiazem R in the prevention of VSA attacks

4. Chrysant, S.G., Lee, J., Melino, M., Karki, S., & Heyrman, R. (2010). Efficacy and tolerability of amlodipine plus olmesartan medoxomil in patients with difficult-to-treat hypertension. Journal of Human Hypertension, 24(11), 730-8.

Objectives: Hypertension is particularly prevalent in patients aged ≥65 years, those with a body mass index ≥30 kg m(-2), Blacks and those with type II diabetes. Here we report a prespecified secondary analysis of the efficacy of amlodipine (10 mg day(-1)), olmesartan medoxomil (40 mg day(-1)), a combination of the two and placebo in these subgroups. Design: Patients were randomized to treatment for 8 weeks. The primary efficacy endpoint was the change from baseline in mean seated diastolic blood pressure (DBP). Secondary efficacy endpoints included the change from baseline in mean seated systolic BP (SBP), proportions of patients achieving BP goal (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes), and the number and percentage of patients achieving a range of BP targets. Safety and tolerability of amlodipine 5 and 10 mg, olmesartan medoxomil 10, 20 and 40 mg, and all possible combinations of the two were also assessed. Results: For each prespecified subgroup, all active treatments resulted in significant BP reductions from baseline (P<0.05). The antihypertensive effect of the combination of amlodipine+olmesartan medoxomil was generally greater than the constituent amlodipine or olmesartan medoxomil monotherapies, regardless of subgroup. In general, more patients receiving combination therapy achieved BP goal than those treated with monotherapies. The safety and tolerability of combinations were similar to monotherapies across the subgroups. Conclusions: These results suggest that the combination of amlodipine+olmesartan medoxomil provides a safe and effective option for the treatment of hypertension in challenging patient populations.

5. Meredith, P.A., & Elliott, H.L. (2010). Benefits of nifedipine GITS in stable coronary artery disease: Further analysis of the "ACTION" database. Advances in Therapy, 27(5), 297-306.

Objectives: Retrospective analyses of specific subgroups of patients from the database of the ACTION study have evaluated the effectiveness of a nifedipine gastrointestinal therapeutic system (GITS) on clinical outcomes. These subgroups included those patients receiving: 1) full "optimal" therapy at baseline; 2) full "optimal" therapy at baseline but excluding renin angiotensin system (RAS)-blocking drugs; 3) treatment with nifedipine GITS who were not treated with RAS blockers versus those treated with RAS blockers but not nifedipine GITS

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Design: Analyses were performed on an intention-to-treat basis. Treatment groups were compared by log-rank test without adjustment for covariates. Hazard ratios with 95% confidence intervals were obtained using Cox proportional hazards models with treatment allocation as the only covariate. Results: 2461 patients randomized in ACTION were receiving optimal therapy (beta blockers, nitrates, aspirin, statins) excluding RAS blockers at baseline. There were reductions associated with nifedipine GITS compared with placebo in all prespecified endpoints but statistical significance was only achieved for debilitating stroke (48%; P<0.02) and coronary angiography (14%; P<0.05). These benefits were paralleled by a -4.1 and -2.8 mmHg difference between the groups for systolic and diastolic blood pressure, respectively. Patients randomized to nifedipine GITS but no RAS blockers (n=2966) when compared to those receiving RAS blockers but no nifedipine GITS (n=880) had highly statistically significant reductions in cardiovascular events (22%), new-onset heart failure (53%), and debilitating stroke (45%). However, the groups differed in their baseline characteristics.. Conclusions: Addition of nifedipine GITS to the treatment regimen of selected patient groups with symptomatic coronary artery disease results in a significant reduction of cardiovascular morbidity. While the interpretation of these subgroup analyses must obviously be cautious, there is a clear message relating to "best practice" treatment of angina, which suggests that "reliance" on RAS blockade may be misplaced and greater attention should be directed towards control of blood pressure

6. Brown MJ. McInnes GT. Papst CC. Zhang J. MacDonald TM. Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial. Lancet. 377(9762):312-20, 2011 Jan 22

Objectives: Test whether a combination of aliskiren and amlodipine is superior to each monotherapy in early control of blood pressure without excess of adverse events, and if initial control by monotherapy impairs subsequent control by combination therapy. Design: Double-blind, randomized, parallel-group, superiority trial at 146 care sites in ten countries, with enrolment from Nov 28, 2008, to July 15, 2009. Patients eligible for enrolment had essential hypertension, were aged 18 years or older, and had systolic blood pressure between 150 and 180 mm Hg. Patients were randomly assigned (1:1:2) to treatment with 150 mg aliskiren plus placebo, 5 mg amlodipine plus placebo, or 150 mg aliskiren plus 5 mg amlodipine. Random assignment was through a central interactive voice response system and treatment allocation was masked from the patients. From 16-32 weeks, all patients received combination therapy with 300 mg aliskiren plus 10 mg amlodipine. Our primary endpoints, assessed on an intention-to-treat basis (ie, in patients who received the allocated treatment), were the adjusted mean reduction in systolic blood pressure from baseline over 8 to 24 weeks, and then the final reduction at 24 weeks Results: 318 patients were randomly assigned to aliskiren, 316 to amlodipine, and 620 to aliskiren plus amlodipine. 315 patients initially allocated to aliskiren, 315 allocated to amlodipine, and 617 allocated to aliskiren plus amlodipine were available for analysis. Patients given initial combination therapy had a 6·5 mm Hg (95% CI 5·3 to 7·7) greater reduction in mean systolic blood pressure than the monotherapy groups (p<0·0001). At 24 weeks, when all patients were on combination treatment, the difference was 1·4 mm Hg (95% CI -0·05 to 2·9; p=0·059). Adverse events caused withdrawal of 85 patients (14%) from the initial aliskiren plus amlodipine group, 45 (14%) from the aliskiren group, and 58 (18%) from the amlodipine group. Adverse events were peripheral oedema, hypotension, or orthostatic hypotension Conclusions: Routine initial reduction in blood pressure with a combination such as aliskiren plus amlodipine can be recommended.

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Appendix B: New literature from scan #3 (13)

1. Jamerson, K., M. A. Weber, et al. (2008). "Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients.[see comment]." New England Journal of Medicine 359(23): 2417-28.

2. Nakamura, T., T. Inoue, et al. (2008). "Comparison of renal and vascular protective effects between

telmisartan and amlodipine in hypertensive patients with chronic kidney disease with mild renal insufficiency." Hypertension Research - Clinical & Experimental 31(5): 841-50.

3. Nakayama, K., Y. Kuwabara, et al. (2008). "Valsartan Amlodipine Randomized Trial (VART): design,

methods, and preliminary results." Hypertension Research - Clinical & Experimental 31(1): 21-8.

4. Tepel, M., W. Hopfenmueller, et al. (2008). "Effect of amlodipine on cardiovascular events in hypertensive haemodialysis patients." Nephrology Dialysis Transplantation 23(11): 3605-12.

5. Ogihara, T., A. Fujimoto, et al. (2008). "ARB candesartan and CCB amlodipine in hypertensive patients: the

CASE-J trial." Expert Review of Cardiovascular Therapy 6(9): 1195-201.

6. Ogihara, T., K. Nakao, et al. (2008). "Effects of candesartan compared with amlodipine in hypertensive patients with high cardiovascular risks: candesartan antihypertensive survival evaluation in Japan trial." Hypertension 51(2): 393-8.

7. Ostergren, J., N. R. Poulter, et al. (2008). "The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-

lowering limb: effects in patients with type II diabetes." Journal of Hypertension 26(11): 2103-11.

8. Bangalore, S., F. H. Messerli, et al. (2008). "Verapamil-sustained release-based treatment strategy is equivalent to atenolol-based treatment strategy at reducing cardiovascular events in patients with prior myocardial infarction: an INternational VErapamil SR-Trandolapril (INVEST) substudy." American Heart Journal 156(2): 241-7.

9. Black, H. R., B. Davis, et al. (2008). "Metabolic and clinical outcomes in nondiabetic individuals with the

metabolic syndrome assigned to chlorthalidone, amlodipine, or lisinopril as initial treatment for hypertension: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)." Diabetes Care 31(2): 353-60.

10. Davis, B. R., J. B. Kostis, et al. (2008). "Heart failure with preserved and reduced left ventricular ejection

fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.[see comment]." Circulation 118(22): 2259-67.

11. Schmieder, R. E., S. E. Kjeldsen, et al. (2008). "Reduced incidence of new-onset atrial fibrillation with

angiotensin II receptor blockade: the VALUE trial." Journal of Hypertension 26(3): 403-1

12. Wright, J. T., Jr., S. Harris-Haywood, et al. (2008). "Clinical outcomes by race in hypertensive patients with and without the metabolic syndrome: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).[see comment]." Archives of Internal Medicine 168(2): 207-17.

13. Yui, Y., E. Shinoda, et al. (2007). "Nifedipine retard prevents hospitalization for angina pectoris better than

angiotensin-converting enzyme inhibitors in hypertensive Japanese patients with previous myocardial infarction (JMIC-B substudy)." Journal of Hypertension 25(10): 2019-26.

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Appendix C: New literature from scan #2 (3)

1. Cooper-DeHoff, R. M., Q. Zhou, et al. (2007). "Influence of Hispanic ethnicity on blood pressure control and cardiovascular outcomes in women with CAD and hypertension: findings from INVEST." Journal of Women's Health 16(5): 632-40.

2. Ruilope, L. M., B.-A. Kirwan, et al. (2007). "Uric acid and other renal function parameters in patients with

stable angina pectoris participating in the ACTION trial: impact of nifedipine GITS (gastro-intestinal therapeutic system) and relation to outcome." Journal of Hypertension 25(8): 1711-8.

3. Ruzyllo, W., M. Tendera, et al. (2007). "Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial." Drugs 67(3): 393-405.

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Appendix D: New literature from scan #1 (24)

1. Black HR, Elliott WJ, Grandits G, et al. Results of the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) trial by geographical region. Journal of Hypertension. May 2005;23(5):1099-1106.

2. Cooper-Dehoff R, Cohen JD, Bakris GL, et al. Predictors of development of diabetes mellitus in patients

with coronary artery disease taking antihypertensive medications (findings from the INternational VErapamil SR-Trandolapril STudy [INVEST]). American Journal of Cardiology. Oct 1 2006;98(7):890-894.

3. de Leeuw PW, Ruilope LM, Palmer CR, et al. Clinical significance of renal function in hypertensive

patients at high risk: results from the INSIGHT trial.[see comment]. Archives of Internal Medicine. Dec 13-27 2004;164(22):2459-2464.

4. Derosa G, Cicero AFG, Bertone G, et al. Comparison of the effects of telmisartan and nifedipine

gastrointestinal therapeutic system on blood pressure control, glucose metabolism, and the lipid profile in patients with type 2 diabetes mellitus and mild hypertension: a 12-month, randomized, double-blind study. Clinical Therapeutics. Aug 2004;26(8):1228-1236.

5. Frishman WH, Hainer JW, Sugg J, Group MFS. A factorial study of combination hypertension treatment

with metoprolol succinate extended release and felodipine extended release results of the Metoprolol Succinate-Felodipine Antihypertension Combination Trial (M-FACT). American Journal of Hypertension. Apr 2006;19(4):388-395.

6. Hemels MEW, Van Noord T, Crijns HJGM, et al. Verapamil versus digoxin and acute versus routine serial

cardioversion for the improvement of rhythm control for persistent atrial fibrillation. Journal of the American College of Cardiology. Sep 5 2006;48(5):1001-1009.

7. Inoue S, Tomino Y. Effects of calcium antagonists in hypertensive patients with renal dysfunction: a

prospective, randomized, parallel trial comparing benidipine and nifedipine. Nephrology. Oct 2004;9(5):265-271.

8. Investigators JE, Investigators JE. Effect of Losartan and Amlodipine on Left Ventricular Diastolic Function

in Patients With Mild-to-Moderate Hypertension (J-ELAN): rationale and design. Circulation Journal. Jan 2006;70(1):124-128.

9. Jerums G, Allen TJ, Campbell DJ, et al. Long-term renoprotection by perindopril or nifedipine in non-

hypertensive patients with Type 2 diabetes and microalbuminuria. Diabetic Medicine. Nov 2004;21(11):1192-1199.

10. Koylan N, Bilge AK, Adalet K, Mercanoglu F, Buyukozturk K, Group TTS. Comparison of the effects of

trimetazidine and diltiazem on exercise performance in patients with coronary heart disease. The Turkish trimetazidine study (TTS). Acta Cardiologica. Dec 2004;59(6):644-650.

11. Leenen FHH, Nwachuku CE, Black HR, et al. Clinical events in high-risk hypertensive patients randomly

assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.[see comment]. Hypertension. Sep 2006;48(3):374-384.

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12. Mancia G, Ruilope L, Palmer C, et al. Effects of nifedipine GITS and diuretics in isolated systolic hypertension--a subanalysis of the INSIGHT study. Blood Pressure. 2004;13(5):310-315.

13. Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in

hypertensive patients with coronary artery disease be dangerous? Annals of Internal Medicine. Jun 20 2006;144(12):884-893.

14. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients

with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.[see comment]. JAMA. Nov 10 2004;292(18):2217-2225.

15. Ried LD, Tueth MJ, Taylor MD, Sauer BC, Lopez LM, Pepine CJ. Depressive symptoms in coronary artery disease patients after hypertension treatment. Annals of Pharmacotherapy. Apr 2006;40(4):597-604.

16. Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes.[see comment]. New

England Journal of Medicine. Nov 4 2004;351(19):1941-1951.

17. Vranic II, Matic M, Perunicic J, Simic T, Soskic L, Milic N. Adenosine cardioprotection study in clinical setting of paroxysmal supraventricular tachycardia. Prostaglandins Leukotrienes & Essential Fatty Acids. Jun 2006;74(6):365-371

18. Whelton PK, Barzilay J, Cushman WC, et al. Clinical outcomes in antihypertensive treatment of type 2

diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Archives of Internal Medicine. Jun 27 2005;165(12):1401-1409.

19. Kojima S, Shida M, Yokoyama H. Comparison between cilnidipine and amlodipine besilate with respect to

proteinuria in hypertensive patients with renal diseases. Hypertension Research - Clinical & Experimental. Jun 2004;27(6):379-385.

20. Vora A, Karnad D, Goyal V, et al. Control of rate versus rhythm in rheumatic atrial fibrillation: a

randomized study.[see comment]. Indian Heart Journal. Mar-Apr 2004;56(2):110-116.

21. Hjemdahl P, Eriksson SV, Held C, Forslund L, Nasman P, Rehnqvist N. Favourable long term prognosis in stable angina pectoris: an extended follow up of the angina prognosis study in Stockholm (APSIS). Heart. Feb 2006;92(2):177-182.

22. Liu L, Zhang Y, Liu G, et al. The Felodipine Event Reduction (FEVER) Study: a randomized long-term

placebo-controlled trial in Chinese hypertensive patients.[see comment]. Journal of Hypertension. Dec 2005;23(12):2157-2172.

23. Lubsen J, Wagener G, Kirwan B-A, de Brouwer S, Poole-Wilson PA, investigators A. Effect of long-acting

nifedipine on mortality and cardiovascular morbidity in patients with symptomatic stable angina and hypertension: the ACTION trial.[see comment]. Journal of Hypertension. Mar 2005;23(3):641-648.

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