the july 2012 digital edition of pharmacy practice news

Sixty years ago, Henry Knowles Beecher, MD,

and Donald Todd, MD, published a provocative study in the Annals of Sur-gery. The study showed that patients given neuro-muscular blocking agents were six times as likely to die in recovery as those who did not receive the drugs. Most of that excess mortality resulted from respiratory events.

Six decades later, shock-ingly little has changed. As many as 100,000 patients suffer respiratory compli-cations and other adverse events after surgery each year in the United States because they experience residual paralysis from neuromuscular blocking agents (NMBAs), experts warn.

The lack of clinical standards for monitoring post-surgery weakness means the situation is unlikely to improve anytime soon, according to Sorin Brull, MD, a professor of anesthesiology at Mayo Clinic in Jacksonville, Fla. Pharmacists who specialize in critical care and anesthesiology share Dr. Brull’s concern that the guidance gap may place patients at risk.

Lenalidomide maintenance therapy after initial treatment significantly prolonged

progression-free survival (PFS) among patients with newly diagnosed multiple myeloma dur-ing three new randomized Phase III clinical trials. But that benefit came at the price of an increased rate of secondary cancers.

Experts consider the findings a significant advance in melanoma treatment, but they acknowledge that many questions remain about what represents optimal therapy.

The three studies, which were published in the May 10, 2012 online edition of The New Eng-land Journal of Medicine, are “setting the stage

Boceprevir, used in combination with peginterferon and ribavirin,

achieved high rates of sustained viro-logic response in patients with hepati-tis C who failed prior treatment with peginterferon and ribavirin alone, a new study has found.

The results, documented in both par-tial and null responders, are potentially practice-changing, according to Janet Nguyen, PharmD, BCPS, vice president

of network strategy, at A-Med Health Care, Huntington Beach, Calif., who wasnot associated with the study. “This is the first time boceprevir has shown efficacy in null responders,” Dr. Nguyensaid. Such patients, she noted, “are usu-ally unlikely to respond to retreatmentwith an interferon-based therapy.”

The results were based on an interim analysis from PROVIDE, an ongoing,

With one brief anecdote about a toddler dying after exposure to a discarded fen-

tanyl patch while visiting his grandmother in a nursing home, FDA Commissioner Margaret Hamburg, MD, crystallized the sometimes tragic consequences that can occur when safe drug disposal methods fall short.

“Nobody noticed that he had stuck the patch on himself; he suffered an overdose and passed away two days later,” related Dr. Hamburg during an April press telebriefing with repre-sentatives from the Centers for Disease Con-trol and Prevention (CDC), Drug Enforcement Administration (DEA) and Office of National Drug Control Policy (ONDCP). “As a physician, stories like this have both a professional and personal impact on me. Fentanyl patches have

Post-Op Paralysis and NMBAs Still a Threat to Patient Safety

Time To ProgressionLonger in Myeloma PtsTaking LenalidomideThree trials show benefit, but secondarycancer risk triggers concern

Adding Boceprevir to Hepatitis C Therapy Deemed Practice-Changer

Highlighting the Good,The Bad and the UglyOf Rx Drug Misuse Progress cited, but poor medication disposal, ‘pill mills’ still causing harm

Printer-friendly versions available online

pharmacypracticenews.com The Pharmacist’s News Source Volu

• see HEPATITIS C, page 34• see DRUG MISUSE, page 40

• see NEUROMUSCULAR, page 31

• see LENALIDOMIDE, page 10

New Product

Pfi zer Injectables introduces cytarabineinjection.

See page 44.

Continuing Education

The unSUMMIT for Bedside Barcoding introduces online CE for BPOC.

See page 44.

in this issue

CapsulesCompounding pharmacylinked to multistate ocular infections.

3

Up Front

ASHP Late-BreakerAntibiotic stewardship program emphasizes care,not cost.

6

Operations & Mgmt

Practice PearlsPisa Syndrome triggered by psychoactive drugs.

8Managing cardiotoxicity from metoclopramide.

9Hem/Onc PharmacySame-day pegfilgrastim and cabazitaxel urged.

26Metronomic chemotherapyscores in breast cancer.

26Critical CareKeeping an eye on colistin at both ends of the dosingspectrum.

32Infectious DiseaseSwitch to extendedpiperacillin/tazobactaminfusion cuts cost.

37Journal ScanPharmacists’ impact ondiabetes, plus a call for more autism education.

38

Clinical

Emerging Therapies in the SystemicTreatment of Metastatic MelanomaSee page 16

Educational Review

40th ANNIVERSARY YEAR 1972–2012

ume 39 • Number 7 • July 2012

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Compounding Pharmacy Linked To Multistate Eye Disease Outbreak

Health officials have tied contaminated drugs from a compounding pharmacy in Florida to an outbreak of fungal eye infections in nearly three dozen patients

who underwent invasive ophthalmic procedures. The Centers for Disease Control and Prevention (CDC) and the FDA said the

cases, which occurred in at least seven states, resulted from the use of unsterile eyemedications provided by Franck’s CompoundingLab, in Ocala. Of the 33 known cases of fungalendophthalmitis, 70% involved some degree ofvision loss; half of the patients required repeatophthalmic surgery, officials said.

The investigation began in March by the LosAngeles County Department of Public Health. Nine cases of fungal endophthalmitis were linked to using a dye called Brilliant Blue-G (BBG) from Franck’s. In every case, patients had undergone a vitrectomy with peeling of the epiretinal membrane, according to the investigation report. The investigation expanded to involve intravitreal injection of triamcinolone, which also came from Franck’s.

As of April 30, health officials had confirmed 18 of the reported cases. Tests revealed the presence of Fusarium incarnatum-equiseti and i Bipolaris hawaiiensis, two mold species present in air, soil and water.

Post-procedural endophthalmitis occurs in 0.04% of patients who receive intravitreal injections or undergo pars plana vitrectomy, a surgery that involvesremoval of vitreous gel from the eye. Most cases of the complication involve bacteria rather than fungus, health officials said.

The CDC is warning clinicians that Franck’s has not recalled or halted production of its other sterile compounded products and recommends that clinicians and patients avoid using any compounded products labeled as sterile from Franck’s until the root cause and extent of contamination are identified.

—Gabrielle N. Rosen

The five most-viewed articles last month on pharmacypracticenews.com:

1. Med Errors and C. difficile Infections Pose Big Risks in ICUs

2. Vancomycin Plus Piperacillin-Tazo May Trigger Acute Kidney Injury

3. Rivaroxaban Edges Standard Therapy for PulmonaryEmbolism

4. Changes Are Coming for Stress Ulcer Prevention Therapy

5. Overweight Patients Often Dosed Inaccurately in EDs

Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

JULY2012watch

surf

‘Our goal is not to be

the antibiotic police; rather, we round and partner

with the ID physicians and

make clinical interventions

that are focused on

improving patient care.’

—Kristie Zappas, PharmD

heardherefirst

See article, page 6

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EDITORIAL BOARD

ADMINISTRATION

Robert Adamson, PharmD, Livingston, NJ

Ernest R. Anderson Jr., MS, RPh, Boston, MA

ANESTHESIOLOGY/PAIN

Julie A. Golembiewski, PharmD, Chicago, IL

Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

David S. Craig, PharmD, BCPS, Tampa, FL

Robert L. Barkin, MBA, PharmD, Chicago, IL

BIOTECHNOLOGY

Indu Lew, PharmD, Livingston, NJ

CARDIOLOGY

C. Michael White, PharmD, Storrs, CTs

CNS/PSYCHIATRY

Charles F. Caley, PharmD, Storrs, CT

Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA

Larry Ereshefsky, PharmD, San Antonio, TX

COMPLEMENTARY AND ALTERNATIVE MEDICINE

Cathy Rosenbaum, PharmD, Cincinnati, OH

CRITICAL CARE

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

INFECTIOUS DISEASES

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH

Peggy McKinnon, PharmD, Lexington, MAMM

David P. Nicolau, PharmD, Hartford, CT

Robert P. Rapp, PharmD, Lexington, KY

INTERNAL MEDICINE

Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP, Des Moines, IA

NUCLEAR PHARMACY

Jeffrey Norenberg, PharmD, Albuquerque, NM

ONCOLOGY

Robert T. Dorr, PhD, RPh, Tucson, AZ

Robert Ignoffo, PharmD, San Francisco, CA

Philip E. Johnson, MS, RPh, FASHP, Tampa, FL

Cindy O’Bryant, PharmD, Aurora, CO

Ali McBride, PharmD, MS, BCPS, St. Louis, MO

Sara S. Kim, PharmD, BCOP, New York, NY

PEDIATRICS

Gretchen Brummel, PharmD, BCPS, Hudson, OH

REIMBURSEMENT

Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

TECHNOLOGY

Thomas Van Hassel, RPh, Yuma, AZ

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Pharmacy Practice News • July 2012

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Baltimore—Not all health systems have the resources to include a dedicated infec-tious disease (ID) physician in their anti-biotic stewardship programs. But a large community teaching hospital in Florida has shown that a slightly more mod-est staffing model still can significantly improve the quality of antibiotic care.

The program, at Florida Hospital— Orlando, a 1,067-bed acute-care facility, included two infectious-disease phar-

macists and five decentralized clinicalpharmacists. Although a dedicated IDphysician was not part of the team, “ourpharmacists round with ID physiciansup to three times per week, and thatgives us the opportunity to prospective-ly review patients’ antibiotic orders andintervene where appropriate,” said Kris-tie Zappas, PharmD, a clinical specialistin infectious diseases at the hospital.

Nearly 90% of the ID pharmacists’

recommendations were accepted in a recent study of the program, which Dr. Zappas presented as a poster at the American Society of Health-System Pharmacists’ 2012 Summer Meeting. The program also showed that those rec-ommendations yielded improvements in several clinical outcomes, including the proper de-escalation or discontinuation of antibiotics and enhanced “bug-to-drug” matching, Dr. Zappas reported.

The study was based on a retrospec-tive chart review of antibiotic stew-ardship activities performed at Florida Hospital—Orlando from December 2010 to December 2011. Data analyzed during the study included the targeted antimi-crobial agent, formulary restriction sta-tus, type of intervention, prescriber spe-cialty, outcome of the intervention, and the estimated cost savings for accepted interventions.

A total of 1,182 interventions were included in the analysis. According to Dr. Zappas, 72% of the interventions targeted broad-spectrum antimicrobi-als, including piperacillin/tazobactam, doripenem, daptomycin, cefepime, linezolid, micafungin, tigecycline and meropenem. Twelve percent of the rec-ommendations targeted restricted for-mulary agents. Prospective audit and feedback resulted in antimicrobials being de-escalated in 40% and discon-tinued in 58% of cases. Moreover, 48% of the recommendations were made to non-ID physicians, and physicians accepted 87% of the recommendations.

Real-Time Interventions

Dr. Zappas stressed that although the study itself was retrospective, it is the prospective nature of the antibiotic stewardship program that makes it such an effective tool for improving patient care—and for documenting the value of having pharmacists on the ID care team.

“The beauty of having a decentral-ized pharmacy model is that we are on the floor rounding with physicians and so we can actually see, within minutes, antibiotic orders coming through the system,” Dr. Zappas said. “That allows us to assess those orders up-front, rather than working behind the scenes and trying to retrospectively change a drug order that may not be appropriate, where the patient might have been on that drug for the good part of a day.”

The system allows for such rapid-fire interventions in part because the hospi-

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ASHP Late-Breaker

6 Operations & Management

tal uses computerized prescriber orderentry (CPOE), Dr. Zappas noted. “It’svery real-time,” she said. “The physicianenters the antibiotic order for a patientwhile in that patient’s room, and within a few minutes we are reviewing the orderand can make an assessment based on labvalues, patient history, drug-drug inter-actions, formulary restrictions, durationof therapy, order sets, etc.”

Dr. Zappas said her team derives con-siderable satisfaction from ensuring thatthe right antibiotic is being prescribedfor the right infection. “When we dofind a bug-drug mismatch, I feel that wehave a huge opportunity to intervene[and improve clinical outcomes],” shenoted. Although the study showed thatsuch mismatches were the least commontarget of pharmacist interventions (twoof 1,182; 0.17%), “those numbers are defi-nitely an underestimate of what we’vesince been seeing empirically. We nowhave a lot more tools in place—for exam-ple, rapid access to culture sensitivity tests—that help us identify mismatchesand act on them accordingly.”

Dr. Zappas underscored the benefitsof having rapid access to key test results.“Prior to CPOE, where we relied on thephysicians to access the results of culturesensitivity testing, we sometimes were ata disadvantage,” she said. “For example,say the culture results came back at 11am but the prescribing physician hadalready rounded at 8 am. Pre-CPOE, wemay have had to wait another 20 hours of not having those culture results [to guidetherapy]. Now that our pharmacists dohave access to those values, we can callthe physician and let them know that thepatient may have the opportunity to havea more optimal antibiotic on board.”

The improvements in antibiotic thera-py achieved in the study also translatedinto savings—$122,291 over the course of the 13-month review, Dr. Zappas report-ed. But she stressed that finances are nota primary driver of the initiative.

“We’re sensitive to the idea that a lot of antibiotic stewardship programsare almost exclusively focused on cost.But that’s not us; our goal is not to bethe antibiotic police. Rather, we roundand partner with the ID physicians andmake clinical interventions that arefocused on improving patient care.”

Dr. Zappas added that future plansinclude adding a dedicated ID physicianto the antibiotic stewardship team.

Steven J. Martin, PharmD, BCPS, FCCP,FCCM, professor and chair, Departmentof Pharmacy Practice, University of Toledo, in Ohio, said that the results of Dr. Zappa’s research are not surprising.“Pharmacists focus on important detailsin medication use that impact both out-come and costs,” he said. “Since pharma-cists do not prescribe, they more strictly follow drug-use pathways, including organism- and susceptibility-based anti-

biotic selection, de-escalation protocols and IV to PO conversions.”

Dr. Martin said he was encouraged to hear that the Florida program is planning to add a dedicated ID physician. “The ID physician is important in stewardship programs to help influence prescribing changes, consult with difficult-to-manage infections and educate other physicians,” he said. Still, “many of the daily routinefunctions of a successful program can and should be managed by pharmacists.”

—David Bronstein

60

50

40

30

20

0

Incid

en

ce, %

41%(479/1,182)

0.7%(8/1,182)

0.17%(2/1,182)

59%(693/1,182)

Antimicrobial Antimicrobial Bug-Drug IV to PO Discontinuation De-escalation Mismatch

Figure. Types of Interventions.

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ASHP Late-Breaker

Operations & Management 7

Although the rise in prescribing of antipsychotic medications and

other psychoactive medications has been associated with increases in the number of patients reporting improved quality of life, it also is associated with increased rates of various adverse effects (AEs). One of the identifiable outcomes of increased use of neurolep-tic agents is Pisa syndrome, or pleuro-thotonus.

Pisa syndrome, a rare type of truncal dystonia, was first described by Ekbom et al in Germany in 1972 as a side effect of neuroleptic treatment in 3 elderly women taking haloperidol.1,2 Ekbom et al initially attributed the syndrome to long-term neuroleptic use, but otherreports suggested that the syndrome is present with other medication classes, such as cholinesterase inhibitors and antiemetics.1,2 Pisa syndrome generally occurs when another agent is added to an already existing antipsychotic or neuroleptic medication regimen, but the condition usually disappears after discontinuation of the offending agent.2

Tables 1 and 2 provide lists of typical and atypical antipsychotic medications and their side-effect profiles.

Hallmark Presentation Of Pisa Syndrome

Pisa syndrome is a condition charac-terized by abnormally sustained postur-ing with a flexion of the body and head to one side and slight axial rotation of the trunk, so a person appears that they are leaning like the tower of Pisa.3

The syndrome has been described as a spasm of the lower back muscles. The characteristics of its development and prognosis indicate that drug-induced Pisa syndrome can have clinical features of acute dystonia or it can have a similar appearance to tardive dystonia. There are criteria in place for the diagnosis of Pisa syndrome including the tonic flex-ion of the trunk to one side, a remark-able indifference to grossly abnormal posture, and current narcoleptic (or antidepressant) treatment.

Reviewing the Literature

The syndrome is more common-ly noted in the elderly female popu-lation suffering from dementia, but it also has been reported in adolescents.3

The clinical features of Pisa syndrome suggest a complex pathophysiology; a dopaminergic-cholinergic imbalance or

serotonergic or noradrenergic dysfunc-tion are possible implications. Previ-ous cases of induction of the condition by neuroleptics and improvement with trihexyphenidyl suggest that dopami-nergic-cholinergic imbalance is a main factor. Thus, theoretically, cholinergic excess could be another factor in Pisa syndrome, especially the imbalance that is noticed in Alzheimer’s disease.4 There

is the potential for the development of Pisa syndrome in Alzheimer’s diseasepatients with cholinergic excess.

In 1990, Yassa et al evaluated 133 psy-chogeriatric patients (47 men, 86 wom-en) over a 5-year period, looking for casesof Pisa syndrome.4 Eleven patients devel-oped Pisa syndrome (8 women, 3 men),which ranged in duration from 2 to 120days after the start of neuroleptic thera-

py. The prevalence rate was 8.3% (9.3% in women and 6.4% in men). Anticholiner-gics were not an effective treatment, and the only remedy was discontinuation of the neuroleptic.

There have been no other systematic studies of Pisa syndrome in patients tak-ing psychoactive agents; the remain-ing literature describes case reports. In one such case in 2000, Kwak et al

Managing Pisa Syndrome Related to Psychoactive DrugsAbimbola Farinde, PharmD, MS,BCPP, CGP, FASCPClinical Staff PharmacistClear Lake Regional Medical CenterWebster, Texas

Table 1. Typical Antipsychotic Drugs

Drug NameDosage Forms

Average Dose Titrat-ed to mg

Equiva-lents, mg

D2 Effects

5HT2 Effects

Muscarinic Effects

-1 Adrener-gic Effects

Antihistamine Effects

Chlorpromazine T, I 600-800 100 ++++ ++++ ++++ ++++ ++++

Fluphenazine T, L, I, LAI 10-20 2 ++++ ++ + + ++

Perphenazine T 60-80 10 ++++ ++++ + ++ +++

Trifluoperazine T 30-40 5 ++++ +++ + ++ ++

Thioridazine T 600-800 100 ++++ ++++ ++++ ++++ ++++

Mesoridazinea T 300-400 50 ++++ ++++ +++ ++++ ++++

Haloperidol T, L, I, LAI 10-20 2 ++++ ++ + + +

Molindonea T 50-100 10 +++ + ++ + +

Thiothixene C 30-40 5 ++++ + + ++ +++

Loxapine C 75-100 12.5 +++ ++++ ++ +++ ++++

a No longer on market in United States

+, low level; ++, moderate level; +++, high level; ++++, very high level; C, capsule; I, injection; L, liquid; LAI, long-acting injection; T, tablet

Adapted from Hahn, Albers, and Reist. Psychiatry, 2008 Edition.

Table 2. Atypical Antipsychotic Drugs

Drug NameDosage Forms

Average Dose, mg

Chlorproma-zine equiva-lents, mg

D2 Effects

5HT2 Effects

Muscarinic Effects

-1 Adren-ergic Effects

Antihistamine Effects

Clozapine T, ODT 300-600 60 ++ ++++ ++++ ++++ ++++

Aripiprazole (Abilify, Bristol-Myers Squibb)

T, ODT, L, I 15-30 2-4 ++++ +++ + ++ ++

Risperidone T, ODT, L, LAI

2-8 1-2 ++ +++ + +++ ++

Olanzapine T, ODT, I 5-20 3 +++ +++ ++ ++ ++

Quetiapine T, T (ER) 400-600 50 + ++ 0 ++ ++

Ziprasidone C, I 80-160 5-10 +++ +++ + + +

Paliperidone (Invega, Janssen)

T (ER),I, LAI

6-12 2 ++ +++ 0 ++ ++

Asenapine (Saphris, Organon)

T (sublingual)

5-10 NA NA NA NA NA NA

Iloperidone (Fanapt, Novartis)

T 12-24 NA NA NA NA NA NA

Lurasidone (Latuda, Sunovion)

T 40-160 NA NA NA NA NA NA

+, low level; ++, moderate level; +++, high level; ++++, very high level; C, capsule; ER, extended release I, injection; L, liquid;LAI, long-acting injection, NA, not available; ODT, orally disintegrating tablet; T, tablet

Adapted from Hahn, Albers, and Reist. Psychiatry, 2008 Edition.


Practice Pearls

8 Clinical

described a 53-year-old woman whohad been taking donepezil therapy for1 month in combination with risperi-done. The patient experienced dystonia,which lasted 1 week after discontinu-ation of donepezil.5 The patient thenreceived rivastigmine, but the dystonia reappeared.5 In 2005, Vanacore et alreported a reaction in an 83-year-oldpatient who had been taking rivastig-mine for 5 months.6 This patient expe-rienced dystonia that resolved 3 weeksafter discontinuation of rivastigmine. In2007, Huvent-Grelle et al identified dys-tonia in a 78-year-old woman who hadbeen taking galantamine for 11 months and who also was taking an atypicalantipsychotic; her dystonia resolved 15days after galantamine discontinuation.7

While I was training at the NorthTexas Veterans Healthcare System, inDallas, a 70-year-old white male vet-eran presented to the system’s outpatientmental health clinic with complaints of short-lived muscle spasms that causedabnormal postures and disruptive move-ments. A clinical pharmacist performeda comprehensive review of the patient’spsychotropic medication profile, whichshowed that the patient was taking per-phenazine (4 mg three times a day) forpsychosis, diphenhydramine (25 mg oncea day) for extrapyramidal side effects,donepezil (10 mg once a day) for mild

dementia, and lorazepam (2 mg as need-ed) for anxiety. The patient had been on perphenazine for 2 years without sig-nificant complaints but recently began to experience persistent spasms that were becoming increasingly bothersome. The attending physician switched the patient’s antipsychotic medication from the typical antipsychotic perphenazine to the atypical antipsychotic risperidone at a dosage of 2 mg daily, with dose assessment and adjustments made when warranted. Approximately 2 weeks after the switch to risperidone, the frequen-cy of dystonic reactions and posturing began to diminish significantly. Donepe-zil had been considered to be a potential contributing factor to the syndrome, but a risk–benefit assessment led to the deci-sion to continue the donepezil at the current dose. The patient’s clinical team decided that the attending physician and clinical pharmacist would assess the patient during his routine visits to the outpatient mental health clinic to closely monitor for any recurrence of symptoms. No recurrences were identified at the 3-month assessment mark.

Approach and Recommendation(s)

When any patient distinctly presents with symptoms that may be sugges-tive of Pisa syndrome, the clinical team

should perform a thorough evaluation of the patient’s medication regimen to specifically identify long-term use of any antipsychotic medication or cholinester-ase inhibitor. To identify the offending agents, it is best to determine which medication the client has been on for a longer period of time. With consideration being given to the pros and cons of dis-continuation, the clinical pharmacist can work alongside the prescribing physician to determine which decision would be in the best interest of the patient. If the offending agent is determined to be the antipsychotic medication, an alternative antipsychotic that is less likely to cause extrapyramidal side effects can be con-sidered; if the offending agent is deter-mined to be a cholinesterase inhibitor, a dose reduction may be considered or discontinuation may be warranted based on the severity of the Pisa syndrome. For any patient who presents with Pisa syn-drome, there is a high likelihood that dis-continuation of the offending agent will result in disappearance of the symptoms.

Future Direction

The widespread use of antipsychotic medications and cholinesterase inhibi-tors can lead to an increasing number of cases of Pisa syndrome, so clinicians should to be aware of this AE. There are no conclusive data on the mecha-

nism by which cholinesterase inhibitors cause Pisa syndrome, only theories, butthe available evidence shows that these agents have the potential to cause thisAE, and clinicians must be aware of thisand address it immediately.

Dr. Farinde reported no relevant fi nancial confl icts of interest.

References

1. Shuster J. Institute for Safe Medication Practices adverse drug reactions: Pisa syn-drome seen with donepezil. Hosp Pharm. 2001;36(10):1036-1041.

2. Suzuki T, Matsuzaka H. Drug-induced Pisa syndrome (pleurothotonus): epidemiology and management. CNS Drugs. 2002;16(3):165-174.

3. Wyckoff. Behavioral alert: update on Pisa syndrome. Gero Services. http://www.geroser-vices.com/pisa.asp. Accessed June 4, 2012.

4. Yassa R, Bloom D. Lorazepam and anticho-linergics in tardive akathisia. Biol Psychiatry. 1990;27(4):463-464.

5. Kwak YT, Han IW, Baik J, Koo MS. Relationbetween cholinesterase inhibitors and Pisa syndrome. Lancet. 2000;355(9222):2222.

6. Vanacore N. Suzzareddu G, Maggini M, Casula A, Capelli P, Raschetti R. Pisa syndrome in a cohort of Alzheimer’s disease patients. ActaNeurol Scand. 2005;111(3):199-201.

7. Huvent-Grelle D, Roche J, Camus FE, Dewailly P, Puisieux F. Relationship between cholinesterase inhibitors and Pisa syn-drome in a cohort of five French patients with Alzheimer’s disease. J Am Geriatr Soc.2007;55(9):1472-1475.

Although metoclopramide has beenavailable for decades, its side-effect

profile continues to evolve. In 2009,the FDA required a black box warn-ing regarding the increased risk for tar-dive dyskinesia when metoclopramide isused at high doses or over long periodsof time. Several cardiovascular adverseeffects (AEs) are listed in the metoclo-pramide prescribing information,1 andreports of the drug’s cardiovascular AEsfirst appeared in the literature in 1974.2

Since then, a number of case reports sup-porting the view that metoclopramidehas significant cardiovascular AEs haveappeared in the literature.

Between January 1966 and February of this year, dozens of cases of cardiovas-cular AEs have been reported, including

multiple cases of sinus or cardiac arrest,3-11

extreme bradycardia,4,5,7,9,12 bradycar-dia followed by total heart block,9,12-14

acute hypotension,14-20 circulatory col-lapse,20 QT prolongation,21-23 torsades de pointes,8,22,24,25 supraventricular tachycar-dia (SVT),24,26-28 and ST-segment depres-sion.1,26 Cases of congestive heart failure have occurred following chronic meto-clopramide doses of 40 mg per day.27 The metoclopramide prescribing information lists several AEs, including atrioventricu-lar (AV) block, bradycardia, heart failure, hypertension/hypotension, and SVT but not circulatory collapse, cardiac arrest, torsades de pointes, QT prolongation, and ST-segment depression.1

Age and dose do not appear to be con-tributory factors for cardiovascular AEs

from metoclopramide. Although the patients in most of the cases were elderly, middle-aged individuals also have had AEs, for example cardiac arrest, fol-lowing metoclopramide.6 Previous car-diovascular disease, atrial fibrillation,3

autonomous dysfunction,10 hyperbiliru-binemia,6 halothane anesthesia,15,17 and the presence of a pericardial drainage

tube all have been suggested as underly-ing predisposing or contributory factors for development of cardiac AEs withmetoclopramide.12 However, in some cases there has been no clear associationwith any risk factors.

The route of administration may be a causative factor. In all cases, metoclo-pramide was given by IV either peripher-ally or via a central venous line. The rateof injection also may be causative. In a number of cases, metoclopramide was administered over seconds, rather thanover 1 to 2 minutes as recommended in the product labeling.1,16

In most cases the reactions occurred immediately, were associated with nor-mal doses administered via IV or centrallines, and resolved. Rechallenge occurredin several of the cases. The likelihood of these events occurring and the mecha-nism by which metoclopramide affects the cardiovascular system is unclear, butit has been shown to directly affect theheart, to block presynaptic autorecep-tors, to enhance catecholamine release and cholinergic neurotransmission, andto cause 5-HT3 receptor blockade and5-HT4 receptor antagonism.

Support for a mechanism involving a

Managing Cardiovascular Adverse Effects of MetoclopramideMartha M. Rumore, PharmD,JD, LLM, FAPhA

Assistant Director, Pharmacy Clinical & Educational ServicesCohen Children’s Medical CenterNorth Shore-LIJNew Hyde Park, New York Adjunct ProfessorPharmacy & Health OutcomesTouro College of PharmacyNew York, New York

Table. Recommendations For Clinicians

Recognize factors such as underlying cardiac abnormalities and familial long QT interval.

Perform baseline and periodic electrocardiograms.

Avoid concomitant use with other QT-prolonging drugs.

Monitor serum concentrations of magnesium and potassium in critically ill patients.

Report any cardiovascular adverseeffects to FDA MedWatch.

Administer IV metoclopramideslowly over at least 2 minutes.

• see METOCLOPRAMIDE, page 35


Practice Pearls

Clinical 9

for a new era of treatment for multiple myeloma,” according to C. Ola Landgren, MD, PhD, head of the multiple myeloma section at the National Cancer Institute. “There are a lot of questions still to be answered, but clearly, there is a lot of benefit to patients in having access to oral drugs that can extend the time frame before the disease becomes active.”

Philip McCarthy, MD, a professor of oncology and director of the Blood & Marrow Transplant Program at Roswell Park Cancer Institute, in Buffalo, N.Y., and lead investigator on one of the studies, noted that “until these studies, [there was] no confirmed Phase III data suggesting a benefit to using lenalido-mide maintenance for multiple myelo-ma patients after primary therapy.”

Survival Results

In the largest of the three trials, a French study involving more than 600 patients (IFM 2005-02), lead investi-gator Michel Attal, MD, and his col-leagues treated patients, all of whom were below the age of 65 years, with induction therapy and transplantation followed by a two-month lenalidomide (Revlimid, Celgene) consolidation. Patients without progressive disease were randomized to maintenance treat-ment with either lenalidomper day, increased to 15 mgper day after three months if tolerated) or placebo until relapse. At a median follow-up of 45 months, the primaend point, median progressifree survival, was 41 monththe lenalidomide maintenancversus 23 months in the p

arm (hazard ratio [HR], 0.50; P<0.001). In another of the three trials, the

460-patient CALGB (Cancer and Leu-kemia Group B) 100104 study, in which patients received lenalidomide doses ranging from 5 to 15 mg per day, inves-tigators found an overall survival (OS) benefit with lenalidomide in addition to improved PFS. At a median follow-up of 34 months, 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) had died (P(( =0.03). Median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P(( <0.001).

Finally, the international MM-015 study, led by the Myeloma Unit at the University of Torino, in Italy, random-ized 459 patients aged 65 years or older to melphalan-prednisone induction fol-lowed by placebo maintenance (MP) or melphalan-prednisone-lenalidomide induction followed by placebo mainte-nance (MPR) or melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R). The initial maintenance dose of lenalido-

mide was 10 mg per day for days 1-21, with a seven-day drug-free period; the cycle was repeated until progression. The median follow-up in this trial was 30 months. Patients in the MPR-R arm had a median PFS of 31 months compared with 14 months for those in the MPR arm (P(( <0.001). That benefit appeared to be confined to patients between the ages of 65 and 75; patients over age 75 showed no significant improvement (P(( =0.001).

Increased Risk for Secondary Cancers

Although these studies showed thatlenalidomide maintenance increased PFS, all three studies also showed that it significantly increased risks for secondary malignancies. The specific types of secondary cancers varied withthe trial: “The French study showed a two- to threefold increase in solid tumors, all different kinds, as well as a two- to threefold increase in hema-tologic disorders, in particular Hodg-kin’s lymphoma and acute lymphoblas-tic leukemia,” observed Dr. McCarthy,who led the CALGB study. “The Italian

ch patients did not undergo splant but had a lot of mel-lan exposure, showed an ease of acute myelogenousemia and myelodysplasticsyndrome in the lenalido-mide arm. We also foundthose cancers increased ith lenalidomide ... at a

similar rate but [saw] no increased instance of [acute lymphoblastic leuke-mia] or Hodgkin’s lymphoma.”

This finding is not new; concerns about secondary cancers were raised in December 2010 when preliminary data from the three trials were released. “But if you look at the CALGB 100104 cumu-lative incidence [CI] risk analysis, the CI risk for secondary malignancy is higher with lenalidomide maintenance, but the CI risk for progression or death is higher in the placebo arm,” Dr. McCarthy noted.

Commenting on the findings in an interview, Dr. Landgren said, “Com-pared with the general population, people with multiple myeloma are atgreater risk for certain other malig-nancies no matter what treatment they undergo.” She noted that although mul-tiple myeloma confers risks, “it’s also obvious that in all three of these stud-ies, there is enrichment of that risk, particularly the risk for hematologic

malignancies. In the three randomizedstudies, based on small numbers, there are more hematologic secondary malig-nancies in the lenalidomide arm versusthe placebo arm. We don’t yet know themechanisms, but we are working hard to look into that. Statistically speaking, thebenefits are quite profound, but if you happen to be the person who developsthat [adverse] outcome, it’s devastating.”

Is Overall Survival Improved?

The cost–benefit ratio of improved PFS versus secondary malignancies might be easier to assess if the OS ben-efit was clear-cut, said Jacob Laubach, MD, instructor in internal medicine atHarvard Medical School, in Boston, and a hematologist-oncologist at the Dana-Farber Cancer Institute, also in Boston.“If an overall survival benefit had beenseen in each of the three studies, I think the use of lenalidomide maintenancewould be even more clear-cut. But that’sthe strength of having three large studiesinvolving over 1,000 patients. Because there’s an overall survival benefit in [only] one of the three studies, there is still an issue of how best to use lenalido-mide maintenance.”

The subset analysis in the CALGB study suggests a possibility for fine-tun-ing the use of lenalidomide maintenance.“The analysis shows that all subgroups benefited from lenalidomide mainte-nance in time to progression whereasonly certain subgroups appeared to ben-efit from lenalidomide in overall sur-vival,” said Dr. Laubach. Specifically, “patients who received lenalidomide as part of their consolidation,” said Dr. McCarthy, “seemed to do better thanthose who got something else and then lenalidomide maintenance.”

Another lingering question: What is the optimal duration of maintenance therapy? “Some progressions do occur late,” Dr. McCarthy said, “and it may be that you need to continue exposure tothis drug for a prolonged period.”

Dr. Laubach said that the use of lenalid-omide maintenance must be considered on a patient-by-patient basis. “Just as wechoose induction regimens and wheth-er to use transplant based on unique patient characteristics, we must come tothe point of maintenance therapy withlenalidomide with the same questions in mind. What was the patient’s prior treat-ment? Response to therapy? The tox-icities that occurred during prior treat-ment? All of these questions factor into the decision about whether to employ lenalidomide maintenance.”

—Gina Shaw

The MM 015 study was supported by Celgene, manufacturer of lenalidomide

(Revlimid). Celgene supplied thelenalidomide and placebo for the American

and French studies.

Cost, Side Effects Remain a Challenge

Management of multiple myeloma patients on long-term maintenancelenalidomide will pose some challenges, noted Kathleen West, BS, PharmD,

a clinical pharmacy specialist with Roswell Park Cancer Institute’s Division ofBlood and Marrow Transplantation, In Buffalo, NY.

“Because of the side effects, particularly secondary cancers, there will be a lotmore monitoring and follow-up needed. Patients will have to come in on a regu-lar basis and make sure their counts are okay,” Dr. West noted.

Cost will also be a factor. A 10-mg tablet of lenalidomide costs approximately $550, so a year’s worth of the drug on a maintenance schedule like those usedin the trials would cost approximately $160,000 per year, according to Dr. West.“Because these are new studies of lenalidomide as maintenance therapy, I’m not sure how insurers will respond in terms of coverage,” she said. “Each company will probably be different; right now, even when we recommend a multiple myeloma patient for transplant, the insurers differ as to whether they’ll approve it.”

Don McLeod, a spokesman for the Centers for Medicare and Medicaid Services (CMS), said there currently is no National Coverage Determination on lenalido-mide for maintenance therapy in multiple myeloma. “It is left to [local] contrac-tor discretion,” he said.

Like CMS, it appears that many private insurers have not yet issued a deter-mination of coverage for lenalidomide as maintenance therapy in this setting.WellPoint, for example, already covers lenalidomide with the combination ofdexamethasone in the treatment of multiple myeloma on Tier 2 on its commer-cial formulary (with prior authorization), but that is for initial therapy. As far asmaintenance therapy, said WellPoint corporate communications director Lori McLaughlin, “We are in the process of reviewing the new data and how it per-tains to our prior authorization criteria.”

—G.S.

LENALIDOMIDEcontinued from page 1

‘Because there’s an overall survival benefit in [only]

one of the three studies, there is still an issue of how

best to use lenalidomide maintenance.’

—Jacob Laubach, MDnance treat-

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Medication Delivery

111514B 11/11

PREMIXED AMIODARONE. Indications and UsageNEXTERONE (amiodarone HCl) Premixed Injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication.

Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONEmay be safely administered for longer periods if necessary.

Important Risk InformationNEXTERONE (amiodarone HCl) Premixed Injection is contraindicated in patients with:

Known hypersensitivity to any of the components of NEXTERONE, including iodine

Cardiogenic shock

Marked sinus bradycardia

Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available

NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.

Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported in 16% (288/1836) of patients treated with intravenous amiodarone. Monitor the initial rate of infusion closely and do not exceed the recommended rate. In somecases, hypotension may be refractory and result in a fatal outcome. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including: vasopressors, positive inotropic agents and volume expansion.

In 4.9% (90/1836) of patients in clinical trials, drug-related bradycardia that was not dose-related occurred while patients were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available.

Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia.

The most common adverse reactions leading to discontinuation (1-2%) of intravenous amiodarone therapy are hypotension, asystole/cardiac arrest/pulseless electrical activity, VT, and cardiogenic shock.

Other important adverse reactions are torsade de pointes (TdP), congestive heart failure, liver function test abnormalities, pulmonary disorders, and thyroid abnormalities.

Drug Interactions: Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism andincrease serum concentration of amiodarone. Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A.This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, inpatients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.

Please see brief summary of Full Prescribing Information on the following pages.

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NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use

Brief Summary of Prescribing Information. See PI for Full Prescribing Information.

1 INDICATIONS AND USAGENEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2) in full prescribing information].

Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

4 CONTRAINDICATIONSNEXTERONE is contraindicated in patients with:

iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage

thrombotic thrombocytopenic purpura, or severe periarteritis (inflammation around blood vessels).

5 WARNINGS AND PRECAUTIONSNEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.

5.1 HypotensionHypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients.

Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate [see Dosage and Administration (2) in full prescribing information].

In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2) in full prescribing information].

5.2 Bradycardia and Atrio-ventricular BlockIn 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available.

5.3 Liver Enzyme ElevationsElevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment.

Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended [see Dosage and Administration (2) in full prescribing information].

against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE

or withdrawing NEXTERONE.

5.4 ProarrhythmiaLike all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see Drug Interactions (7) in full prescribing information].

Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatal breakthrough or exacerbated arrhythmias.

5.5 Pulmonary DisordersEarly-onset Pulmonary Toxicity

treated with intravenous amiodarone. Findings have included pulmonary infiltrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death.

ARDSTwo percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy.

Pulmonary FibrosisOnly 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary fibrosis. In that patient, the condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone).

5.6 Loss of VisionCases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressedto permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Re-evaluate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination, during administration of NEXTERONE.

5.7 Long-Term UseThere has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks. See package insert for oral amiodarone.

5.8 Thyroid AbnormalitiesAmiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal.

There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2) in full prescribing information].

Hyperthyroidism and ThyrotoxicosisHyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear.

MCPPN2139.indd 1 11/15/11 6:21 PM

Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism.

The institution of antithyroid drugs, -adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism.

When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosisis limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning.

Neonatal Hypo- or HyperthyroidismAmiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE.

HypothyroidismHypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue oral amiodarone in some patients.

5.9 SurgeryPerform close perioperative monitoring in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics.

5.10 Corneal Refractive Laser SurgeryAdvise patients that most manufacturers of corneal refractive laser surgery devices contraindicatecorneal refractive laser surgery in patients taking amiodarone.

5.11 Electrolyte DisturbancesCorrect hypokalemia or hypomagnesemia whenever possible before initiating treatment with NEXTERONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.

6 ADVERSE REACTIONS6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received intravenous amiodarone for at least one week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days.

The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electricalactivity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse reactions. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%).

Table 4 lists the most common (incidence 2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related.

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting.

6.2 Post-Marketing ExperienceThe following adverse reactions have been identified during post-approval use of amiodarone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever

Cardiovascular: hypotension (sometimes fatal), sinus arrestrr

Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema

Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma

Hepatic: hepatitis, cholestatic hepatitis, cirrhosis

Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing

Musculoskeletal: myopathy, muscle weakness, rhabdomyolysisll

Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri

Pancreatic: pancreatitis

Renal: renal impairment, renal insufficiency, acute renal failurell

Respiratory: bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest and yyARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and /or mass, pleuritis

Thyroid: thyroid nodules/thyroid cancerdd

Vascular: vasculitisrr

Baxter Healthcare Corporation Deerfield, IL 60015

Baxter, Galaxy, Nexterone and the Sphere Graphic are trademarks of Baxter International Inc.

Sourced from: 07-19-65-459 Rev. November 2010

Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN

CONTROLLED AND OPEN-LABEL STUDIES (>2% INCIDENCE)

Controlled Studies(n=814)

Study Event

Body as a wholeFever

Cardiovascular SystemBradycardiaCongestive heart failureHeart arrestHypotensionVentricular tachycardia

Digestive SystemLiver function tests normalNausea

Body as a whole24 (2.9%)

Cardiovascular 49 (6.0%)18 (2.2%)29 (3.5%)

165 (20.2%)15 (1.8%)Digestive System

35 (4.2%)29 (3.5%)


Cardiovascular 41 (4.0%)21 (2.0%)26 (2.5%)

123 (12.0%)30 (2.9%)Digestive System

29 (2.8%) 43 (4.2%)


Cardiovascular 90 (4.9%)39 (2.1%)55 (2.9%)

288 (15.6%)45 (2.4%)

Digestive System64 (3.4%)

72 (3.9%)

Open-Label Studies(n=1022)

Total(n=1836)

MCPPN2139.indd 1 11/15/11 6:21 PM

Recent Advances and Emerging Therapies in the Systemic Treatment of Metastatic Melanoma

Although surgery offers a great cure rate forpatients with early-stage melanoma, those whohave either metastatic disease or a high risk for recurrence are given a much poorer prognosis. In fact, the median overall survival (OS) of patients with stage IV melanoma is only 6 to 9 months.2-4

Dacarbazine remains the only cytotoxic chemo-therapy that is FDA-approved for the treatment ofmetastatic melanoma. However, dacarbazine hasmodest clinical efficacy, with a response rate ofonly about 10%.2,4-6 The FDA also has approvedhigh-dose interleukin-2 (IL-2) for the treatment ofadvanced melanoma because of the agent’s abili-ty to induce a durable response. Unfortunately, thisresponse is observed in only a small subset ofpatients, and IL-2 is associated with significanttoxicities, such as capillary leak syndrome, that fre-quently require intensive monitoring in a dedicat-ed unit or intensive care facility.7,8 Otheragents—including temozolomide (Temodar, Scher-ing-Plough), cisplatin, carboplatin, vinblastine,paclitaxel, carmustine, and lomustine (CeeNu, Bris-tol-Myers Squibb)—are commonly used off-label to treat melanoma, but none of these agents ortheir various combinations have been found tooffer a survival advantage over dacarbazine alone.9

Clearly, more active and less toxic drugs are

needed for patients with advanced melanoma. Inthis article, we review recent advances and emerg-ing therapeutic approaches in the systemic treat-ment of metastatic melanoma.

Newly Approved DrugsFor Late-Stage Melanoma

Ipilimumab

Immunotherapy has been used to treat mela-noma for decades. Cancer cells, such as those thatmake up melanoma, have tumor-associated anti-gens that can be recognized by T cells. This rec-ognition leads to a host response that targets thetumor cells.10 The standard immunotherapy, high-dose IL-2, enhances this response but elicits adurable clinical response in only a small subset ofpatients.8,11,12 Accordingly, researchers have active-ly sought to identify and develop more effectiveimmunologic agents with better safety profiles.

Ipilimumab (Yervoy, Bristol-Myers Squibb) is afully human monoclonal antibody that binds tocytotoxic T-lymphocyte antigen-4 (CTLA-4), aco-inhibitory receptor molecule found on the sur-face of activated T cells. T-cell activation beginswhen the T-cell receptor binds to an antigen pre-sented by a major histocompatibility complex on

antigen-presenting cells, such as dendritic cells.Cluster of differentiation 28 (CD28), a co-stimu-latory receptor molecule found on T cells, bindsto B7 (CD80/CD86) found on antigen-presentingcells, leading to T-cell proliferation and IL-2 pro-duction. As T cells become activated, CTLA-4 isupregulated to the cell surface, where it competessuccessfully with CD28 for B7 to halt further cellproliferation in a self-regulatory mechanism. Ipili-mumab blocks CTLA-4 on the cell surface, therebypreventing CTLA-4 from binding to B7 moleculesand allowing CD28 to bind to these moleculesinstead, leading to further T-cell proliferationand IL-2 production.13,14 Ultimately, this can helpincrease the immune response to cancer cells.

Initial clinical studies revealed that ipilimumabcould be a promising new therapy for metastat-ic melanoma.15,16 A Phase I/II trial of ipilimumab(≤10 mg/kg every 3 weeks) in 23 patients withmetastatic melanoma demonstrated a disease control rate of 39%, with at least 2 patients expe-riencing a durable response of longer than 21 months.15 These encouraging results led to sev-eral Phase III trials of ipilimumab in patients withmetastatic melanoma (Table 1).17,18

In the first Phase III study of ipilimumab,676 previously treated patients with unresect-able stage III or IV melanoma were randomlyassigned, in a 3:1:1 ratio, to receive ipilimumabwith a glycoprotein 100 (gp100) peptide vaccine(n=403), ipilimumab alone (n=137), or the gp100peptide vaccine alone (n=136).17 Ipilimumab wasgiven at a dose of 3 mg/kg every 3 weeks for 4doses. The median OS of patients who receivedipilimumab alone (10.1 months) was significant-ly longer than that of patients who received thegp100 vaccine alone (6.4 months; hazard ratio[HR], 0.66; P=0.003). However, the median OS of patients who received ipilimumab with the gp100 vaccine did not differ significantly from that of patients who received ipilimumab alone. The risk for disease progression in patients who received ipilimumab alone was 36% lower than

JEFFREY T. YORIO, MDFellow, Hematology and Oncology

KEVIN B. KIM, MDAssociate Professor

Department of Melanoma Medical OncologyThe University of TexasMD Anderson Cancer CenterHouston, Texas

Melanoma, the malignant transformation of melanocytes,

most commonly occurs in the skin but also may arise

from the mucosal surfaces or in the choroid of the eyes.

Melanoma is the fifth and sixth most common cancer in men and

women, respectively, in the United States.1 In 2012, more than

76,000 people will be diagnosed with malignant melanoma, and

more than 9,000 people will die from the disease nationally.1

Educational Review

Pharmacy Practice News • July 201216 Clinical

that for patients who received the gp100 vaccine alone (P<0.001). The median progression-free survival (PFS) durations of the 3 groups were similar (2.76 months in the combination group, 2.86 months in the ipilimumab-alone group, and 2.76 months in the gp100 vaccine-alone group). The results of this trial led to the FDA’s approval of the drug for the treatment of metastatic mel-anoma in March 2011.

In the second Phase III study of ipilimumab, 502 treatment-naive patients with metastatic melanoma were randomized to receive dacar-bazine with or without ipilimumab.6 During the induction phase, ipilimumab was given at a dose of 10 mg/kg every 3 weeks for 4 doses. During the maintenance phase, patients who did not experience severe toxicity during the induction phase were given additional doses of ipilimumab (10 mg/kg every 12 weeks). The median OS dura-tion of the patients who received dacarbazine plus ipilimumab (11.2 months) was significant-ly longer than that of the patients who received dacarbazine alone (9.1 months; P<0.001). The 3-year OS rates in the dacarbazine plus ipilim-umab group and the dacarbazine-only group were 20.8% and 12.2%, respectively. The risk for disease progression in the patients who received dacarbazine plus ipilimumab was 24% lower than that for the patients who received dacarbazine alone (P=0.006).

As with other immune-stimulating agents, ipi-limumab induces immune-related adverse events (AEs). In the first Phase III trial, the most common immune-related AEs among those receiving ipili-mumab alone were diarrhea (28%), pruritus (24%), rash (19%), and colitis (8%).17 Grade 3 or 4 diar-rhea and colitis was seen in 5% of the patients.

The addition of dacarbazine to ipilimumab in the second Phase III trial also resulted in notable ele-vations in serum liver enzyme levels. Of the 247 patients receiving the combination, elevations in alanine aminotransferase (ALT) and aspartate ami-notransferase (AST) were observed in 33% and 27% of the patients, respectively.6 Grade 3 or 4 ele-vations in ALT and AST were seen in 21% and 17%, respectively. Endocrine immune-related AEs such as hypothyroidism, hypopituitarism, and adrenal insufficiency were observed but were uncommon.

Patients who develop grade 2 diarrhea should be considered for treatment with oral steroids such as budesonide, whereas patients with grade 3 and 4 diarrhea should discontinue ipilimumab and receive high-dose systemic corticosteroids until improvement.18 Infliximab, an anti-tumor necrosis factor-α antibody, has been used withsome success to treat patients who are unrespon-sive to high-dose steroids. The use of high-dose IV corticosteroids also has been suggested for grade 3 or 4 elevations in serum liver enzyme levels and endocrinopathies.

VemurafenibThe Ras/Raf/MEK/extracellular signal-regulated

kinase (ERK) pathway is a key pathway for cell proliferation, particularly in cancer cells (Figure).19

In 2002, Davies et al reported that nearly 60% of melanomas harbor a mutation in BRAF, whichFcodes for a serine-threonine protein kinase involved in the Ras/Raf/MEK/ERK pathway.20 Most

Figure. Commonly activated signal transduction pathways in melanoma.ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin

Table 1. Clinical Data From Positive Phase III Studies of Melanoma

Trial and Regimen NTreatment Setting

Primary End Point Results

Hazard Ratio (95% CI) P Value

NCT00094653

136 Second-line OS, 6.4 mo Reference

Ipilimumab 137 OS, 10.1 mo 0.66 (0.51-0.87) 0.003

Ipilimumab + gp100 vaccine 403 OS, 10.0 mo 0.68 (0.55-0.85) <0.001

NCT00324155

Dacarbazine + placebo 252 First-line OS, 9.1 mo Reference

Dacarbazine + ipilimumab 250 OS, 11.2 mo 0.72 (0.59-0.87) <0.001

NCT01006980

Dacarbazine 338 First-line;V600E BRAF mutation

OSa Reference

Vemurafenib 337 OSa 0.37 (0.26-0.55) <0.001

Dacarbazine 338 PFS, 1.6 mo Reference

Vemurafenib 337 PFS, 5.3 mo 0.26 (0.20-0.33) <0.001

NCT01227889 (BREAK-3)

Dacarbazine 63 First-line;V600E BRAF mutation

PFS, 2.7 mo Reference

Dabrafenib 187 PFS, 5.1 mo 0.30 (0.18-0.51) <0.0001

NCT01245062 (METRIC)

Chemotherapyb 108 ≤1 prior systemic therapy; V600E BRAF mutation

PFS, 1.5 mo Reference

Trametinib 214 PFS, 4.8 mo 0.45 (0.33-0.63) <0.001

CI, confidence interval; gp100, glycoprotein 100; OS, overall survival; PFS, progression-free survival

a Inadequate number of patients in follow-up to provide reliable estimates of the survival curveb Dacarbazine or paclitaxel Dacarbazine or paclitaxel

Text continues on page 18

AKT

PI3K

p70S6K

mTOR

IF4E

PTEN

Cell membranereceptor

Transcriptionfactors

Cyclin D1 MMP-2

Tumor cell survival, proliferation, invasion

Nucleus

ERK 1/2

Raf

Ras

MEK 1/2


Educational Review

Clinical 17

BRAF mutations are the result of a single nucleo-Ftide substitution in which valine is replaced by glu-tamic acid at codon 600 (V600E) of exon 15, EEleading to the constitutive activation of the MEK protein and ERKs, which are essential to melano-ma cell proliferation. Melanoma cells with the BRAF mutation do not require Ras activation to Fproliferate, indicating that the BRAF mutation is a Fdriving force behind melanoma cell growth.

To inhibit the Raf/MEK/ERK pathway, research-ers investigated sorafenib (Nexavar, Bayer), an inhibitor of multiple kinases, including BRAF, CRAF, and vascular endothelial growth fac-tor receptor (VEGFR). However, 2 Phase II tri-als of sorafenib at a dose of 400 mg twice daily revealed that the drug elicited little or no response in patients with metastatic melanoma; additionally, the presence of the BRAF mutation was not corre-Flated with response.21,22 Similarly, 2 large random-ized Phase III trials revealed that the addition of sorafenib to front- or second-line carboplatin or paclitaxel yielded no additional clinical benefit in patients with metastatic melanoma.23,24

Despite the underwhelming results with sorafenib, researchers used scaffold-based drug design methods to develop increasingly selec-tive inhibitors of the mutated Raf kinase. One of these new drugs, PLX4032 (later named vemu-rafenib [Zelboraf, Roche]), was found to have a high affinity for the mutant BRAF kinase.25 A first-in-human Phase I trial of oral vemurafenib enrolled 55 patients and found the maximum tolerated dose (MTD) of the drug to be 960 mg twice a day.26 Thirty-two patients with metastatic melano-ma harboring a BRAF mutation were then enrolled Fin the dose-extension cohort and received vemu-rafenib at a dose of 960 mg twice a day. Of these 32 patients, 26 had a partial or complete response (CR), for an overall response rate (ORR) of 81% with a confirmed response rate of 56% per Response Evaluation Criteria in Solid Tumors (RECIST).

Subsequently, a large Phase II study of vemu-rafenib was conducted in 132 previously treated patients who had metastatic melanoma harbor-ing a V600E BRAF mutation.F 27 The ORR, which was validated by an independent review com-mittee, was 53%, with a median PFS duration of 6.8 months, thus confirming the promising results of the Phase I study.

A concurrent, large multicenter randomized Phase III trial was then conducted to compare the clinical benefit of vemurafenib with that of dacar-bazine in treatment-naive patients with metastat-ic melanoma harboring a V600E BRAF mutation F(Table 1).5 Six hundred seventy-five patients were randomized to receive either vemurafenib or dacarbazine, with the primary end points being OS and PFS. At the time of the interim analysis, the hazard ratio for death in the vemurafenib group was 0.37 (P<0.001), and the estimated median PFS duration of patients in the vemurafenib arm (5.3 months) was significantly longer than that of patients in the dacarbazine arm (1.6 months; HR, 0.26; P<0.001). The study was stopped at the time of the interim analysis so that patients in the dacarbazine arm could receive vemurafenib.

Overall, patients in the Phase III trial tolerated vemurafenib fairly well.5 The most common AEs were arthralgias, fatigue, and cutaneous events. Twelve percent of patients experienced grade 2

or 3 photosensitivity reactions, but the use of sunblock helped prevent the blistering typical-ly observed in grade 3 reactions. Eighteen per-cent of patients developed either cutaneous squamous cell carcinomas (SqCC) or keratoac-anthomas; fortunately, these were all treated by simple excision with no further complications or evidence of SqCC in other organs.

These SqCCs could have been the result of the paradoxical activation of the Ras/Raf/MEK/ERK pathway in premalignant skin lesions that lack a BRAF mutation.28,29 Poulikakos et al demonstrat-ed that the binding of vemurafenib to BRAF, which forms a dimer with another Raf kinase, actual-ly leads to transactivation of adenosine triphos-phate (ATP)-bound Raf, causing the downstream activation of MEK and ERK in wild-type BRAF cells.30 Many vemurafenib-induced SqCCs harbor a mutation in Ras that ultimately becomes activat-ed when vemurafenib binds to wild-type BRAF.28,29

Based on the statistically significant improve-ment in both OS and PFS and the acceptable safety profile, in summer 2011 the FDA approved vemurafenib for the treatment of metastatic mel-anoma harboring a V600E BRAF mutation. How-Fever, despite the high response rate, a majority of patients will have disease progression within 1 year, and a long-term clinical benefit is expected only in a small subset of patients. Therefore, more effec-tive therapeutic strategies are urgently needed.

Emerging Targeted Therapies

Selective Raf Inhibitors

The successful development of vemurafenib has generated great interest in the clinical eval-uation of selective Raf inhibitors in patients with metastatic melanoma harboring a BRAF mutation.One such agent, dabrafenib (GSK2118436, Glaxo-SmithKline) is an orally available, highly potent ATP-competitive inhibitor of BRAF.31 In a PhaseI/II study in patients with advanced solid tumors, dabrafenib was well tolerated, and the MTD was not reached.32 Dabrafenib inhibited the phosphor-ylation of ERK in a dose-dependent manner, and based on the pharmacokinetics and pharmacody-namics of the drug and its early clinical activity in the Phase I study, investigators recommended a dose of 150 mg twice daily for further studies. Of the 16 patients in the study who had metastatic

melanoma harboring a V600 BRAF mutation and Freceived at least 150 mg of dabrafenib twice daily, 10 (63%) had a partial response. Interestingly, of the 10 patients in the study who had active brain metastases measuring at least 3 mm at baseline, 7 also had a clinical response in the brain lesions.33

Subsequently, a Phase II study of dabrafenib enrolled 76 patients who had metastatic melano-ma harboring a V600E/K BRAF mutation.F 34 Ofthese 76 patients, 45 (59%) had a confirmed response to dabrafenib, and the median PFS dura-tion was 27.4 weeks. The common AEs associated with dabrafenib were arthralgia, pyrexia, fatigue, hyperkeratosis, and SqCC of the skin.

Recently, a Phase III study (NCT01227889) was conducted to compare the PFS associated with dabrafenib to that associated with dacarbazine in treatment-naive patients with V600E BRAF-mutated melanoma. The results demonstrated that patients who received dabrafenib had a signifi-cantly longer median PFS over dacarbazine (6.7 vs. 2.9 months, respectively; HR, 0.35, 95% confi-dence interval [CI], 0.20-0.61).35 The ORR also wassuperior in the dabrafenib arm (50% vs. 6%). The OS data are not available because the study was not designed to compare the OS, and the follow-up thus far is too short for OS evaluation.

Another promising selective Raf inhibitor is LGX818 (Novartis). The results of a Phase I trial of the drug (NCT01436656) will be available shortly.

MEK Inhibitors

Another approach to treating metastatic mel-anoma is to inhibit the mitogen-activated protein (MAP) kinase pathway at the level downstreamof BRAF kinase. This pathway is commonly acti-vated in melanoma and is induced not only by mutated BRAF, but also by kinase-activating NRAS mutations or other upstream aberrations, Ssuch as receptor kinase phosphorylation. In this signal transduction pathway, the MAP kinase kinase (MEK) protein is the direct substrate of activated BRAF kinase. Therefore, targeting the MEK protein can inhibit the MAP kinase pathway.

The results of clinical trials of first-generation MEK inhibitors were disappointing. For exam-ple, CI-1040 (Pfizer) and PD0325901 (Pfizer) had poor clinical activity and caused significant AEs, including retinal vein occlusion, which resulted

Table 2. Ongoing Phase III Clinical Trials for Metastatic Melanoma

Trial and RegimenTreatment Setting

Mutation Criteria

Primary End Point N

NCT01584648

Dabrafenib (GSK2118436) plus trametinib (GSK1120212) versus dacarbazine

First-line V600E BRAF mutation

PFS 340

NCT01597908

Dabrafenib plus trametinib versus vemurafenib (Zelboraf, Roche)

First-line V600E/K BRAF mutation

OS 694

NCT01280565

Masitinib versus dacarbazine First-line C-Kit (juxtamembrane)

OS 200

NCT01515189

Ipilimumab (3 mg/kg) versus ipilimumab (10 mg/kg)

First-line Any OS 700

OS, overall survival; PFS, progression-free survival


Text continued from page 17

Educational Review


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MCPPN2241.indd 1 6/14/12 12:58 PM

in the discontinuation of their devel-opment.36,37 Selumetinib (AZD6244, AstraZeneca) is an orally available, highly selective, allosteric inhibitor of MEK1/2. Although in vitro stud-ies revealed that melanoma cell lines containing a BRAF mutation Fwere particularly sensitive to selu-metinib,38,39 a randomized Phase II study showed that the drug had no clinical benefit over temozolomide in chemotherapy-naive patients with metastatic melanoma.40 The

differences in the median PFS dura-tion (78 vs 80 days) and ORR (5.8%vs 9.4%) between the patients whoreceived selumetinib and those whoreceived temozolomide, respectively,were not statistically significant, andthe response rates among patientswith melanoma containing a BRAFmutation in each group were boththe same, at 11%.

Clinical outcomes with the next-generation, hydrogen sulfate (Hyd-sulfate) formulation of selumetinib,which has better oral bioavailability

than does the original crystalline formulation, are more promising. A Phase I dose-finding study revealed the MTD of Hyd-sulfate selumetinib to be 75 mg twice daily.41 In a sep-arate Phase I study of combination regimens containing Hyd-sulfate selu-metinib, patients with metastatic mel-anoma with a BRAF mutation had a Fhigher clinical response rate and lon-ger median time to progression than did those without a BRAF muta-tion, suggesting that BRAF muta-Ftion is a positive predictive factor for

Hyd-sulfate selumetinib.42 A random-ized Phase II study comparing dacar-bazine plus Hyd-sulfate selumetinib with dacarbazine alone in treatment-naive patients with BRAF-mutated melanoma (NCT00936221) recent-ly completed patient accrual, and the results of this study are highly anticipated.

Another potent, highly selective, non–ATP-competitive MEK1/2 inhibi-tor is trametinib (GSK1120212, Glaxo-SmithKline). Although a Phase I study revealed the MTD of trametinib to be 3 mg per day, 2 mg per day was cho-sen as the recommended dose for future studies on the basis of pharma-cokinetic, clinical activity, and safety data.43 The results of a recent Phase II study of trametinib (2 mg/d) in 97 previously treated patients with met-astatic melanoma harboring a V600 BRAF mutation are encouraging.F 44

In this study, of the 57 patients who had not been previously treated with a BRAF inhibitor (of whom 81% had a V600E BRAF mutation and 75% had FM1c disease), 14 (25%) had a con-firmed response, and the median PFS duration was 4 months (CI, 3.5-5.6 months). However, of the 40 patients who had previously received a BRAF inhibitor, none had a confirmed clin-ical response, and the median PFS duration was 1.8 months (CI, 1.8-2.0 months). The marked differences in clinical response and PFS between the 2 groups suggest that the mech-anisms of resistance to BRAF inhibi-tors also might confer resistance to MEK inhibitors. The results of an open-label randomized Phase III study (NCT01245062) comparing the PFS associated with trametinib with those associated with dacar-bazine or paclitaxel in patients with metastatic melanoma harboring a V600 BRAF mutation was recent-Fly announced (Table 1, page 17). The trametinib arm had a statistically sig-nificant improvement in all 3 clinical parameters (RR, PFS and OS.)45 The median PFS was 4.8 months for the trametinib arm compared with 1.4 months for the chemotherapy arm (HR, 0.44; CI, 0.31-0.64; P<0.0001). In addition, a HR for OS was 0.54 (CI, 0.32-0.92) with a P value of 0.0136, Pfavoring the trametinib arm.

Other MEK inhibitors in the early phases of clinical investigation include AS703026 (EMD/Merck Serono), E6201 (Eisai), MEK162 (Novartis), and GDC-0973 (Genentech).

The common AEs of MEK inhibi-tors include skin rash, diarrhea, nau-sea, vomiting, peripheral edema, and fatigue.36,37,40,41,43,44 Visual disturbanc-es, such as blurry vision or flash-ing lights, are common but generally mild. Serious ocular toxicity, including


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Educational Review


central serous retinopathy and reti-nal vein occlusion, is uncommon. The decreased left ventricular ejection fraction associated with the use of MEK inhibitors is mostly asymptomat-ic and is reversible upon discontinua-tion of the drugs.

Combination Strategies Using Targeted Therapies

Despite the high response rates observed with Raf inhibitors and the promising clinical activity of MEK inhibitors in patients with advanced melanoma harboring a BRAF muta-Ftion, the durations of response to these drugs are relatively short because of acquired drug resistance. Recent studies have elucidated a number of mechanisms of resistance to these drugs, including acquisi-tion of activating NRAS mutations,46

acquisition of activating MEK muta-tions,47 upregulation of upstream receptor kinases,48 upregulation of CRAF kinase,49 induction of splicing variants of BRAF kinase,50 increased Cot expression,51 and activation of PI3K/AKT signaling pathways.52,53

Loss of BRAF mutations and the Fdevelopment of secondary mutations to the drug-binding domain of BRAF kinase have not been observed at the time of drug resistance, however.46,48

A recent study found that although vemurafenib universally inhibited the phosphorylation of tumoral ERK1/2 protein within 14 days of treatment, the phosphorylated-ERK1/2 was re-upregulated at the time of disease progression in a subset of patients.54

This finding suggests that in at least some patients, the reactivation of the MAP kinase pathway is associat-ed with resistance to the Raf inhibi-tors and can, at least partially, bypass the inhibition of the BRAF mutations. FIn vitro studies have shown that the addition of a MEK inhibitor can delay the development of drug resistance to a selective Raf inhibitor.47

On the basis of these encouraging findings, a Phase I study of dabrafenib plus trametinib (NCT01072175) was conducted in patients with metastatic melanoma. The clinical data generated from the study’s interim analysis are promising.55,56 Given at the recom-mended doses for a Phase II study, the combination of dabrafenib (150 mg twice daily) and trametinib (1-2 mg per day) was well tolerated, with mild AEs, the most common of which were pyrexia, chills, nausea, diarrhea, and fatigue.55 Skin toxicity, including the development of cutaneous SqCC, occurred much less commonly than was anticipated based on the safety data of dabrafenib treatment alone, suggesting that treatment with the selective Raf inhibitor paradoxically

activated MAP kinase in the normal skin, and the concurrent treatment with MEK eliminated this paradoxical MAP kinase activation. Of the 65 patients who had metastatic melano-ma containing a V600E/K/D BRAFmutation and who had never received a BRAF inhibitor, 43 (66%) had objec-tive responses, including 5 (8%) CRs.55

Of the 26 patients who previously had been treated with a selective Raf inhib-itor, 5 (19%) had partial responses.56

The updated results of the Phase II study showed that median PFS was

10.8 months among 24 BRAF inhibitor-naive patients who received 150 mg of dabrafenib twice daily and 2 mg of tra-metinib once daily.57

KIT Inhibitors

Preclinical findings demonstrating the essential role of stem cell factor and its receptor, KIT tyrosine kinase, in the proliferation and survival of melanocyte precursors,58,59 and KIT’s frequent expression in melanoma specimens59,60 led investigators to conduct 3 studies evaluating the use

of imatinib (Gleevec, Novartis) in patients with metastatic melanoma in the early 2000s.61-63 Imatinib had min-imal clinical activity, with only 1 of 63 patients (who had not been selected on the basis of genomic biomarkers) responding to the drug.

Interest in KIT-targeted therapy in melanoma was renewed when Cur-tin et al showed that KIT mutation Tand/or amplification is more com-mon in certain subtypes of melano-ma than in others.64 In their analysis


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Educational Review

Clinical 21

of 102 primary melanomas, they used a comparative genomic hybridization assay and found KIT mutations and/or Tincreased copy numbers of KIT in 36% Tof acral lentiginous melanomas, 39% of mucosal melanomas, and 28% of melanomas that developed in chron-ically sun-damaged skin. Following this novel discovery, a number of case reports have emerged showing that KIT inhibitors have clinical benefit in patients who have melanoma harbor-ing KIT mutations.T 65-68 Additionally,

the interim analysis of a Phase II study of imatinib in patients with advanced acral lentiginous melanoma, mucosal melanoma, or melanoma in chronic sun-damaged skin revealed that 5 of 10 patients with melanoma harboring a KIT mutation had a clinical response Tto the drug.69 However, none of 10 patients with KIT amplification with-Tout a mutation had a response.

In another Phase II study of ima-tinib in 43 patients with metastatic melanoma harboring a KIT mutationTor amplification, 10 (23%) patients had

an overall clinical response, and 9 of the 10 responders had a KIT mutation Tin exon 11 or 13.70 In a separate Phase II study of imatinib in a similar pop-ulation, 4 (16%) of 25 patients had a durable clinical response, including 2 patients who had CRs.71 The response rate among patients who had muta-tions affecting recurrent hotspots of the KIT gene or a higher T KIT mutant-Tto-wild-type allele ratio (>1) was 40%, whereas the response rate among patients who did not have these fea-tures was 0% (P=0.05), suggesting

that the presence of a functional-ly relevant KIT mutation is required Tfor imatinib or other KIT inhibitors to have clinical benefit.

Emerging Immunotherapies

Anti-PD1 Antibody

Like CTLA-4, programmed death 1 (PD-1) is a member of the CD28 family. PD-1 is expressed in activated T cells, memory T cells, and regulato-ry T cells and is involved in T-cell reg-ulation. Upon binding to its ligands, PD-L1 and PD-L2 (which are highly expressed in tumor cells and the anti-gen-presenting cells found in tumors), PD1 suppresses T-cell effector func-tion. Tumoral PD-L1 expression has been associated with negative prog-nosis in cancer patients.72,73

MDX-1106 (Bristol-Myers Squibb), a fully human immunoglobulin G4 monoclonal antibody against PD-1, can interrupt the binding of PD-1 with its ligands, thereby reactivating T-cell function.74 In a Phase I dose-escalat-ing study evaluating a single dose of the drug (with 2 additional doses every 4 weeks allowed in patients in whom continued clinical benefit was observed), MDX-1106 was well toler-ated with only one serious AE (coli-tis).75 Of the 39 patients in the study, 3 patients, including one with metastat-ic melanoma, had a clinical response to MDX-1106.

Another Phase I study evaluated the safety profile of a biweekly dos-ing schedule of MDX-1106 in patients with refractory metastatic non-small cell lung cancer, renal cell carcinoma, melanoma, or prostate cancer.76 The MTD of the drug was not reached up to a dose of 10 mg/kg every 2 weeks. Common AEs included fatigue, nau-sea, diarrhea, xerostomia, and pruritus, but grade 3 or 4 AEs were uncommon. In the preliminary response evalua-tion, 6 (38%) of 16 patients had objec-tive responses; among these patients, 3 patients with metastatic melano-ma had a partial response. The clinical investigation of MDX-1106 is ongoing.

Adoptive T-cell Therapy

In the mid-1980s, Rosenberg et al found that tumor-infiltrating lym-phocytes (TILs) isolated from murine sarcomas and colon adenocarcino-mas that had been transplanted into syngeneic mice could be expanded with IL-2 in vitro. When infused back into the donor mice, the TILs could mediate the regression of metastat-ic tumors.77 They later reported the regression of metastatic melanoma lesions in 11 of 20 patients who were treated with the adoptive transfer of TILs and IL-2 infusion following a



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single dose of cyclophosphamide.78

Other researchers found that when the adoptive transfer of TILs and IL-2infusion were preceded by a 7-day regimen of cyclophosphamide andfludarabine, which depleted the num-ber of endogenous regulatory cellsand lymphocytes competing with thetransferred TILs for growth-promoting homeostatic cytokines, 6 of 13 patientshad a clinical response.79 Notably, thisapproach resulted in the persistentclonal repopulation of T cells, whichproliferated in vivo and traveled totumor sites in these patients.

In an expanded Phase II study conducted by the same group ofinvestigators, lympho-depleting che-motherapy followed by TIL transferand high-dose IL-2 infusion elicit-ed a response rate of 51% among 35patients with metastatic melano-ma.80 When TIL transfer and IL-2 infu-sion were preceded by myeloablativechemoradiation (lympho-deplet-ing chemotherapy plus 2 or 12 Gy oftotal-body irradiation), clinical activ-ity of the regimen was even better,with response rates of 52% and 72%,respectively.81 Of 20 patients whohad CRs in these trials of adoptive TILtransfer, only 1 patient’s disease hasrelapsed. The other patients continueto have CRs 3 to 7 years following thecompletion of the treatment.81,82

In another study, CD4-positiveT-cell clones targeting the DPB1*0401-restricted epitope of a peptide derived from NY-ESO-1 were isolated from theperipheral blood mononuclear cells ofpatients with metastatic melanomaand expanded in vitro, and the anti-gen-specific CD4-positive T cells wereinfused back into the patient.83 Onepatient had a complete resolution of lung and nodal metastases that was accompanied by the persistent pres-ence of the NY-ESO-1–specific CD4-positive T cells and lasted for at least2 years. This finding suggests that theadoptive transfer of antigen-specificCD4-positive T cells may be used to treat advanced melanoma.

ConclusionAfter a long drought in the devel-

opment of successful therapies, recent advances in targeted therapy and immunotherapy have set a newstandard of treatment for metastaticmelanoma. However, the arrival of ipi-limumab and vemurafenib in the clin-ic has generated more questions andchallenges. For example, it is not clearwhich of these agents, ipilimumab orvemurafenib, should be offered first in patients with metastatic disease,especially in those with limited orslowly progressing metastatic lesions;in addition, the optimal sequencing

of high-dose IL-2 with these agentsremains unknown. Whether a Rafinhibitor should be added to sub-sequent therapy following the fail-ure of BRAF inhibition is also unclear.The optimal combination of target-ed drugs and/or immunotherapeu-tic agents will need to be determinedto maximize their clinical benefit inpatients with metastatic melanoma. We hope that these important ques-tions soon will be addressed withrationally designed clinical studies.

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81. Dudley ME, Yang JC, Sherry R, et al.Adoptive cell therapy for patients withmetastatic melanoma: evaluation of intensivemyeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233-5239, PMID: 18809613.

82. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive celltransfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer.2008;8(4):299-308, PMID: 18354418.

83. Hunder NN, Wallen H, Cao J, HendricksDW, Reilly JZ, Rodmyre R, et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 2008;358(25):2698-2703, PMID: 18565862.

Orlando, Fla.—Adding granulocyte colony-stimulating factor (G-CSF) to the treatment regimen of patients with acute myeloid leukemia (AML) who have undergone consolidation chemo-therapy reduces the incidence of febrileneutropenia–related hospitalizationsand potentially has a positive effect on survival, a new study suggests.

The research adds to the evidence that G-CSF can be an effective adjuncttherapy in patients with the hemato-logic malignancy, according to Amber Bradley, PharmD, who led the study when she was a postgraduate year 2 hematology/oncology pharmacy resi-dent at the University of North Carolina (UNC) Lineberger Comprehensive Can-cer Center, in Chapel Hill. Dr Bradley presented the results at the Hematol-ogy/Oncology Pharmacy Association annual meeting (poster pp3).

Study DetailsIn the UNC study, the investigators

retrospectively reviewed six years of electronic health records and identi-fied patients who were diagnosed with AML and who received consolidation therapy with high-dose cytarabine (HiDAC). Patients were divided into two groups: those who received G-CSF in the first cycle (n=35) and those who did not (n=43). G-CSF reduced the incidence of febrile neutropenia admissions after cycle 1 of HiDAC: The adverse reaction occurred in five (14%) of the patients in the G-CSF group versus 16 (37%) patients not given the growth factor therapy (P(( =0.039), Dr. Bradley reported. However, there was no statistically significant difference found for admissions after cycles 2 through 4. The difference found in cycle 1 could not be attributed to a dif-

ference in antimicrobial prophylaxis in the two groups, the investigators noted.

The researchers added that a vari-ety of factors could have confound-ed the results seen after cycles 2 to 4, including crossover (n=22), where some patients received G-CSF in cycle 1 but not in subsequent cycles, and vice versa. The discrepancy also may have been due to the fact that “our numbers were not sufficiently powered at that point [in the study],” said Dr. Bradley, who is now clinical assistant professor at the University of Georgia College of Pharmacy, in Augusta. “There is a potential that it could have been statis-tically significant and we didn’t capture that, based on the lower numbers of patients in cycles 2 to 4.”

The secondary end point of study, overall survival (OS), favored patients who received G-CSF during the first

cycle (P(( =0.014), although specific OS data were not included in the poster. In an ongoing analysis examining fac-tors that could have confounded these survival results, more patients who received G-CSF with the first cycle went on to receive a stem cell transplant, Dr. Bradley noted, adding that prospective studies are needed to further evaluate these findings.

A History of G-CSF Efficacy

The UNC study is not the first to show that G-CSF can be an effective add-on therapy for patients with AML. In 2000, a randomized trial of 194 patients with AML (J Clin Oncol(( 2000;18:780-l787) showed that those given G-CSF after consolidation therapy with HiDAC plus mitoxantrone had “dramatically” lower rates of neutropenia compared

Should G-CSF Be Standard Procedure After AML Consolidation?


• see CONSOLIDATION, page 45


Educational Review

Clinical 25

Orlando, Fla.—Providing growth fac-tor support with pegfilgrastim (Neu-lasta, Amgen) on the same day as caba-zitaxel (Jevtana, Sanofi) was safe andconvenient for patients in a study pre-sented at the annual meeting of theHematology/Oncology Pharmacy Asso-ciation (HOPA).

With “same-day pegfilgrastim, patientsdon’t have to make another visit to theclinic the next day to receive [it, and]they don’t have to pay a copay to self-administer it at home,” said AdrienneSevin, PharmD, a postgraduate year 2oncology pharmacy resident at the Uni-versity of Texas MD Anderson CancerCenter, in Houston, who led the study.She said that all patients at MD Andersonare being offered same-day pegfilgrastimwith cabazitaxel. “This is our standardprocedure now.”

It is not standard procedure every-where, however. The National Compre-hensive Cancer Network guidelines rec-ommend administration of granulocytecolony-stimulating factor (G-CSF) 24 to72 hours after a patient completes che-

motherapy. Although there have been mixed results in studies of patients with various cancers—some showing that administering G-CSF on the same day as chemotherapy is safe and others showing that it increases the risk for febrile neu-tropenia (J Oncol Pract 2010;6:133-140; tJ Support Oncol 2009;7:225-228)—there lare few studies that provide information on same-day G-CSF in patients with prostate cancer.

Furthermore, the high incidence of neutropenia observed in the TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated with a Taxotere-Containing Regimen) trial of cabazitaxel has led to some additional reluctance among clinicians to give growth factor on the same day as this agent. In TROPIC, patients who received cabazitaxel had a roughly 20% greater incidence of grade 3/4 neutropenia, and the product label-ing carries a black box warning that neutropenic deaths have been reported among patients treated with the agent. “Because of the high incidence of neu-

tropenia that was found in the TROPIC trial with cabazitaxel, I think people are kind of scared to … provide same-day pegfilgrastim,” Dr. Sevin said.

At MD Anderson, however, clinicians have not been observing high rates of neutropenia in their patients who receive cabazitaxel, and thus clinicians chose to offer same-day pegfilgrastim because of the increased convenience for patients.

Study Results Detailed

In the study presented at HOPA, the researchers conducted a retrospec-tive chart review of all patients who received pegfilgrastim after cabazitaxel for the treatment of metastatic castrate-recurrent prostate cancer at MD Ander-son between July 17, 2010 and Oct. 3, 2011. Twenty-nine patients received the growth factor less than 24 hours after receiving cabazitaxel and three patients received pegfilgrastim 25 or more hours after receiving cabazitaxel.

Only one patient had febrile neutrope-nia after receiving same-day pegfilgras-tim. This resulted in a dose reduction and

delayed treatment. However, that patienthad been very heavily pretreated. “He had received nine cycles of docetaxel, aswell as other chemotherapy, and radia-tion, and he had a performance score of 3, so we think a lot of that contributed tohim having a worse response,” Dr. Sevin said. “Because it was only one out of 29 patients, we plan on continuing same-day pegfilgrastim with cabazitaxel.”

Commenting on the study, William Figg Sr., PharmD, senior clinician and head of the molecular pharmacology section at the National Cancer Insti-tute’s Center for Cancer Research, in Bethesda, Md., said a prospective, randomized trial is needed before any changes are made to practice. “These data are very encouraging; however, they are not mature enough to justify a change in practice,” Dr. Figg said. “The numbers were small and the study was retrospective.”

—Kate O’Rourke

Drs. Sevin and Figg reported norelevant fi nancial confl icts of interest.

Same-Day Pegfilgrastim and Cabazitaxel Urged

Orlando, Fla.—Metronomic chemo-therapy with oral cyclophosphamideand methotrexate provides clinical ben-efit in 10% of patients and may offer analternative for those who might not beable to tolerate more aggressive therapy due to residual toxicity from previoustreatments, a new study found.

The regimen, which employs low dos-es given in a frequent or continuousschedule, “could be a potential optionfor patients who have poor performancestatus, are minimally symptomatic orthose who prefer an oral therapy,” saidLauren Radvansky, PharmD, BCPS, a postgraduate year 2 oncology pharmacy resident at the University of Texas MDAnderson Cancer Center, in Houston,who presented the results at the annualmeeting of the Hematology/Oncology Pharmacy Association (poster T14).

In the study, investigators conducteda retrospective chart review of patientswith metastatic breast cancer (MBC)who received metronomic cyclophos-phamide and methotrexate at MDAnderson from Jan. 1, 2001 to Aug. 1,2011. The majority of patients receiveda standard methotrexate oral dose—2.5mg twice daily on day 1 and day 2 every week. The cyclophosphamide dose, incontrast, at 50 mg daily, was less thanconventional dosing. In the 29 patientswho received the therapy, approximate-ly 50% of patients had at least two

sites of metastatic disease and 97% of patients had progressive disease at study entry. Patients had received a median of five lines of prior chemotherapy, with a range of two to 10 lines of therapy.

The median time to treatment failure was six weeks. Overall, the clinical benefit rate—defined as no progression of disease at 24 weeks, as documented by the clinical oncologist—was 10%, Dr. Radvansky reported. In patients who had received four or fewer lines of prior chemotherapy, the clinical ben-efit rate was 23%.

The most common non-hematologic toxicity was nausea/vomiting (44%). Anemia was the most common hema-tologic toxicity, with all-grade anemia occurring in 83% and grade 3/4 ane-mia occurring in 24% of patients. Other grade 3/4 toxicities included leukopenia (17%), neutropenia (3%) and thrombo-cytopenia (14%).

Before this study, Dr. Radvansky said, two single-arm Phase II stud-ies had been published evaluating low-dose, oral cyclophosphamide and methotrexate in MBC (J Egypt Natl ((Canc Inst 2008;20:134-140; Ann Oncol

2002;13:73-80). Both found an overall clinical benefit of 31%, but the role of this metronomic chemotherapy is not well established in MBC.

Dr. Radvansky said her small, ret-rospective study provides further evi-dence that metronomic chemotherapy with cyclophosphamide and methotrex-ate is a “potential therapeutic option for heavily pretreated MBC patients. In metastatic breast cancer, the goal is palliative, so you do not want patients to experience severe toxicities [while you are trying] to control their disease because this can lead to a decreased quality of life.”

Not Enough Strength In Numbers?

Robert Livingston, MD, a professor of medicine and hematologic oncology at the University of Arizona Cancer Center, in Tucson, does not think the regimen has enough activity to be used. “I am afraid the bottom line is that the [regimen] has insufficient activity to be widely adopted,” he said. “It is impor-tant to understand that ‘clinical benefit’ is a vague, subjective term.” He said a

more useful definition of benefit wouldbe objective response rate or time toprogressive disease.

Dr. Livingston added that the Uni-versity of Arizona Cancer Center doesnot use this metronomic regimen, butresearchers at his institution are “inter-ested in a metronomic approach to chemotherapy, with hope that other metronomic regimens of chemo, per-haps combined with anti-angiogenic agents, may be more effective.”

—Kate O’Rourke

Drs. Radvansky and Livingston reported no relevant fi nancial confl icts of interest.

Metronomic Chemo Shows Modest Benefit in Metastatic Breast Cancer‘I am afraid the bottom line is that the [regimen] has

insufficient activity to be widely adopted.’

—Robert Livingston, MD


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Important Safety InformationLevetiracetam in Sodium Chloride Injection is an antiepileptic drug indicated when oral administration is temporarily not feasible in adults (16 years and older) with: partial onset seizures; myoclonic seizures in patients with juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures.

Levetiracetam should be gradually withdrawn to minimize the potential of increased seizure frequency.

Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Levetiracetam in Sodium Chloride Injection causes neuropsychiatric reactions including somnolence and fatigue, muscle coordination diffi culties and behavioral abnormalities as well as hematological abnormalities. The most common adverse reactions observed with Levetiracetam were somnolence, weakness, infection and dizziness. Important behavioral adverse reactions include hallucinations, delusions, and non-psychotic mood disorders including suicide ideation, aggression, anger, apathy, conduct disorder, irritability, depression, nervousness, anxiety and emotional lability.

Dosing must be individualized according to seizure type, patient’s renal function status and therapy objective. Based on animal data, Levetiracetam may cause fetal harm and therefore should be used during pregnancy after consideration of the potential benefi t-risk ratio. Levetiracetam should be gradually withdrawn to minimize the potential of increased seizure frequency.

Please see following pages for accompanying full Prescribing Information.

MCPPN2236.indd 1 6/11/12 6:00 PM

Brief Summary of Risk Information for LEVETIRACETAM IN SODIUM CHLORIDE INJECTION, for intravenous useWARNINGS AND PRECAUTIONSNeuropsychiatric Adverse Reactions Partial Onset Seizures: Levetiracetam can cause central nervous system adverse reactions: 1) somnolence and fatigue: levetiracetam 14.8%, placebo 8.4%. In a study without titration, 45% reported somnolence from 4000 mg/day; considered “serious” by 0.3% levetiracetam, versus 0% of placebo patients; discontinuation: 3% levetiracetam, versus 0.7% of placebo patients; dose reduction: 1.4% levetiracetam versus 0.9% placebo; 0.3 % levetiracetam patients were hospitalized for somnolence. Asthenia: levetiracetam 14.7%, versus 9.1% placebo; treatment discontinuation: 0.8% versus 0.5% placebo; dose reduction: 0.5% versus 0.2% of placebo; 2) coordination difficulties (ataxia, abnormal gait, or incoordination): 3.4% levetiracetam versus 1.6% placebo; discontinuation from ataxia: 0.4% levetiracetam versus 0% placebo; dose reduction: 0.7% levetiracetam versus 0.2% placebo; one patient hospitalized from worsening of pre-existing ataxia. Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment. 3) behavioral abnormalities (psychotic symptoms and other behavioral and mood symptoms): Psychotic symptoms: 5 (0.7%) levetiracetam versus 1 (0.2%) placebo. Two (0.3%) levetiracetam patients hospitalized and treatment discontinued. Both developed in the first treatment week, resolved in 1 to 2 weeks following discontinuation. Two events of hallucinations, occurred after 1-5 months and resolved within 2-7 days while remaining on treatment. One psychotic depression occurring within a month, resolved within 45 days while treatment continued. Other behavioral symptoms (aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.): 13.3% levetiracetam versus 6.2% placebo; approximately half reported within the first 4 weeks; treatment discontinued in 1.7% levetiracetam versus 0.2% placebo; dose reduction in 0.8% levetiracetam versus 0.5% placebo. Serious behavioral event causing hospitalization in 0.8% levetiracetam versus 0.2% placebo. Attempted suicide after 4-6 months treatment (one completed suicide) in 4 (0.5%) levetiracetam versus 0% placebo. Myoclonic Seizures: Somnolence and behavioral abnormalities: It is expected that the events seen in partial seizure patients would occur in patients with juvenile myoclonic epilepsy (JME). In JME patients JME experiencing myoclonic seizures: somnolence occurred in 11.7% of levetiracetam versus 1.7% of placebo patients (no treatment discontinuations); dose reduction in 1.7% levetiracetam versus 0% of placebo. Non-psychotic behavioral disorders (aggression and irritability): 5% levetiracetam versus 0% placebo. Non-psychotic mood disorders (depressed mood, depression, and mood swings) 6.7% levetiracetam versus 3.3% placebo. Dose reduction or discontinuation: 5.0% of levetiracetam versus 1.7% placebo. Primary Generalized Tonic-Clonic Seizures: Behavioral symptoms appeared to be associated with levetiracetam. Gait disorders and somnolence were described in patients with primary generalized seizures, but no difference between placebo and levetiracetam groups and no appreciable discontinuations. In some patients levetiracetam causes behavioral abnormalities: irritability 6.3% levetiracetam versus 2.4% placebo. In patients with idiopathic generalized epilepsy, non-psychotic behavioral disorders (abnormal behavior, aggression, conduct disorder, and irritability): 11.4% levetiracetam (one discontinued due to aggression) versus 3.6% placebo; non-psychotic mood disorders (anger, apathy, depression, mood altered, mood swings, negativism, suicidal ideation, and tearfulness): 12.7% levetiracetam versus 8.3 placebo. Suicidal ideation in one levetiracetam patient. Delusional behavior in one patient requiring lowering of the levetiracetam dose. In a long-term open label study of various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior, one characterized by auditory hallucinations and suicidal thoughts (led to drugdiscontinuation), the other as worsening of pre-existent schizophrenia (did not lead to discontinuation). Withdrawal Seizures: Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency. Hematologic Abnormalities: Minor, butstatistically significant, decreases in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam patients. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 109/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts. Hepatic Abnormalities: No meaningful changes in mean liver function tests

(LFT) in controlled trials in adult patients; lesser LFT abnormalities were similar in drug and placebo patients in controlled trials (1.4%). No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment. Laboratory Tests: Relatively infrequent abnormalities seen in hematologic parameters and liver function tests. ADVERSE REACTIONS: Most common (≥ 5%) versus placebo include: somnolence, asthenia, infection, and dizziness; important behavioral (< 5%) include depression, nervousness, anxiety, and emotional lability. See full prescribing information for adverse reactions in specific types of seizures and incidence when levetiracetam was added to concurrent AED therapy. Postmarketing Experience: Additional adverse events reported worldwide (alphabetically): abnormal liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression identified in some), thrombocytopenia and weight loss. Alopecia was reported; recovery was observed in majority of cases where levetiracetam was discontinued. Reports of suicidal behavior (completed suicide, suicide attempt and suicidal ideation) with marketed levetiracetam. See Patient Counseling Information. USE IN SPECIFIC POPULATIONS. Pregnancy Category C: No adequate and well-controlled studies in pregnant women. Animal studies: evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy. Discontinuation of antiepileptic treatments may result in disease worsening, which can be harmful to the mother and the fetus. North American Antiepileptic Drug Pregnancy Registry: Physicians are advised to recommend that pregnant levetiracetam patients enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry, toll free number 1-888-233-2334 (must be done by the patients themselves), website http://www.aedpregnancyregistry.org. Effect on Laborand Delivery: unknown. Nursing Mothers: Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Safety in Pediatric Use: Safety and effectiveness below age 16 years have not been established. Geriatric Use: No overall differences in safety were observed compared to younger subjects. Numbers of clinical trial subjects were insufficient to assess effectiveness in the elderly. A study in 16 elderly subjects (age 61-88 years) with oral administration of single dose and multiple twice-daily doses for 10 days showed no pharmacokinetic differences related to age alone. Levetiracetam is substantially excreted by the kidney, with concomitant risk of adverse reactions in patients with impaired renal function. Accordingly, care should be taken in dose selection for the elderly, and it may be useful to monitor renal function. Use in Patients with Impaired Renal Function:Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renalfunction receiving levetiracetam and supplemental doses should be given to patients after dialysis. OVERDOSAGE: Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans: The highest known dose of oral levetiracetam received in the clinical development program was 6000 mg/day. Only drowsiness was observed in the few known cases of overdose in clinical trials. Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma observed in overdoses in postmarketing use. Treatment or Management of Overdose: No specific overdose antidote. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions to maintain airway. General supportive care is indicated including monitoring of vital signs and observation of clinical status. A Certified Poison Control Center should be contacted for up to date information. Hemodialysis: Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. Patient Counseling: Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician as suicide, suicide attempt and suicidal ideation have been reported in patients treated with levetiracetam. To report SUSPECTED ADVERSE REACTIONS, contact Mylan Institutional LLC at 1-877-4RX INFO or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.g /

MCPPN2237.indd 1 6/11/12 6:03 PM

“It’s definitely something we all needto be paying more attention to,” saidIshaq Lat, PharmD, FCCM, clinicalcoordinator of critical care/emergen-cy medicine at University of ChicagoMedical Center. Residual paralysis fromNMBAs “is a potentially serious adverseevent that clearly is contributing toincreased morbidity and mortality. Andthis isn’t just something we need toheed in the post-anesthesia care unit[PACU]; these patients also can presentin the ICU if they have trouble being weaned off a ventilator. So critical carepharmacy can play a major role in alert-ing physicians to this risk and poten-tially intervening to hasten recovery.”

Incidence

Although there are no firm data onthe incidences of NMBA-related resid-ual paralysis and its associated negativeeffects, Dr. Brull offered some estimatesat the 2012 annual meeting of the Inter-national Anesthesia Research Society, inBoston. Of the roughly 40 million surger-ies performed in the United States eachyear, about 60%, or 24 million, involvegeneral anesthesia. If residual paralysisoccurs in as much as 40% of patientswho receive general anesthesia—admit-tedly near the top end of the range—hesaid, that equates to 10 million patients.Critical respiratory events will affect0.8% of those patients, and another 0.1%will require emergent reintubation in thePACU. The total: approximately 100,000cases per year of potential harm “directly related” to residual paralysis.

“I know it doesn’t happen here,” Dr.Brull said facetiously, referring to theanesthesiologists in the audience. “Butit does happen.”

Monitoring Still a Challenge

Part of the problem is that the clini-cal tests for residual paralysis are notespecially accurate. That goes for sub-jective train-of-four monitoring, feel-ing for the contraction of the affectedmuscles, or evaluating patients by theirclinical correlates—how firmly they canbite a tongue depressor, squeeze a handor hold up their heads. “All of the clini-cal tests, all of them, have a very lowpredictive value,” Dr. Brull said. “Eventhough 100% of clinicians use them,99.9% of us are wrong half the time.”

That might be an overstatement,but the condition does seem to have a way of eluding anesthesiologists, saidGlenn Murphy, MD, director of car-diac anesthesia and clinical research atNorthShore University HealthSystem,in Chicago. Dr. Murphy said that thevast majority of clinicians report neverhaving seen a case of the complication,which seems unlikely, he said, given

that “I see it a couple of times a month. If quantitative neuromuscular monitors are used in the PACU, most clinicians would discover that adverse respiratory events related to residual neuromuscu-lar block are not rare events.”

Nor is it a trivial complication safe-ly ignored. “There’s clearly a patient safety issue involved here,” Dr. Murphy said. Adverse events can range from mild airway obstruction to life-threat-ening hypoxemic episodes. Residual paralysis also affects the quality of recovery, said Dr. Murphy, who has conducted studies on the issue. “When we leave patients with residual block, they experience a variety of unpleasant symptoms of muscle weakness during the PACU admission.”

In one such study, Dr. Murphy’s group randomized patients to quantitative neuromuscular monitoring [TOF-Watch SX, Bluestar Enterprises] or no moni-toring in the operating room (Anesthe-((siology 2011;115:946-954). “When we evaluated them for symptoms and signs of muscle weakness, they clearly felt a lot worse” when experiencing residual block, he said.

The available reversal agents are at least partly to blame, he added. Neo-stigmine in particular does not work very well. “In the best of circumstances, it takes an average of 10 to 15 minutes to achieve complete neuromuscular recovery. The problem is we are pulling the endotracheal tube out without dem-onstrating that full recovery of muscle activity has occurred.”

As it happens, the muscles that main-tain airway tone are exquisitely sensitive to blocking agents. When weak, they can obstruct and collapse. Small degrees of residual block appear to be more threat-

ening for patients who are predisposed to airway difficulties—those with sleep apnea and chronic obstructive pulmonary disease, for example. “The majority of patients with a little bit of residual block in the PACU will feel weak, but won’t develop life-threatening problems,” Dr. Murphy said. “But if a patient with mini-mal pulmonary or cardiac reserve is left with incomplete neuromuscular recov-ery, significant adverse respiratory events may occur following tracheal extubation.”

As same-day surgeries become more common and the use of short-acting anesthetics like propofol and desflurane broadens, residual paralysis is likely to become a common postoperative occur-rence, Dr. Murphy added.

More Research in the Works

Aaron Kopman, MD, a retired profes-sor of anesthesiology at New York Medi-cal College, in Valhalla, has been working with Dr. Brull on a journal article about residual paralysis. “While there’s general consensus as to what should be done in terms of monitoring, there is a huge dis-connect between what neuromuscular aficionados suggest and what’s done in the real world,” Dr. Kopman said. “Prob-ably 50% of anesthesiologists don’t use proper monitoring even though it’s avail-able.” Why the practice gap? Although Dr. Kopman said the answer is compli-cated, one issue is that most nerve stimu-lators do not provide quantitative data. “They don’t give you a number you can deal with. Without that, I think people tend not to use the devices.”

The lack of official guidelines doesn’t help, Dr. Kopman added. Another bar-rier is what he said was the fate of articles and editorials on the subject: “They fall into a black hole.”

For Dr. Brull, the solution is clear: “I ... feel very strongly that [the] Ameri-can Society of Anesthesiologists [ASA]should come up with some standards for perioperative monitoring.”

Jeffrey L. Apfelbaum, MD, chair of the ASA’s Committee on Standards and Practice Parameters, said the panel will not be reviewing issues related to resid-ual paralysis this year. “We recognize that it’s an area of interest and it is in queue for consideration.”

For Critical Care Pharmacists, Questions Remain

Dr. Lat said there are several ques-tions related to residual paralysis and NMBAs that still need to be resolved. “In such a heterogenous population as the U.S.—and given the increasing demand for surgical services, such as same-day surgery—we need to pin-point exactly what factors predispose patients to incomplete recovery,” he said. “Is it obesity, where the phar-macokinetics of these agents may be poorly understood? Is it age-related? Or a combination of both?”

Dr. Latt added that economic factors are also in play. “Reducing patient through-put due to residual paralysis reducespotential efficiency (and revenue), while also introducing adverse events into the surgical/anesthesia system,” he said. “Introducing harm events also introduces the potential for lower reimbursementfrom third-party payers if they feel that these events at some point can be avoided with better anesthesia care.”

Tricia A. Meyer, MS, PharmD, an assistant professor of anesthesiology in the Department of Anesthesiol-ogy at Texas A&M University Collegeof Medicine, in Temple, agreed thatmany challenges remain when it comes to addressing the problem of residualparalysis. First and foremost, she not-ed, the condition is usually not top-of-mind for pharmacists “unless they have a practice in the operating room.” And the condition itself is a puzzle.“Although we understand the use andmechanism of reversal agents such as neostigmine, for example, we do not fully appreciate the many variables that can alter the effectiveness of this agent,such as excessive doses of NMBAs or use of these agents in older patients with lower rates of clearance.”

Yet another challenge has to be consid-ered, Dr. Lat pointed out—drug shortages. “Neostigmine may not be 100% effective as a reversal agent, but it has its role—when it’s available,” he said. “Recently,this has not been the easiest drug to pro-cure. So the ongoing drug shortage crisis may exacerbate the problem of hastening patient’s time to recovery.”

—Adam Marcus, with additional reporting by David Bronstein

NEUROMUSCULARcontinued from page 1

‘We need to pinpoint exactly what factors predispose

patients to incomplete recovery.’

—Ishaq Lat, PharmD, FCCM

Tactile evaluation for monitoring patients on NMBAs.


Critical Care

Clinical 31

Houston—Two new studies presented at the annual meeting of the Society of Critical Care Medicine (SCCM) under-score the pitfalls associated with colis-tin therapy at divergent ends of the dosing spectrum. Give too little of the antibiotic, one study suggests, and you risk treatment failure. But at higher doses, the risk for nephrotoxicity can be significant—especially compared with other standard therapies.

A Pharmacokinetics Puzzle

Colistin’s penchant for causing nephro-toxicity is not new. The drug first became widely used in the 1950s and 1960s, but was abandoned after it was linked to significant nephrotoxicity and neurotox-icity and safer antibiotics became avail-able. With the rise of multidrug-resistant strains of bacteria, however, colistin has gained traction as a last-line treatment

option. But there’s a common problem associated with the drug: a knowledge gap regarding its pharmacokinetics, pharmacodynamics and toxicodynamics. That may be part of the reason why there is significant variability in colistin dosing recommendations, according to Giulia Vicari, PharmD, BCPS, a pharmacist at Community Health Network, in India-napolis, who presented one of the studies at SCCM (abstract 38).

Dr. Vicari pointed out, for example, that for a 60-kg person, labeling in the United States recommends 400 to 800 mg per day colistin base activity (CBA), whereas European labeling recom-mends 240 to 480 mg per day CBA. But sticking to U.S. labeling does not eliminate dosing variability. According to the label, the drug should be given in 2.5 to 5 mg/kg of CBA per day in two to four divided doses in order to achieve maximum concentrations of approximately 2 mg/L. However, the standard treatment recommendations also include provisions for drastic dose reductions in cases of renal dysfunction.

To see how this variability plays out in clinical practice, Dr. Vicari and her colleagues retrospectively reviewed the charts of patients with gram-nega-tive bacteremia who were treated with intravenous colistin between January 2005 and August 2010. The investiga-tors included data from 76 patients in their analysis. Microbiological suc-cess was defined as clearance of blood-stream infection or documented clini-cal improvement by day 7.

A total of 52 patients achieved micro-biological success and 24 patients fell into the failure group, reported Dr. Vic-ari, who led the study when she was a postgraduate year 2 (PGY2) resident at the Cleveland Clinic, in Ohio. In a uni-variate analysis, the average colistin dose was significantly higher in the success group than in the failure group (2.90 vs. 1.50 mg/kg per day; P=0.011). The fact

that the average dose in the failure group didn’t even reach the low end of the recommended dose in U.S. labeling was significant, Dr. Vicari noted. “It probably reflects the fact that many of the physi-cians in the study did drastically reduce doses in the patients with renal dysfunc-tion, as allowed in the drug’s labeling for renally impaired patients,” she said.

Colistin dose in milligram-per-kilo-gram per day based on body weight and the Pitt Bacteremia Score were indepen-dent predictors of microbiological out-come at day 7 of colistin therapy (adjust-ed odds ratio, 1.705; P=0.036). Patients who were alive at seven days (n=61) received significantly higher colistin doses (2.7 mg/kg per day) than patients who did not survive to seven days (n=15; 1.5 mg/kg per day; P=0.007). Roughly one-third of patients experienced acute kidney insufficiency as determined by the RIFLE (Risk, Injury, Failure, Loss, ESRD) criteria: risk (n=10), injury (n=7) and failure (n=10).

“Our results are consistent with recent data demonstrating that higher colistin

doses achieve [superior rates of ] clini-cal and/or microbiological success,” Dr.Vicari said, citing at least one study (Int ((J Antimicrob Agents 2010;35:194-199).

More Insights Into Nephrotoxicity

In the second study presented at SCCM, researchers showed that colis-tin may be more nephrotoxic than poly-myxin B (abstract 759). Darowan Aka-jagbor, PharmD, BCPS, led the study when she was a PGY2 resident at theUniversity of Maryland Medical Cen-ter, in Baltimore. She is now an assis-tant professor at D’Youville College of Pharmacy, in Buffalo, N.Y., and a criti-cal care pharmacist at Upstate MedicalCenter in Syracuse, N.Y.

In 2009, the University of Maryland Medical Center switched from using polymyxin B to colistin because of a

polymyxin B shortage and because thedoctors thought polymyxin B was morenephrotoxic based on anecdotal evi-dence. The retrospective study examinedoutcomes of patients treated with either antibiotic who were seen at the medicalcenter between 2008 and 2010. Patientshad to be at least 18 years old and tohave received polymyxin B or colistinintravenously for at least 72 hours. TheRIFLE criteria were used to determinethe incidence of nephrotoxicity. Thestudy cohort included 106 patients whohad received colistin and 67 patients whowere given polymyxin B.

Patients who received colistin had higher rates of acute renal failure thanpatients who received polymyxin B(60.4% vs. 41.8%; P=0.02). To more fully understand the clinical significance forthat difference, the investigators drilled a bit deeper into the type of renal dysfunc-tion that was emerging in the colistingroup. They found that the majority of the patients with colistin-induced acuterenal failure had reversible kidney inju-ry, and only one patient progressed to

end-stage renal disease. Although there was no direct correlation between higher dose and increased risk for nephrotoxici-ty, a higher percentage of patients receiv-ing more than 5 mg/kg per day (ideal body weight [IBW]) of colistin developed nephrotoxicity. Colistin dosing varied significantly and was calculated based on either weight (IBW or adjusted body weight) or a fixed dose of 150 mg (every eight to 24 hours).

“If you look at the literature, there was nothing that told you that one drug is more nephrotoxic than the other,” Dr. Akajagbor said. “In our study, we did see a higher incidence of nephrotoxicity with colistin. This means our patients should be monitored more closely.”

Lessons Learned

Douglas Fish, PharmD, BCPS, chair of the Department of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sci-ence, in Aurora, said that the two SCCM studies hold some important clues for dosing colistin in a way that balances safety and efficacy. In the case of Dr. Vicari’s study, he noted, the results sug-gest that once the decision to use colistin has been made, the dosing should be as aggressive as possible to achieve the best possible efficacy. “Nephrotoxicity will likely occur in a sizable number of patients, especially with higher doses,” he said. “However, if a patient is already being exposed to the risks of drug ther-apy, the drugs should be dosed in such a way as to maximize the potential ben-efits.” Because most cases of nephrotox-icity were reversible, achieving clinical success through adequate dosing should be the primary consideration, instead of avoidance of toxicity, Dr. Fish added.

As for the University of Maryland Medical Center study, he said clini-cians should definitely take the results into account when managing patients. “Whether colistin is truly more neph-rotoxic than polymyxin B needs confir-mation from other studies, but the 42% nephrotoxicity seen in polymyxin B–treated patients in Dr. Akajagbor’s study still represents an important limitation to the use of the drug,” he said.

Dr. Fish added that careful monitor-ing for nephrotoxicity is required in every patient receiving either of these agents, but especially in higher-risk patients with factors such as advanced age or greater severity of illness, or those with previous renal impairment.

—Kate O’Rourke

Drs. Akajagbor, Vicari and Fish reported no relevant fi nancial confl icts of interest.

Colistin Poses Risks at Both Ends of the Dosing Spectrum

‘In our study, we did see a higher incidence of nephrotoxicity

with colistin. This means our patients should be

monitored more closely.’

—Darowan Akajagbor, PharmD, BCPS


Critical Care

32 Clinical

References:1. JHP Pharmaceuticals, Brevital Sodium Prescribing Information. Rochester, MI. January 2009.

Brevital® should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (e.g. pulse oximetry) andcardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual other than thepractitioner performing the procedure should be present to continuously monitor the patient.

BBrevital®® S fSodium is contraindicated in patients in whom general anesthesia is contraindicated, in those with latent or manifest porphyria, or in patients witha known hypersensitivity to barbiturates. Intra-arterial injection of barbiturate solutions can result in necrosis, which may lead to gangrene and possible amputation and thereby should be avoided. Caution should be exercised in debilitated patients or patients with impaired function of respiratory, circulatory, renal, hepaticor endocrine systems and in those with severe anemia or those who are extremely obese. Side effects include but are not limited to circulatory depression, hypotension, respiratory depression (including apnea), skeletal muscle hyperactivity (twitching), seizures, emergence delirium, restlessness,anxiety, nausea, hiccups, emesis, coughing and pain at the injection site. Following massive exposure to any barbiturate, pulmonary edema, circulatory collapse withloss of peripheral vascular tone, and cardiac arrest may occur.

MK354A

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(methohexital sodium for injection, USP)42023-106-01 Brevital® Sodium 2.5 gm 50 mL MDV 1

(methohexital sodium for injection, USP)42023-105-01 Brevital® Sodium 500 mg 50 mL MDV 1

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In adults, when administering intravenously, the onset of action occurswithin 30 seconds resulting in rapid sleep induction. The induction dose usually provides anesthesia for 5 to 7 minutesIn children, when administering intramuscularly, the onset of actionoccurs within 2 to 10 minutes; when administered rectally, the onset of action occurs within 5 to 15 minutes

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open-label study of patients who par-ticipated in the peginterferon and riba-virin control arms of Phase II and III studies of boceprevir (Victrelis, Merck) and who failed to achieve SVR. After treatment with the triple-drug regimen, SVR was achieved in 40% (19 of 47) of prior null responders (defined as <2 log10 decline in hepatitis C virus [HCV] RNA at treatment week 12 in the prior study), according to the study, which

was presented in Barcelona, Spain atthe International Liver Congress/annu-al meeting of the European Association for the Study of the Liver (EASL).

The triple-drug combination alsowas effective in prior partial respond-ers/relapsers: 68% (62 of 91) of thosepatients achieved an SVR. The total

proportion of patients in whom SVR was achieved was 59% (81 of 138), not-ed lead study researcher, Jean-Pierre Bronowicki, MD, PhD, of the University Henri Poincare of Nancy, in Vandoeu-vreples-Nancy, France. Seven percent of patients discontinued treatment due to adverse events; 48% had anemia, 34%

had dysgeusia and 22% had neutropenia, Dr. Bronowicki reported. The degree of interferon responsiveness after lead-in with peginterferon and ribavirin corre-lated with prior response and could help predict SVR for prior null responders, the researchers concluded.

Although impressed with the results, Dr. Nguyen offered a few caveats to keep in mind when evaluating the study. First and foremost, she noted, “the sample size is small.” Concern-ing the null responders who achieved SVR, she said, “This is giving patients a treatment option, but 40% is still low. I would like to see upwards of 60% to 70%.” Nevertheless, she said there was enough evidence “to start acting on it with patients who have tried and failed before. This gives us some data that there could potentially be efficacy.”

More Data on Boceprevir

A related study, presented in a post-er (1141) at EASL by Cooper et al, addressed the absence of head-to-head clinical trials between boceprevir and telaprevir (Incivek, Vertex). The researchers used an indirect compari-son meta-analysis and meta-regression of the current evidence to evaluate the relative efficacy of the two drugs in combination with peginterferon-alfa and ribavirin. Included were Phase II and III randomized placebo-controlled trials evaluating the effi-cacy of boceprevir or telaprevir in adult patients infected with HCV genotype 1; four boceprevir trials and six telaprevir trials met inclusion criteria.

No significant differences were found between boceprevir and telaprevir in SVR among treatment-naive patients (relative risk [RR], 1.14; 95% confidence interval [CI], 0.93-1.37; P=0.20) or treat-ment-experienced patients (RR, 0.80; 95% CI, 0.18-3.45; P=0.30). Nor were there significant differences between boceprevir and telaprevir in relapse or in discontinuation of therapy among both groups. Boceprevir and telapre-vir were shown to be comparable in efficacy, whether with standard-dose therapy durations or response-guided therapy durations. Among treatment-naive response-guided patients, telapre-vir was associated with increases in rash (RR, 1.43; P=0.01) and pruritus (RR, 1.49; P=0.001), whereas boceprevir was asso-ciated with increased neutropenia (RR, 1.46; P=0.05).

Asked to comment on the method used in this study, Steven D. Pearson, MD, MSc, FRCP, president of the Institute for Clini-cal and Economic Review, in Boston, said that it had some merit. “Indirect compar-isons can be ‘valid’ if the technique is well done,” he said. “Many coverage decisions require indirect comparisons. They are more open to question than direct com-parisons, but often direct comparisons

HEPATITIS Ccontinued from page 1

‘The role you can play as a pharmacist with patients’

adherence to [antiviral] therapy can save their lives.’

—Janet Nguyen, PharmD


Infectious Disease

34 Clinical

are not available or even feasible.”The researchers noted that dosing

schedule and side-effect profiles are key factors that allow for differentia-tion between the drugs—a point echoed by Dr. Nguyen. “Telaprevir has a much easier dosing schedule compared with boceprevir, with a three-month duration [compared with six to eight months for boceprevir] and one less blood draw,” she said. As for side effects, she noted that the study “called out the most significant [adverse reactions]—rash for telaprevir and neutropenia for boceprevir.”

Helping patients manage those adverse reactions can have a positive effect on compliance, Dr. Nguyen stressed. That in turn can be a cost-saver—“these are expensive drugs,” she noted. “But they have the potential for curing hepatitis C. So the role you can play as a pharmacist with patients’ adherence to therapy can save their lives.”

—George Ochoa

Drs. Nguyen and Pearson reported norelevant fi nancial confl icts of interest.

direct effect of metoclopramide on theheart may be found in the structuralsimilarity of metoclopramide with pro-cainamide; metoclopramide differs fromprocainamide by only a 2,5 aryl substitu-tion.1 Procainamide prolongs AV conduc-tion and may produce tachycardia andperipheral vasodilation. Procainamideand cholinergic stimulation, in general,have long been known to cause sinusarrest.9 Metoclopramide also is structur-ally related to cisapride (Janssen; with-drawn from the market), which is knownto trigger tachycardia and SVT throughstimulation of 5-HT4 atrial receptors.The cardiotoxic potential of cisapride ismainly due to QT prolongation anddevelopment of torsades de pointes. Thiseffect was deemed especially problematicin patients concomitantly treated withdrugs known to inhibit the cytochromeP450 (CYP)3A4 isoenzyme.29,30 Asrecently as 5 years ago, a new metabolicpathway for metoclopramide, involving the CYP2D6 isoenzyme, was identified.31

Whether or not the cardiovascular AEsof metoclopramide also can be linked tothe CYP isoenzymes is unknown.

Cardiovascular AEs of metoclopramideare rare, but some can be fatal. It is rec-ommended that patients be monitoredfor cardiovascular AEs immediately after receiving IV metoclopramide. Italso is appropriate to warn against rapidIV injection, especially via the centralvenous route. Due to cardiovascular risksassociated with the use of IV metoclo-pramide, recommendations are providedin the Table.

References

1. Package insert. Metoclopramide Injection, U.S.P. Deerfield, IL: Baxter HealthcareCorporation; April 2010.

2. Shaklai M, Pinkhas J, de Vries A. Metoclo-pramide and cardiac arrhythmia (letter). Br Med J. 1974;2(5915):385.JJ

3. Pollera CF, Cognetti F, Nardi M, Mazza D.Sudden death after acute dystonic reac-tion to high-dose metoclopramide. Lancet.1984;324(8400):460-461.

METOCLOPRAMIDEcontinued from page 9

• see METOCLOPRAMIDE, page 36


Infectious Disease

Clinical 35

4. Withington DE. Dysrhythmias following intravenous metoclopramide. Intensive CareMed. 1986;12(5):378-379.

5. Misis Del Campo M, Garro Martinez P, Mesalles Sanjuán E, Gener Reixac J. [Sinusarrest after the administration of intravenous metoclopramide] (letter). Med Clin (Barc).2001;117(6):238-239. Spanish.

6. Bentsen G, Stubhaug A. Cardiac arrest after intravenous metoclopramide—a case of five repeated injections of metoclopramide caus-ing five episodes of cardiac arrest. ActaAnaesthesiol Scand. 2002;46(7):908-910.

7. Tung A, Sweitzer B, Cutter T. Cardiac arrest after labetalol and metoclopramide adminis-tration in a patient with scleroderma. AnesthAnalg. 2002;95(6):1667-1668.

8. Grenier Y, Drolet P. Asystolic cardiac arrest: an unusual reaction following iv metoclo-pramide. Can J Anaesth. 2003;50(4):333-335.

9. Schwartz BG. Metoclopramide and digoxin cause 22 episodes of bradyarrhythmias. Am J Med. 2010;123(6):e5-e6. [Epub 4 June 2010].doi: 10.1016/j.amjmed.2009.10.01.

10. Malkoff MD, Ponzillo JJ, Myles GL, Gomez CR, Cruz-Flores S. Sinus arrest after admin-istration of intravenous metoclopramide. AnnPharmacother. 1995;29(4):381-383.

11. Rumore MM. Lee S, Wang S. Metoclo-pramide-induced cardiac arrest: case report and review of the literature. Clinics and Prac-tice. 2011;1: e83:174-176.

12. Midttun M, Oberg B. Total heart block after intravenous metoclopramide. Lancet. 1994;343(8890):182-183.

13. Maroto Rodríguez B, Jimenez Martin MJ, Rodríguez Aguirregabiria M, Cabezas Martin MH. [Complete atrio-ventricular block fromintravenous infusion of metoclopramide]. Med Intensiva. 2006;30(3):124-125. Spanish.

14. Huerta Blanco R, Hernandez Cabrera M, Quinones Morales I, Cardenes Santana MA. Complete heart block induced by intra-

venous metoclopramide. An Med Interna. 2000;17(4):222-223.

15. Park GR. Hypotension following the intra-venous injection of metoclopramide (letter). Anaesthesia. 1981;36(1):75-76.

16. Hughes RL. Hypotension and dysrhythmia following intravenous metoclopramide(letter). Anaesthesia. 1984;39(7):720.

17. Pegg MS. Hypotension following metoclo-pramide injection (letter). Anaesthesia. 1980;35(6):615.

18. Park GR. Hypotension following metoclo-pramide administration during hypotensive anaesthesia for intracranial aneurysm (let-ter). Br J Anaesth. 1978;50(12):1268-1269.

19. Gupta VK. Recurrent syncope, hypotension, asthma, and migraine with aura: role of meto-clopramide. Headache. 2005;45(10):1413-1416.

20. Lau KK, Chan KW, Lok CM, et al. Circulatory collapse in a patient with gastrinoma after metoclopramide administration. Hong Kong Med J. 2009;15(6):478-481.

21. Ellidokuz E, Kaya D. The effect of metoclo-pramide on QT dynamicity: double-blind, placebo-controlled, cross-over study in healthy male volunteers. Aliment Pharm Ther. 2003;18(1):151-155.

22. Siddique SM, Shariff N, Vesuwala N, Hafiz T.Metoclopramide as a possible cause of pro-longed QT syndrome and torsade de pointes in a patient with heart failure and renal insufficiency. Ann Intern Med.2009;150(7):502-504.

23. Bilgin S, Ustun FE, Eksi A, Sener EB, Kocamanoglu IS, Sarihasan B. The effectsof ondansetron and metoclopramide used for postoperative nausea and vomiting prophy-laxis on the QT interval. Ondokuz Mayis Uni-versitesi Tip Dergisi. 2008;25:117-124.

24. Bevacqua BK. Supraventricular tachycardia associated with postpartum metoclopramide administration. Anesthesiology. 1988; 68(1):124-125.

25. Chou CC, Wu D. Torsade de pointes induced by metoclopramide in an elderly woman with preexisting complete left bundle branch block. Chang Gung Med J. 2001;24(12):805-809.

26. Baguley WA, Hay WT, Mackie KP, Cheney FW, Cullen BF. Cardiac dysrhythmias associ-ated with the intravenous administration of ondansetron and metoclopramide. AnesthAnalg. 1997;84(6):1380-1381.

27. Ahmad S. Metoclopramide-induced acute congestive heart failure (letter). South Med J.1991;84(2):283-284.

28. Magnifico F, Pierangeli G, Contin M, Barlet-ta G, Cortelli P. Acute hypotensive effect of metoclopramide in autonomic failure. ClinAuton Res. 1998;8(1):63-72.

29. Tonini M, De Ponti F, Di Nucci A, Crema F. Review article: cardiac adverse effects of gastrointestinal prokinetics. Aliment Pharma-col Ther. 1999;13(12):1585-1591.

30. Ishizahi T, Horai Y. Review article: cyto-chrome P450 and the metabolism of proton pump inhibitors-emphasis on rabeprazole. Aliment Pharmacol Ther. 1999;13(suppl 3):27-36.

31. Yu J, Paine MJ, Marechal J, Kemp CA, Ward CJ, Brown S, et al. In silico prediction of drug binding to CYP2D6: identification of a newmetabolite of metoclopramide. Drug Metab Dispos. 2006;34(8):1386-1392.

Dr. Rumore reported no relevant fi nancial confl icts of interest.

METOCLOPRAMIDEcontinued from page 35


Practice Pearl

36 Clinical

C onverting from intermittent infu-sions of piperacillin/tazobactam

to extended infusions of the antibi-otic combination is anticipated to saveone community-based teaching hospi-tal nearly $31,000 a year, a new study has shown.

The tradeoff is that the switch entails“a fair amount” of extra work, said leadauthor Timothy Reilly, PharmD, a clini-cal assistant professor at the ErnestMario School of Pharmacy, Rutgers,The State University of New Jersey, inNew Brunswick, and a clinical phar-macist at University Medical Center, inPrinceton, N.J.

Dr. Reilly told Pharmacy Practice Newsthat he and his colleagues had seenclinical trials conducted in academiccenters that documented the clinicaland financial benefits of extended infu-sions. In one such study (Clin Infect Dis2007;44:357-363), the 14-day mortality rate among critically ill patients infect-ed with Pseudomonas aeruginosa who received extended-infusion therapy orintermittent-infusion therapy was 12.2%and 31.6%, respectively (P(( =0.04). Medi-an duration of hospital stay was 21 and38 days, respectively (P(( =0.02).

To see if those benefits could beobtained at their community-basedhospital, a teaching affiliate of the Uni-versity of Medicine and Dentistry of New Jersey, Dr. Reilly and his col-leagues collaborated to determine thechanges necessary to implement a suc-cessful switch to extended piperacil-lin/tazobactam (P/T) infusion. TheRutgers team, which included a nurseeducator, epidemiologist and pharma-cy administrator, assessed all patientswho received P/T in 2010 and calculat-ed how much money they would havesaved had they used extended infusionscompared with intermittent infusions.“The extended infusions allow you togive less drug, so you save about a dosea day,” he explained.

They also took into account the costsfor protocol development, nursing, phar-macy and physician education, addition-al compounding and labeling, re-routing of P/T to the IV medication record andincreased volumetric pump usage.

The study showed that in 2010,78% of all P. aeruginosa isolates hada minimum inhibitory concentration(MIC) greater than 4 mg/L. Eight of these isolates were obtained from criti-cal care areas. The researchers alsofound that the hospital spent $110,856on 11,472 doses of brand and genericP/T. Based on this usage, the research-ers calculated they could save at least$30,749.93 per year, which represents a 28% decrease in expenditures for P/Talone, Dr. Reilly said.

“The clinical impact is really only seen in patients with Pseudomonas isolates with an MIC greater than 4 mg/L who are critically ill, and in 2010 there were only eight isolates [meeting that criteri-on]. So the impact of a switch on clinical outcomes is minimal, but that is because of our patient population. Because we are a community-based teaching hospital, our patients are not as sick as patients in academic hospitals.”

The extra work involved in convert-ing to an extended infusion protocol is worth it, he added. “We have now put this into practice. Ultimately, the major impetus for us to make this change was

the cost savings, while maintaining or improving clinical outcomes.”

More Savings from Continuous Infusions

Israeli researchers reported similarly favorable results with regard to cost of treatment with continuous P/T infu-sion. A retrospective study of 99 criti-cally ill patients, led by Yifat Dudik, from Barzilai Medical Center, in Ash-kelon, Israel, compared outcomes in 56 patients who received P/T continu-ously (9 g/150 mL or 13.5 g/150 mL over 24 hours) or intermittently (4.5 g/100 mL every eight hours during 0.5 hours).

There were no significant differences between the two groups with regard to baseline characteristics.

The study found no differences in length of stay, mortality during treat-ment, length of treatment and clinicaloutcomes between the two groups. How-ever, use of continuous infusion resulted in a “significant” reduction in rehospi-talization and treatment expenditures compared with intermittent infusions.

Yet another study has reported similar findings of cost savings with extended P/T infusion. Roy Guharoy, PharmD, MBA, a professor of medicineat University of Massachusetts Medi-cal School and chief pharmacy officer at UMass Memorial Health Care, in Worcester, doumented a 20% reduc-tion in use during the six months after extended infusion of P/T was imple-mented; this was accompanied by an 18% decrease in pharmacy expendi-tures. This was achieved without any adverse changes in resistance trends against gram-negative pathogens, Dr.Guharoy said.

“Implementation of extended piper-acillin/tazobactam went very well; we had no glitches whatsoever,” he told Pharmacy Practice News. “We involvedeveryone in the process: physicians, pharmacists, nurses and residents. We used intensive education, that’s why itwent so well.”

Investigations of the pharmacokinet-ics and pharmacodynamics of extendedinfusion P/T date back more than 10years, commented Samantha P. Jellinek-Cohen, PharmD, BCPS, CGP, an assis-tant clinical professor at St. John’s Uni-versity and emergency medicine clinicalpharmacy specialist at Beth Israel Medi-cal Center, in New York City. “For theβ-lactams, it is the duration of exposurethat determines the degree of bacterial killing activity. For piperacillin/tazobac-tam, the goal is to achieve free drug con-centrations that exceed the mean inhibi-tory concentration for 40% to 60% of the dosing interval.”

The likelihood of this occurring is greater with extended infusions, in-creasing the opportunity for a favorableclinical response, she said.

“Under the assumption that a change to the extended infusion will improveclinical outcomes,” Dr. Jellinek-Cohenadded, “the authors of these two studiesalso demonstrated that this change canresult in significant cost savings for an institution.”

—Fran Lowry

The studies were fi rst reported at theAmerican Society of Health-System

Pharmacists 2011 Midyear Clinical Meeting,in New Orleans.

Switch to Extended Piperacillin/Tazo Infusion Cuts Cost

Doripenem in the ICU

Extending the infusion time doesn’t just work for piperacillin/tazobactam; other antibiotics used in the ICU can benefit from the dosing strategy.

For example, a study presented at the 2011 ASHP Midyear Clinical Meeting that looked at intermittent versus extended infusions of the ultra-broad spec-trum antibiotic doripenem (Doribax, Janssen) among critically ill patients in the ICU found that extended infusion showed a trend toward decreased mor-tality rates and 30-day readmission rates.

The authors note that doripenem exhibits time-dependent bactericidal activ-ity when the concentration of free drug exceeds the minimum inhibitory con-centration (MIC) for at least 40% of the dosing interval. Extending the infusion over four hours allows for more time above the MIC and lengthens the dura-tion of active antibiotic concentrations compared with intermittent infusions over 30 minutes, they explained.

The investigators compared results in 35 ICU patients who received intermit-tent doripenem infusions in 2010 with results in 30 ICU patients who received extended infusion doripenem in 2011. They found a trend toward decreased mortality, which went from 34% in 2010 to 23% in 2011.

Length of stay also trended downward, at 25.17 days in 2010 compared with 24.87 days in 2011. Readmission rates at 30 days were also lower in the patients who received extended versus intermittent doripenem infusions(17.39% in 2010 vs. 5.77% in 2011).

“At a time when there is increasing antimicrobial resistance, we have to keep investigating new ways to optimize the few antibiotics that we have left,” said Mena Abaskharoun, PharmD, from Morristown Memorial Hospital, Morristown, N.J., who led the study.

—F. L.

Ph

oto

cre

dit

: C

DC

.

Extended infusions of piperacillin/tazobactam in critically ill patients infected with Pseudomonas aeruginosa significantly reduced mortality and the cost of care.


Infectious Disease

Clinical 37

More Evidence of Pharmacists’ Impact on Diabetes Outcomes

Pharmacists Need Help Understanding Autism

This study demonstrated how dia-betes management is a perfect

opportunity for pharmacists to usetheir skills and education. Pharma-cists have been collaborating with physicians and other care providers for years, but we’ve finally begun to

document our efforts and show how our involvement affects outcomes. This will help us get recognized as prescribers by Medicare and Medic-aid, so that payers will accept phar-macists as care providers for billing purposes.

In terms of study design, the base-line HbA1c was a bit on the low side.There were 13 patients with type 1,and although it is not clear from thearticle, individuals with type 1 dia-betes tend to have more finely tuneddisease, so that may have contrib-uted to the low mean baseline. The 34patients with HbA1c values of 8% orhigher is more typical of what I see forthe general population with diabetes.The drop from 9.5% to 7.8% is tremen-dous, and speaks to the pharmacists’impact on outcomes. It is the patientswith higher HbA1cs who are most atrisk for developing very costly compli-

cations of diabetes, and these are the patients for whom collaborative care between pharmacists and physicians will have the greatest effect.

One limitation to the study is that the participants served as their own control group. Having a separate con-trol group of patients who were notenrolled in the HOPE Program wouldhave helped: Comparing outcomes between enrollees and non-enrollees would demonstrate the effect of theprogram as a whole. The same would be true if the program was comparedwith one led by physicians or otherprimary care providers.

The first thing I noticed was the response rate, which was less than

6%. However, the design was appropri-ate and typical of studies where the central component is an online survey.

In some ways, the results are not sur-prising. Autism education is not some-thing that is part of the core curriculum

in pharmacy schools. However, when one considers that autism has been in the forefront of public discussion, and when one looks at the medications involved in managing patients with autism, it is clear it should be part of a phar-macist’s core competency. The push for adding education about autism to

pharmacy education will have to startwith young pharmacists. I was trainedin the 1970s and we didn’t talk about itat all. The only reason I became famil-iar with it is because my specialty ispediatrics.

It was disappointing to see that 18%thought vaccines could cause autism.There is no science for that. [A study appearing in The Lancet in 1998 thatsuggested an association betweenthe measles-mumps-rubella vaccineand autism was later retracted anddeclared fraudulent.] This just tellsme that we’re no different than thepublic—we are influenced by com-

mon myths, especially about things forwhich we don’t have a lot of training.

One thing I would suggest the researchers do is follow up with a survey of pharmacy schools to deter-mine what percentage offer educa-tion on autism. Pharmacists who want to learn more about autism can approach local community organiza-tions involved with autism, and pos-sibly develop teaching sites where stu-dents can learn about the condition.Pharmacists also can work with these organizations and talk to their mem-bers about the medications involvedin treating people with autism.

From American Journal of Health-System Pharmacy

Patients who participated in an employer-sponsored diabetes man-

agement program led by pharmacists achieved significant improvements in hemoglobin (Hb) A1c levels and blood pressure, according to a study from Wake Forest University Baptist Medical Center, in Winston-Salem, N.C. (Am J ((Health-Syst Pharm 2012;69:69-73).

In the study, researchers conducted a retrospective, chart-based evaluation of HbA1c among 98 first-year partici-

pants in the Health Outcome Partner-ship for Employees (HOPE) with Dia-betes Program who had been enrolled in the program for at least six months. Thirteen participants had type 1 dia-betes and 85 participants had type 2. HOPE Program patient visits take place free of charge in the pharmacist-directed ambulatory care clinic at the medical center, and copayments are waived for oral and injectable diabe-tes medications, glucose testing sup-plies and prescriptions for angioten-sin-converting enzyme inhibitors and angiotensin receptor blockers that are

filled at the health system’s outpatient pharmacy.

The average length of enrollment at follow-up was 8.2 months. In that time, the mean HbA1c value among partici-pants decreased from 7.8% at baseline to 7.1% at follow-up (P(( <0.01). Mean systolic blood pressure decreased from 128.8 to 124.9 mm Hg (P(( <0.01), and mean diastolic blood pressure dropped from 77.6 to 74.2 mm Hg (P(( <0.01). Among the participants, 34 had HbA1c

values of at least 8% at enrollment, and they experienced a mean reduction in HbA1c of 1.7 percentage points, from

9.5% to 7.8% (P(( <0.01). However, nine of these 34 still had HbA1c values of 8% orhigher at follow-up.

The team noted that there werereductions in total cholesterol (TC)and triglycerides (TG) among the 92participants for whom baseline data were available. In this group, the meanTC value dropped from 178.5 to 167.0mg/dL (P(( <0.01), and the mean TG val-ue decreased from 160.2 to 135.3 mg/dL (P(( =0.02). There were no signifi-cant differences in the participants’high-density lipoprotein cholesterolvalues, body mass index or weight.

From Research in Social and Administrative Pharmacy

Pharmacists may benefit from educa-tion about autism, say researchers at

the University of Mississippi’s School of Pharmacy. A survey conducted by the team revealed that despite the increased prevalence of autism in the

United States in recent years, many pharmacists are unfamiliar with the condition and its medical manage-ment (Res Soc Adm Pharm (( 2012 Jan 3. [Epub ahead of print]). Researchers emailed 2,543 pharmacists registered in Mississippi to invite them to par-ticipate in a online survey. The survey questionnaire assessed pharmacists’

degree of familiarity and awareness of autism, medications, resources and common myths associated with the condition. The questionnaire also asked participants about their train-ing regarding autism and confidence in medication management.

The team received 147 usable responses, a return rate of 5.8%. After

analyzing the data, the researchersfound that 23% of respondents did notknow that autism is a developmentaldisorder, 32% did not believe thatgenetics has a major role in autism eti-ology, and 18.4% believe that vaccinescan cause autism. More than 90% feltthey could benefit from continuing education in the area of autism, and68% felt there should be an autismcourse or lecture included in phar-macy school curricula.

Drs. Morello and Colbert reported no relevant fi nancial confl icts of interest. —Compiled by Terri D’Arrigo

Candis M. Morello, PharmD, CDE, FCSHPAssociate Professor of Clinical PharmacyAssociate Dean for Student AffairsSkaggs School of Pharmacy and Pharmaceutical Sciences University of California–San DiegoSan Diego, California

COMMENTARY

James Colbert, PharmDAssociate Clinical ProfessorAssociate Dean for Experiential EducationSkaggs School of Pharmacy and Pharmaceutical SciencesUniversity of California–San DiegoSan Diego, California

COMMENTARY


Journal Scan

38 Clinical

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instructions to be flushed, not thrown away; this tragedy indicates that a safe-ty and disposal gap still exists in our homes and hospitals.”

The press briefing was timed to occur immediately prior to the DEA’s 2012 pre-scription drug Take-Back Day. Michele Leonhart, DEA administrator, said that when the first Take-Back Day was held four years ago, 121 tons of expired and/or unused prescription drugs were turned in to thousands of sites nationwide; through 2011, nearly 500 tons of pre-scription drugs available for potential misuse have been taken out of circula-tion via this program, she noted.

Despite such efforts to remove unused or expired prescription drugs from the community, ready access to the medications remains a major source of abuse, according to a new data analy-sis presented during the teleconfer-ence. For example, more than 70% of the 2.4 million Americans who abuse prescription drugs for the first time each year get them from family and friends; roughly one-third are teenag-ers, according to the analysis, which was based on 2009-2010 data from the National Survey on Drug Use and Health. About 55% of casual abusers of prescription drugs (less than once a week over the past year) reported getting them for free from family and friends, whereas 11% purchased them from the same individuals. About 5% took them from these sources without permission.

Among chronic users (those misusing or abusing pain relievers once a week or more over the past year), roughly 41% obtained prescription drugs from family or friends, with or without permission, whereas 25% reported purchasing them from dealers or the Internet; roughly the same percentage obtained the medi-cations from doctors.

Gil Kerlikowske, ONDCP director, said the new data “[show that] prevention is key. Since we know most of these pills are coming from home medicine cabi-nets, we all have a role to play in prop-erly disposing of the unused, expired or unneeded medications that are available in too many of our homes.”

High Stakes for Gaining A Measure of Control

The stakes for eliminating easy access to prescription drugs are high, given the steep rise in abuse of the medica-tions, teleconference speakers stressed. In fact, the current abuse problem is “unprecedented,” noted Ieana Arias, PhD, CDC principal investigator. Dr. Arias related how drug overdose deaths have quadrupled from 10 years ago, and now occur more frequently than

automobile-related fatalities. More than 75% of the prescription drug–related overdoses involve opioids, she said. What’s more, for every 2009 death involving the use of an opioid, there were nine drug rehabilitation admis-sions, and the annual economic impact now approaches $72 billion.

Still, ready access to prescription drugs can’t fully explain the abuse epidemic; there is a wide range of other contribut-ing factors, including the rise of disrepu-table pain clinics or “pill mills” and phar-macies that are complicit in the filling of prescriptions from those clinics. That’s why the telebriefing participants used the event as an opportunity to highlight the successes of the Obama Administra-tion’s year-old plan to combat the nation-al prescription drug abuse problem on several fronts. The administration’s pro-gram includes a strong focus on pre-scription drug monitoring programs; the development of convenient and environ-mentally responsible disposal methods; more effective substance abuse treat-ment; better education for patients and health care providers; law enforcement efforts geared toward shutting down dis-reputable pain clinics or “pill mills” and reducing diversion and doctor shopping; more effective pharmacy practices; and improved clinical practice through clini-cal guideline development.

The goal, said Dr. Arias, is to “use sci-

ence to inform policy, finding the bestpractices for prevention and the bestmodels for laws.”

At the end of the Obama Administra-tion’s efforts, “I can report that substan-tial progress has been made,” said Mr.Kerlikowske, citing that online prescrip-tion drug databases have been institutedin 48 states. He added that the DEA alsohas successfully “taken down operatorsof pill mills through targeted enforce-ment efforts. And finally, we are begin-ning to see some preliminary data indi-cating that young people’s perceptionof risk regarding prescription drugs isincreasing—an important trend that wehope is a harbinger for declines in abuse.”

He stressed the continued importanceof getting the message out to the public.“Last year, Congress did not fund ourmedia campaign; this year we will try andpush forward funding.” Yet according toMr. Kerlikowske, the efforts to increaseawareness of the prescription drug abuseepidemic have put it squarely in the pub-lic consciousness, to the point where hehas heard accounts of realtors instructing homeowners to lock up the medicationsin their homes prior to open houses.

‘Whole Supply Chain’ Involved

According to Ms. Leonhart, the current prescription drug epidemic is being driv-en largely by availability and demand,both of which need to be addressed.

“There are people going to jail for setting up these pill mills, and they are nothing more than major drug traffickers,” she said. “If you are breaking the Controlled Substances Act—whether you are a prac-titioner or drug dealer on the corner—we have ways of catching you.” She stressed that most of the nation’s 1.2 million med-ical practitioners “do their very best, but a few do not, and it is the DEA’s respon-sibility to find them.”

Ms. Leonhart added that the DEA is “monitoring the whole supply chain, from manufacturers to pharmacists,” and is wholly supportive of state efforts on drug monitoring.

“This is all new to a lot of prosecutors,” she said of pill mill and doctor-shopping cases, adding, however, that “the penal-ties are [in place]; now, it is really about education.”

Not Just Florida

For several years, said Ms. Leonhart, Florida was the “national epicenter of pill mills and doctor shopping,” but through DEA efforts like Operation Pill Nation 1 and Operation Pill Nation 2, nearly 100 Florida doctors were caught, and dozens of pill shops were closed. She cited exam-ples of major dealers being apprehended, such as twin brothers in South Florida who were convicted of distributing nearly 20 million oxycodone pills.

DRUG MISUSEcontinued from page 1

• see DRUG MISUSE, page 45

‘Fentanyl patches have instructions to be flushed, not thrown away; this tragedy indicates that a safety and disposal gap still exists in our homes and hospitals.’

—Margaret Hamburg, MD

‘There are people going to jail for setting up these pill mills, and they are nothing more than major drug traffickers.’

—Michele Leonhart

‘We are beginning to see some preliminary data indicating that young people’s perception of risk regarding prescription drugs is increasing—an important trend that we hope is a harbinger for declines in abuse.’

—Gil Kerlikowske, MD


Addiction Medicine

40 Policy

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INDICATIONRECOTHROM Thrombin, topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical.

IMPORTANT SAFETY INFORMATION Contraindications Topical use only – DO NOT INJECT directly into the circulatory system Do not use for the treatment of massive or brisk arterial bleeding Do not administer to patients with known hypersensitivity to RECOTHROM, any

components of RECOTHROM or hamster proteins

Warnings and Precautions Potential risk of thrombosis if absorbed systemically In patients with known hypersensitivity to snake proteins, there may be a potential for

allergic reaction

Adverse Reactions

were consistent with those commonly observed in surgical patients Please see Brief Summary of Full Prescribing Information on following page.

RECOTHROM is human thrombin produced using recombinant DNA technology

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A significant percentage of patients who develop surgical site infections A A

after hip or knee replacement surgery will be readmitted to the hospital for further complications related to wound infections, new research shows.

Preventing such readmissions could save the U.S. health care system as much as $65 million a year, according to research led by Keith Kaye, MD, of Detroit Medical Center/Wayne State

University. Dr. Kaye’s group presentedits findings at the 2012 annual meeting of the Association of Professionals in Infec-tion Control and Epidemiology (APIC).

The research team analyzed data from40 million individuals’ health insuranceclaims. Their goal was to uncover the rateof readmission and the financial effectsof surgical site infections (SSIs) beyondthe initial treatment of the complications.

“The prosthetic joint population was

important to study because these patients are particularly vulnerable to adverse events following [SSIs], leading to unnec-essary pain, suffering and medical costs,” Dr. Kaye said. “Given the government’s focus on reducing readmission rates, such complications could likely be a future tar-get for decreased reimbursement.”

Of the 174,425 patients in the database who underwent hip or knee replacement in 2007, 1.2% were hospitalized for an

SSI within one year of their procedure. Of those, more than 12% were readmitted in the following year due to SSI-related issues. The average hospital stay for the readmission was 8.6 days, at a cost of approximately $7,000 per patient.

In a statement, APIC president Michelle Farber, RN, said, “Infection preventionists need to be familiar with health care qual-ity incentive programs to demonstrate the value of the infection prevention program to the financial health of their organiza-tions and patient experience.”

—Maureen Sullivan

SSIs After Joint Surgery Cost Hospitals Millions

Injectable Cytarabine Introduced

Pfizer Injectables announced the addition of cytarabine

injection to the company’s portfolioof generic oncology products. In March 2012, the FDA approved the abbreviated new drug application for cytarabine injection in the followingpresentations: 100 mg/5 mL (20 mg/mL) single-dose vials,500 mg/25 mL (20 mg/mL)multidose vials, 1,000 mg/50 mL (20 mg/mL) pharmacy bulk packages, and 2 g/20 mL (100 mg/mL) single-dose vials. The drug is FDA-approved for remission induction in acutenon-lymphocytic leukemia of adults and children.

Full prescribing information on cytarabineinjection can be accessed at http://www.pfizer.com/products/#cytarabine.

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BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION

RECOTHROM® Thrombin, topical (Recombinant)

Rx OnlyThe following is a brief summary of the full prescribing information for RECOTHROM Thrombin, topical (Recombinant).

CONTRAINDICATIONSDo not inject directly into the circulatory system. Do not use for the treatment of massive or brisk arterial bleeding.Do not administer to patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM, or hamster proteins.

WARNINGS AND PRECAUTIONSPotential risk of thrombosis if absorbed systemically.In patients with known hypersensitivity to snake proteins, there may be a potential for

allergic reaction.

ADVERSE REACTIONSThe serious adverse event that occurred in ≥ 1% (n=6/583) of patients exposed to RECOTHROM in completed clinical trials was atrial fibrillation. The most common adverse events in patients exposed to RECOTHROM in clinical trials (N=583) were incision site pain (51%), procedural pain (30%), and nausea (28%).

Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical trials have been performed with RECOTHROM applied with absorbable gelatin sponge (Phase 2, Phase 3, and Phase 3b studies) and applied with a spray applicator (Phase 2 study). Adverse events reported in clinical trials were consistent with those commonly observed in surgical patients.

Clinical Trials of RECOTHROM Used in Conjunction with Gelatin SpongeAmong the 411 patients treated with study drug in the randomized, double-blind, Phase 3 study that compared RECOTHROM to bovine thrombin, both applied with gelatin sponge, in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, all but 2 patients (1 patient/treatment group) reported adverse events. Most events were moderate in severity and had a similar incidence in the RECOTHROM and bovine thrombin treatment groups. The most common adverse events were incision site pain (63% for both treatment groups), procedural pain (RECOTHROM 29%; bovine thrombin 34%), and nausea (RECOTHROM 28%; bovine thrombin 35%). Serious adverse eventswere reported by 18% of patients treated with RECOTHROM and 22% with bovine thrombin.

Adverse events of interest were pre-specified, based on the thrombin mechanism of action, use of absorbable gelatin sponge, USP, historical reporting in association with cross-reacting antibodies to bovine thrombin product, and results from Phase 2 clinical trials of RECOTHROM applied with absorbable gelatin sponge. The incidences of these pre-specified adverse events were similar between treatment groups (see Table 1).

Table 1. Events of Interest in the RECOTHROM Phase 3 Study

RECOTHROM Thrombin-JMI†

(N=205) (N=206)AE Category* n (%) n (%)

Patients with any event category 124 (60%) 136 (66%)Bleeding 27 (13%) 24 (12%)Cardiac 41 (20%) 38 (18%)Hypersensitivity 30 (15%) 37 (18%)Nausea + vomiting 68 (33%) 83 (40%)Other infection 26 (13%) 31 (15%)Post-operative wound infection 19 (9%) 22 (11%)Thromboembolic 12 (6%) 10 (5%)

*Adverse events were included in event categories based on a blinded review of the investigator verbatim and coded terms.

†THROMBIN-JMI® Thrombin, Topical (Bovine).

In an open-label, single-group Phase 3b study, 209 patients with documented or highly likely prior exposure to bovine thrombin within the previous 3 years were treated with RECOTHROM when undergoing surgeries (spinal or peripheral arterial bypass or arteriovenous graft formation for hemodialysis access). The most common adverse events were incision site pain (45%), procedural pain (39%), and nausea (27%). Similar to the Phase 3 study, serious adverse events were reported by 22% of patients treated with RECOTHROM.

Clinical Trials of RECOTHROM Applied with Spray ApplicatorIn an open-label, single-group, Phase 2 study in burn patients, 72 patients were treated with RECOTHROM applied with a spray applicator at the burn wound excision site prior to autologous skin grafting. This study included both adults (≥ 17 years of age, n=68) and pediatric patients ≤ 16 years of age (n=4). The most common adverse events in the adult and pediatric age groups included procedural pain (35%), pruritis (25%), and constipation (19%).

ImmunogenicityThe potential development of antibodies to RECOTHROM has been evaluated in multiple clinical trials. These pre-specified evaluations were performed in order to characterize the immunogenicity of RECOTHROM and the neutralizing potential of any detected antibodies. In completed clinical studies 5 of 552 (0.9%) patients exposed to RECOTHROM with both baseline and post-treatment antibody specimens available developed specific anti-RECOTHROM product antibodies. None of these antibodies were found to neutralize native human thrombin.

In the randomized, double-blind, Phase 3 study that compared RECOTHROM to bovine thrombin, both applied with gelatin sponge, in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, the development of specific anti-product antibodies was evaluated in both treatment groups. Blood samples were collected at baseline and at day 29 for 97% of the patients in both treatment groups. For patients randomized to RECOTHROM, the samples were analyzed by ELISA for antibodies to RECOTHROM, Chinese hamster ovary (CHO) host cell protein, and pro-thrombin activator (used in the conversion of single chain precursor to active RECOTHROM). For patients randomized to bovinethrombin, the samples were analyzed by ELISA for antibodies to bovine thrombin product.

At baseline 1.5% of patients (n=3/198) in the RECOTHROM group had positive anti-product antibody titers compared with 5% of patients in the bovine thrombin group (n=10/200). Of the patients who had detectable anti-product antibodies at baseline, 0 of 3 in the RECOTHROM group and 8 of 10 in the bovine thrombin group exhibited ≥ 1.0 titer unit (≥ 10-fold) increases in antibody levels after study treatment.

Treatment with RECOTHROM applied with absorbable gelatin sponge resulted in a statistically significantly lower incidence of specific anti-product antibody development. Three of 198 (1.5%; 95% CI, 0 to 4%) of the patients in the RECOTHROM arm developed specific anti-thrombin product antibodies (1 patient also developed anti-CHO host cell protein antibodies). No patients developed antibodies to pro-thrombin activator. Forty-three of 200 patients (22%; 95% CI, 16 to 28%) in the bovine thrombin arm developed specific antibodies to bovine thrombin product. None of the antibodies in the RECOTHROM group neutralized native human thrombin. Antibodies against bovine thrombin product were not tested for neutralization of native human thrombin. Because the study was not powered to detect a difference in clinical outcomes attributable to antibody formation, no conclusions can be drawn regarding the clinical significance of the difference in antibody formation based on the results of this study.

In the open-label, single group, Phase 3b study in patients with a high likelihood of prior bovine thrombin exposure undergoing spinal, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, 15.6% of patients (n=32/205) had anti-bovine thrombin product antibodies at baseline prior to treatment with RECOTHROM. Following treatment, none of the 200 evaluable patients (patients for whom specimens were available for antibody testing at baseline and post-RECOTHROM treatment) developed antibodies to RECOTHROM.

In the randomized, double-blind, controlled Phase 2 studies of RECOTHROM compared to placebo (RECOTHROM excipients reconstituted with 0.9% sodium chloride, USP) applied in conjunction with absorbable gelatin sponge, which were performed across a range of surgical settings (spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access), the incidence of antibody development to RECOTHROM was 1.2% in the RECOTHROM group (n=1/83) compared to 2.4% (n=1/41) in the placebo group. In the open-label, single group Phase 2 study of RECOTHROM applied with the spray applicator to excised burn wounds, 1 patient developed antibodies following treatment (1.6%, n=1/62).

The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay. The absolute immunogenicity rates reported here are difficult to compare with results from studies of other products due to differences in assay methodology, patient populations, and other underlying factors.

To report SUSPECTED ADVERSE REACTIONS, contact ZymoGenetics, Inc. p , y ,at 1-888-784-7662, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch., g

DRUG INTERACTIONSDrug interactions have not been formally studied.

USE IN SPECIFIC POPULATIONSPregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with RECOTHROM. It is also not known whether RECOTHROM can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RECOTHROM should be given to a pregnant woman only if clearly needed.

Pediatric UseOf the 72 patients undergoing burn wound excision and grafting treated with RECOTHROM applied with the spray applicator in the open-label, single group, Phase 2 study, 4 were pediatric patients. All were age 12 to 16 years. The safety and effectiveness of RECOTHROM in all pediatric age groups have not been fully established.

Geriatric UseOf the total number of patients in Phase 2 and Phase 3 clinical studies of RECOTHROM with absorbable gelatin sponge, 38% were 65 years old and over, while 16% were 75 years old and over.

No substantive differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

For Full Prescribing Information, access www.RECOTHROM.com

Manufactured for ZymoGenetics, Inc.

RT022-06, January 2011


Infectious Disease

44 Policy

Yet although Florida has served as a focal point for the problems of pill millsand doctor shopping, Mr. Kerlikowskestressed that these are issues facedacross the country, citing Texas and Cal-ifornia as other examples of prescrip-tion drug abuse hotbeds. Dr. Hamburg added that the pharmaceutical industry continues to play an important role indiffusing both these issues by develop-ing products “that are less subject toabuse … that serve medical needs butdon’t serve the pleasure-oriented goalsof [some] end users.”

Pharmacy holdups and thefts—like the

quadruple homicide in Long Island last year—are another byproduct of the epi-demic, and another focus of the agen-cies, who are organizing their efforts

with pharmacies and law enforcement.“Clearly, when you are in the disease

of addiction you are going to do almost anything,” said Mr. Kerlikowske. Yet, money plays a major role as well, he said, citing a recent robbery and shoot-ing in a Harlem pharmacy where the perpetrators asked specifically for oxy-codone and Percocet. “With street val-ues of $50, $60, $70 and $80 a pill, there is a financial incentive even if you are not involved in the addiction issue, and it is quite concerning and quite frighten-ing to pharmacy staff,” he said.

Don’t Demonize Opioids

Still, the FDA’s Dr. Hamburg stressed that with the strong focus on prevent-

ing the misuse and abuse of prescrip-tion drugs, the need for opioid medica-tions for those who suffer from chronicpain must not be lost.

“The FDA will continue to work closely with other agencies to help pre-vent misuse and abuse, while improving the safe utilization of opioids,” she said. “Opioids must continue to be available to those in pain, and combating abusewhile still allowing for use is a problem that touches all of us.”

—Donald M. Pizzi

Film-geek alert: the accompanying art for this story was inspired by the original Italian

movie poster for the 1966 Clint Eastwood fi lm, “The Good, the Bad, and the Ugly.”

Young people aged 16 years are atpeak risk for initiating misuse of

prescription pain relievers—despiteprevious estimates suggesting thatpeak risk comes late in high school orsoon after.

In a new study (Arch Pediatr Ado-((lesc Med doi:10.1001/archpediat-rics.2012.209), the authors from Michi-gan State University analyzed 2004-2008 data from the National Survey on Drug Use and Health, an annual,nationally representative, cross-sec-tional assessment. They included intheir sample 119,877 participants aged12 to 21 years who self-reported thatthey had never engaged in extramedi-

cal use of prescription pain relievers before the year in which they were sur-veyed. Extramedical use was defined as use of prescription pain relievers “to get high or for other unapproved indications outside the boundaries set

by prescribing clinicians.” The sam-ple included both youth in school and youth who had dropped out.

Approximately one in 60 young peo-ple aged 12 to 21 years started extra-medical use of prescription pain reliev-ers, the study found. Peak risk was concentrated at about 16 years, when approximately one in 30 to 40 youth initiated extramedical use (meta-anal-ysis summary estimate, 2.8%). Lower

i k i f d

cians and public health professionals will share our surprise that for youth in the United States, the peak risk for starting extramedical use of prescrip-tion pain relievers generally occurs before the final year of high school, not during the post-secondary school years,” the authors wrote.

li h f h i fi di

peak risk at age 16 years and a notableacceleration in risk between ages 13 and 14 years,” they wrote, “any strict focus on college students or 12th grad-ers might be an example of too little toolate in the clinical practice sector and inpublic health work.”

—George Ochoa

with patients not given G-CSF (12 vs.19 days, respectively; P<0.001). Themedian duration of hospitalization also was significantly shorter in the G-CSFgroup (24 vs. 27 days; P<0.001). How-ever, several key clinical outcomes didnot improve, including the incidenceof microbiologically documented infec-tions, two-year disease-free survival andtwo-year OS rates.

Dr. Bradley said she was familiar withthe 2000 study and is encouraged that,in her small group of patients, therewas “a trend toward improved OS.” Sheadded that those gains are especially promising, given the fact that there hasbeen some concern that G-CSF–typegrowth factors can stimulate the forma-tion of leukemic blast cells and worsenthe course of AML. “Our results are

likely to lessen those concerns, at least in this specific population.”

Still, there are no guidelines stating that G-CSF therapy should be given to all patients after consolidation, Dr. lBradley pointed out. A report from the American Society of Clinical Oncology on the use of growth factors (http://jco.ascopubs.org/content/24/19/3187.long) states only that the treatment “can be recommended” after consolida-tion therapy in AML. “That’s why we saw the need for our study,” she noted. “There really isn’t much consensus on this issue.”

No Change in Practice?

Asked to comment on the poster, Daisy Yang, PharmD, BCOP, clinical pharmacy specialist at the University of Texas MD Anderson Cancer Center, in Houston, said that a large prospective study is needed before any changes are made

in guideline recommendations or other clinical policies. “It is a pretty interest-ing study and it [was] done fairly well,” Dr. Yang said. “But I think we need to do some prospective studies to confirm [the results].”

Dr. Yang added that the study is a good starting point for further discussion on providing growth factor prophylacti-cally to patients with AML who are in remission after intensive chemotherapy. “The authors implied that overall sur-vival seemed to be a little bit longer for patients who received growth factors; however, there are a lot of different

variables that play into that,” she said. In particular, Dr. Yang said she would have liked to see the breakdown on whichpatients had favorable, intermediate orunfavorable cytogenetic abnormalities.

Dr. Bradley agreed that more research is needed. In fact, she noted, UNC inves-tigators are continuing to analyze data from the study, including those pertain-ing to cytogenetic and other risk factors.

—Kate O’Rourke

Drs. Bradley and Yang reported norelevant fi nancial confl icts of interest.

Not-So-Sweet 16: Mid-teens Most Apt To Start Painkiller Misuse

DRUG MISUSEcontinued from page 40

CONSOLIDATIONcontinued from page 25

‘Any strict focus on college students or 12th graders

might be an example of too little too late in the clinical

practice sector and in public health work.’

‘It is a pretty interesting study and it [was]

done fairly well. But I think we need to do some

prospective studies to confirm [the results].”

—Daisy Yang, PharmD, BCOP

risk estimates were found at ages 12 to 14 years andages 19 to 21 years.

“We suspect thatmany physicians,other prescrib-ing clini-

In light of their findings,the authors stressed the need

for prevention programsand early outreach

timed to mid-adolescence.

“With the


Addiction Medicine

Policy 45

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SAMSCA® (tolvaptan) tablets for oral use

WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUMSAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely.Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.INDICATIONS AND USAGE:

Important Limitations

CONTRAINDICATIONS:Urgent need to raise serum sodium acutely: SAMSCA has not been studied in a setting of urgent need to raise serum sodium acutely.Inability of the patient to sense or appropriately respond to thirst:

Hypovolemic hyponatremia:

Concomitant use of strong CYP 3A inhibitors:

Anuric patients: WARNINGS AND PRECAUTIONS:Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae (see BOXED WARNING): Osmotic

Gastrointestinal Bleeding in Patients with Cirrhosis:

Dehydration and Hypovolemia:

in response to thirst.Co-administration with Hypertonic Saline:

Drug Interactions:Other Drugs Affecting Exposure to Tolvaptan:CYP 3A Inhibitors:concentrations [see Dosage and Administration (2.3), Drug Interactions (7.1)]

[see Contraindications (4.4)] CYP 3A Inducers:

increased [see Dosage and Administration (2.3), Drug Interactions (7.1)].P-gp Inhibitors:cyclosporine [see Dosage and Administration (2.3), Drug Interactions (7.1)].Hyperkalemia or Drugs that Increase Serum Potassium:

ADVERSE REACTIONS:Clinical Trials Experience:

Table 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials

System Organ ClassMedDRA

Preferred Term

Tolvaptan 15 mg/day-60 mg/day

(N = 223)n (%)( )

Placebo

(N = 220)n (%)

Gastrointestinal Disorders

ConstipationGeneral Disorders and Administration Site Conditions

a

AstheniaPyrexiaMetabolism and Nutrition Disorders

bb

Anorexia c

Renal and Urinary Disordersdd

a b c d

reactions

SAMSCA® (tolvaptan)

Blood and Lymphatic System

Investigations: Prothrombin time prolonged; Gastrointestinal Disorders: Ischemic colitis; Metabolism and Nutrition Disorders: Diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis; Nervous System: Cerebrovascular accident; Renal and Urinary Disorders: Urethral hemorrhage; Reproductive System and Breast Disorders (female): Vaginal hemorrhage; Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure; Vascular disorder: Deep vein thrombosis.DRUG INTERACTIONS:Effects of Drugs on Tolvaptan:Ketoconazole and Other Strong CYP 3A Inhibitors:

[see Dosage and Administration (2.3) and Contraindications (4.4)].Moderate CYP 3A Inhibitors:

[see Dosage and Administration (2.3) and Warnings and Precautions (5.5)].Grapefruit Juice: [see Dose and Administration (2.3) and Warnings and Precautions (5.5)].P-gp Inhibitors:

[see Dose and Administration (2.3) and Warnings and Precautions (5.5)].Rifampin and Other CYP 3A Inducers:

[Dosage and Administration (2.3) and Warnings and Precautions (5.5)].Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide:

Effects of Tolvaptan on Other Drugs:Digoxin:

Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide:

Lovastatin:

change.Pharmacodynamic Interactions:

USE IN SPECIFIC POPULATIONS:[see Clinical Pharmacology (12.3)].

Pregnancy: Pregnancy Category C.

[see Nonclinical Toxicology (13.3)].Labor and Delivery: Nursing Mothers:

of SAMSCA to the mother.Pediatric Use:Geriatric Use:

plasma concentrations.Use in Patients with Hepatic Impairment:

Use in Patients with Renal Impairment:

[seeContraindications 4.5) and Clinical Pharmacology (12.3)].Use in Patients with Congestive Heart Failure:

OVERDOSAGE:

50

considered.

PATIENT COUNSELING INFORMATION:[see FDA-Approved Medication Guide (17.3)].

Concomitant Medication:counter drugs since there is a potential for interactions.Strong and Moderate CYP 3A inhibitors and Pg-p inhibitors:

[see Dosage and Administration (2.3), Contraindications (4.4), Warnings and Precautions (5.5) and Drug Interactions (7.1)].Nursing:

SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

© 2012 Otsuka Pharmaceutical Co., Ltd.

MCPPN2221.indd 1 4/19/12 4:23 PM

of physicians surveyed (N=57) would recommend SAMSCA to a colleague1

In this same survey (patient cases; N=150), physicians weresatisfied or very satisfied with SAMSCA 90% of the time1100%

©2012 Otsuka America Pharmaceutical, Inc. March 2012 0712A-4220K

UNMET NEED. FILL IT.

15 mgNDC: 59148-020-50

30 mgNDC: 59148-021-50

Unique oral treatment for clinically significant hypervolemic

and euvolemic hyponatremia

VVATERFREECLEARANCE

VV22

Order SAMSCA® (tolvaptan)

Indication and important limitations • SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L

or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

• Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA. It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients

Important safety information SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.

Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients.

• Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours

• Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended

• Gastrointestinal bleeding in patients with cirrhosis: Use in cirrhotic patients only when the need to treat outweighs this risk

• Avoid use with: CYP 3A inhibitors and CYP 3A inducers. Reduced dose of SAMSCA may be needed if used with P-gp inhibitors

• Co-administration with hypertonic saline is not recommended

• Monitor serum potassium in patients with levels >5 mEq/L and in those receiving drugs known to increase serum potassium

Commonly observed adverse reactions: (SAMSCA vs placebo) thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%).

Reference: 1. Market Rx 2010.

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following page.Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850.Samsca is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

For more information about SAMSCA, visit samsca.com or call 1-877-726-7220.

MCPPN2222.indd 1 4/19/12 4:26 PM

the july 2012 digital edition of pharmacy practice news

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