proposed us package insert vfend i.v. (voriconazole) for … · 2009-03-31 · cmax* (µg/ml) (cv%)...

Version 10.0 Proposed text of labeling - 22May02 revisions incorporated 1

PROPOSED US PACKAGE INSERT

PRODUCT NAMEVFEND® (voriconazole) TabletsVFEND® I.V. (voriconazole) for Injection

Version 22 May 02

DESCRIPTION

VFEND® (voriconazole), a triazole antifungal agent,is available as film-coated tablets for oraladministration, and as a lyophilized powder forsolution for intravenous infusion.

The structural formula is:

F

F

C H3

N N

FO H

N

N

N

VFEND is designated chemically as (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H -1,2,4-triazol-1-yl)-2-butanol with an empiricalformula of C16H14F3N5O and a molecular weight of349.3.

VFEND drug substance is a white to light-coloredpowder.

VFEND Tablets contain 50 mg or 200 mg ofvoriconazole. The inactive ingredients includelactose monohydrate, pregelatinized starch,croscarmellose sodium, povidone, magnesiumstearate and a coating containing hydroxypropylmethylcellulose, titanium dioxide, lactosemonohydrate and triacetin.

VFEND I.V. is a white lyophilized powdercontaining nominally 200 mg voriconazole and 3200mg sulfobutyl ether beta-cyclodextrin sodium in a 30

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mL Type I clear glass vial.

VFEND I.V. is intended for administration byintravenous infusion. It is a single dose,unpreserved product. Vials containing 200 mglyophilized VFEND are intended for reconstitutionwith Water for Injection to produce a solutioncontaining 10 mg/mL VFEND and 160 mg/mL ofsulfobutyl ether beta-cyclodextrin sodium. Theresultant solution is further diluted prior toadministration as an intravenous infusion (seeDOSAGE AND ADMINISTRATION).

CLINICAL PHARMACOLOGY

Pharmacokinetics

General Pharmacokinetic Characteristics

The pharmacokinetics of voriconazole have beencharacterized in healthy subjects, special populationsand patients.

The pharmacokinetics of voriconazole are non-lineardue to saturation of its metabolism. Theinterindividual variability of voriconazolepharmacokinetics is high. Greater than proportionalincrease in exposure is observed with increasingdose. It is estimated that, on average, increasing theoral dose in healthy subjects from 200 mg Q12h to300 mg Q12h leads to a 2.5-fold increase inexposure (AUCτ) while increasing the intravenousdose from 3 mg/kg Q12h to 4 mg/kg Q12hproduces a 2.3- fold increase in exposure (Table 1).

Table 1Population Pharmacokinetic Parameters of Voriconazole in Volunteers

200 mg Oral Q12h 300 mg Oral Q12h 3 mg/kg IV Q12h 4 mg/kg IV Q12h

AUCτ* (µg•h/mL)(CV%)

19.86(94%)

50.32(74%)

21.81(100%)

50.40(83%)

*Mean AUCτ are predicted values from population pharmacokinetic analysis of data from 236 volunteers

During oral administration of 200 mg or 300 mg twice

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daily for 14 days in patients at risk of aspergillosis(mainly patients with malignant neoplasms oflymphatic or hematopoietic tissue), the observedpharmacokinetic characteristics were similar tothose observed in healthy subjects (Table 2).

Table 2Pharmacokinetic Parameters of Voriconazole in Patients at Risk for Aspergillosis

200 mg Oral Q12h(n=9)

300 mg Oral Q12h(n=9)

AUCτ* (µg•h/mL )(CV%)

20.31(69%)

36.51(45%)

Cmax* (µg/mL)(CV%)

3.00(51%)

4.66(35%)

*Geometric mean values on Day 14 of multiple dosing in 2 cohorts of patients

Sparse plasma sampling for pharmacokinetics wasconducted in the therapeutic studies in patients aged12-18 years. In 11 adolescent patients who received amean voriconazole maintenance dose of 4 mg/kg IV,the median of the calculated mean plasmaconcentrations was 1.60 µg/mL (inter-quartile range0.28 to 2.73 µg/mL). In 17 adolescent patients forwhom mean plasma concentrations were calculatedfollowing a mean oral maintenance dose of 200 mgQ12h, the median of the calculated mean plasmaconcentrations was 1.16 µg/mL (inter-quartile range0.85 to 2.14 µg/mL).

When the recommended intravenous or oral loadingdose regimens are administered to healthy subjects,peak plasma concentrations close to steady state areachieved within the first 24 hours of dosing. Withoutthe loading dose, accumulation occurs during twice-daily multiple dosing with steady-state peak plasmavoriconazole concentrations being achieved by day 6in the majority of subjects (Table 3).

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Table 3Pharmacokinetic Parameters of Voriconazole from Loading Dose and Maintenance Dose Regimens(Individual Studies in Volunteers)

400 mg Q12h on Day 1,200 mg Q12h on Days 2 to 10

(n=17)

6 mg/kg IV** Q12h on Day 1,3 mg/kg IV Q12h on Days 2 to 10

(n=9)Day 1, 1st dose Day 10 Day 1, 1st dose Day 10

AUCτ* ( µg•h/mL)(CV%)

9.31(38%)

11.13(103%)

13.22(22%)

13.25(58%)

Cmax (µg/mL)(CV%)

2.30(19%)

2.08(62%)

4.70(22%)

3.06(31%)

*AUC τ values are calculated over dosing interval of 12 hoursPharmacokinetic parameters for loading and maintenance doses summarized for same cohort of volunteers**IV infusion over 60 minutes

Steady state trough plasma concentrations withvoriconazole are achieved after approximately 5days of oral or intravenous dosing without a loadingdose regimen. However, when an intravenousloading dose regimen is used, steady state troughplasma concentrations are achieved within one day.

Absorption

The pharmacokinetic properties of voriconazole aresimilar following administration by the intravenousand oral routes. Based on a populationpharmacokinetic analysis of pooled data in healthysubjects (N=207), the oral bioavailability ofvoriconazole is estimated to be 96% (CV 13%).

Maximum plasma concentrations (Cmax) are achieved1-2 hours after dosing. When multiple doses ofvoriconazole are administered with high fat meals,the mean Cmax and AUCτ are reduced by 34% and24%, respectively (see DOSAGE ANDADMINISTRATION).

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In healthy subjects, the absorption of voriconazole isnot affected by coadministration of oral ranitidine,cimetidine, or omeprazole, drugs that are known toincrease gastric pH.

Distribution

The volume of distribution at steady state forvoriconazole is estimated to be 4.6 L/kg, suggestingextensive distribution into tissues. Plasma proteinbinding is estimated to be 58% and was shown to beindependent of plasma concentrations achievedfollowing single and multiple oral doses of 200 mgor 300 mg (approximate range: 0.9-15 µg/ml).Varying degrees of hepatic and renal insufficiencydo not affect the protein binding of voriconazole.

Metabolism

In vitro studies showed that voriconazole ismetabolized by the human hepatic cytochrome P450enzymes, CYP2C19, CYP2C9 and CYP3A4 (seeCLINICAL PHARMACOLOGY - DrugInteractions).

In vivo studies indicated that CYP2C19 issignificantly involved in the metabolism ofvoriconazole. This enzyme exhibits geneticpolymorphism. For example, 15-20% of Asianpopulations may be expected to be poormetabolizers. For Caucasians and Blacks, theprevalence of poor metabolizers is 3-5%. Studiesconducted in Caucasian and Japanese healthysubjects have shown that poor metabolizers have, onaverage, 4-fold higher voriconazole exposure(AUCτ) than their homozygous extensivemetabolizer counterparts. Subjects who areheterozygous extensive metabolizers have, onaverage, 2-fold higher voriconazole exposure thantheir homozygous extensive metabolizercounterparts.

The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating

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radiolabelled metabolites in plasma. Since thismetabolite has minimal antifungal activity, it doesnot contribute to the overall efficacy ofvoriconazole.

Excretion

Voriconazole is eliminated via hepatic metabolismwith less than 2% of the dose excreted unchanged inthe urine. After administration of a singleradiolabelled dose of either oral or IV voriconazole,preceded by multiple oral or IV dosing,approximately 80% to 83% of the radioactivity isrecovered in the urine. The majority (>94%) of thetotal radioactivity is excreted in the first 96 hoursafter both oral and intravenous dosing.

As a result of non-linear pharmacokinetics, theterminal half-life of voriconazole is dose dependentand therefore not useful in predicting theaccumulation or elimination of voriconazole.

Pharmacokinetic-pharmacodynamicRelationships

In ten clinical trials, the median values for theaverage and maximum voriconazole plasmaconcentrations in individual patients across thesestudies (N=1121) was 2.51 µg/mL (inter-quartilerange 1.21 to 4.44 µg/mL) and 3.79 µg/mL (inter-quartile range 2.06 to 6.31 µg/mL), respectively. Apharmacokinetic-pharmacodynamic analysis ofpatient data from 6 of these 10 clinical trials(N=280) could not detect a positive associationbetween mean, maximum or minimum plasmavoriconazole concentration and efficacy. However,PK/PD analyses of the data from all 10 clinical trialsidentified positive associations between plasmavoriconazole concentrations and rate of both liverfunction test abnormalities and visual disturbances(see ADVERSE REACTIONS).

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Pharmacokinetics in Special Populations

Gender

In a multiple oral dose study, the mean Cmax and AUCτ forhealthy young females were 83% and 113% higher,respectively, than in healthy young males (18-45 years). Inthe same study, no significant differences in the mean Cmax

and AUCτ were observed between healthy elderly malesand healthy elderly females (>65 years).

In the clinical program, no dosage adjustment was made onthe basis of gender. The safety profile and plasmaconcentrations observed in male and female subjects weresimilar. Therefore, no dosage adjustment based on genderis necessary.

Geriatric

In an oral multiple dose study the mean Cmax and AUCτ inhealthy elderly males (≥ 65 years) were 61% and 86%higher, respectively, than in young males (18-45 years). Nosignificant differences in the mean Cmax and AUCτ wereobserved between healthy elderly females ( ≥ 65 years) andhealthy young females (18-45 years).

In the clinical program, no dosage adjustment was made onthe basis of age. An analysis of pharmacokinetic dataobtained from 552 patients from 10 voriconazole clinicaltrials showed that the median voriconazole plasmaconcentrations in the elderly patients (>65 years) wereapproximately 80% to 90% higher than those in theyounger patients (≤65 years) after either IV or oraladministration. However, the safety profile ofvoriconazole in young and elderly subjects was similar and,therefore, no dosage adjustment is necessary for theelderly.

Pediatric

A population pharmacokinetic analysis was conducted onpooled data from 35 immunocompromised pediatricpatients aged 2 to <12 years old who were included in twopharmacokinetic studies of intravenous voriconazole(single dose and multiple dose). Twenty-four of these

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patients received multiple intravenous maintenance dosesof 3 mg/kg and 4 mg/kg. A comparison of the pediatricand adult population pharmacokinetic data revealed thatthe predicted average steady state plasma concentrationswere similar at the maintenance dose of 4 mg/kg every 12hours in children and 3 mg/kg every 12 hours in adults(medians of 1.19 µg/mL and 1.16 µg/mL in children andadults, respectively). (See PRECAUTIONS, PediatricUse).

Hepatic Insufficiency

After a single oral dose (200 mg) of voriconazole in 8patients with mild (Child-Pugh Class A) and 4 patientswith moderate (Child-Pugh Class B) hepatic insufficiency,the mean systemic exposure (AUC) was 3.2-fold higherthan in age and weight matched controls with normalhepatic function. There was no difference in mean peakplasma concentrations (Cmax) between the groups. Whenonly the patients with mild (Child-Pugh Class A) hepaticinsufficiency were compared to controls, there was still a2.3-fold increase in the mean AUC in the group withhepatic insufficiency compared to controls.

In an oral multiple dose study, AUCτ was similar in sixsubjects with moderate hepatic impairment (Child-PughClass B) given a lower maintenance dose of 100 mg twicedaily compared to six subjects with normal hepatic functiongiven the standard 200 mg twice daily maintenance dose.The mean peak plasma concentrations (Cmax) were 20%lower in the hepatically impaired group.

It is recommended that the standard loading dose regimensbe used but that the maintenance dose be halved in patientswith mild to moderate hepatic cirrhosis (Child-Pugh ClassA and B) receiving voriconazole. No pharmacokineticdata are available for patients with severe hepatic cirrhosis(Child-Pugh Class C) (see DOSAGE ANDADMINISTRATION).

Renal Insufficiency

In a single oral dose (200 mg) study in 24 subjects withnormal renal function and mild to severe renal impairment,systemic exposure (AUC) and peak plasma concentration(Cmax) of voriconazole were not significantly affected by

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renal impairment. Therefore, no adjustment is necessaryfor oral dosing in patients with mild to severe renalimpairment.

In a multiple dose study of IV voriconazole (6 mg/kg IVloading dose x 2, then 3 mg/kg IV x 5.5 days) in 7 patientswith moderate renal dysfunction (creatinine clearance 30-50 mL/min), the systemic exposure (AUC) and peakplasma concentrations (Cmax) were not significantlydifferent from those in 6 volunteers with normal renalfunction.

However, in patients with moderate renal dysfunction(creatinine clearance 30 - 50 mL/min), accumulation of theintravenous vehicle, SBECD, occurs. The mean systemicexposure (AUC) and peak plasma concentrations (Cmax) ofSBECD were increased by 4-fold and almost 50%,respectively, in the moderately impaired group comparedto the normal control group.

Intravenous voriconazole should be avoided in patientswith moderate or severe renal impairment (creatinineclearance <50 mL/min), unless an assessment of thebenefit/risk to the patient justifies the use of intravenousvoriconazole (see DOSAGE AND ADMINISTRATION-Dosage Adjustment).

A pharmacokinetic study in subjects with renal failureundergoing hemodialysis showed that voriconazole isdialyzed with clearance of 121mL/min. The intravenousvehicle, SBECD, is hemodialyzed with clearance of 55mL/min. A 4-hour hemodialysis session does not remove asufficient amount of voriconazole to warrant doseadjustment.

Drug Interactions

Effects Of Other Drugs On Voriconazole

Voriconazole is metabolized by the human hepaticcytochrome P450 enzymes CYP2C19, CYP2C9, andCYP3A4. Results of in vitro metabolism studies indicatethat the affinity of voriconazole is highest for CYP2C19,followed by CYP2C9, and is appreciably lower forCYP3A4. Inhibitors or inducers of these three enzymesmay increase or decrease voriconazole systemic exposure

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(plasma concentrations), respectively.

The systemic exposure to voriconazole is significantlyreduced or is expected to be reduced by the concomitantadministration of the following agents and their use iscontraindicated:

Rifampin (potent CYP450 inducer): Rifampin(600 mg once daily) decreased the steady state Cmax

and AUCτ of voriconazole (200 mg Q12h x 7days) by an average of 93% and 96%, respectively,in healthy subjects. Doubling the dose ofvoriconazole to 400 mg Q12h does not restoreadequate exposure to voriconazole duringcoadministration with rifampin. Coadministrationof voriconazole and rifampin is contraindicated(see CONTRAINDICATIONS, PRECAUTIONS -Drug Interactions).

Carbamazepine and long acting barbiturates(potent CYP450 inducers): Although not studiedin vitro or in vivo, carbamazepine and long actingbarbiturates (e.g. phenobarbital, mephobarbital) arelikely to significantly decrease plasma voriconazoleplasma concentrations. Coadministration ofvoriconazole with carbamazepine or long actingbarbiturates is contraindicated (seeCONTRAINDICATIONS, PRECAUTIONS -Drug Interactions).

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Minor or no significant pharmacokinetic interactionsthat do not require dosage adjustment:

Cimetidine (non-specific CYP450 inhibitor andincreases gastric pH): Cimetidine (400 mg Q12hx 8 days) increased voriconazole steady state Cmax

and AUCτ by an average of 18% (90% CI: 6%,32%) and 23% (90% CI: 13%, 33%), respectively,following oral doses of 200 mg Q12h x 7 days tohealthy subjects.

Ranitidine (increases gastric pH): Ranitidine(150 mg Q12h) had no significant effect onvoriconazole Cmax and AUCτ following oral dosesof 200 mg Q12h x 7 days to healthy subjects.

Macrolide antibiotics: Co-administration oferythromycin (CYP3A4 inhibitor;1g Q12h for 7days) or azithromycin (500 mg qd for 3 days) withvoriconazole 200 mg Q12h for 14 days had nosignificant effect on voriconazole steady state Cmax

and AUCτ in healthy subjects. The effects ofvoriconazole on the pharmacokinetics of eithererythromycin or azithromycin are not known.

Effects Of Voriconazole On Other Drugs

In vitro studies with human hepatic microsomes show thatvoriconazole inhibits the metabolic activity of thecytochrome P450 enzymes CYP2C19, CYP2C9, andCYP3A4. In these studies, the inhibition potency ofvoriconazole for CYP3A4 metabolic activity wassignificantly less than that of two other azoles,ketoconazole and itraconazole. In vitro studies also showthat the major metabolite of voriconazole, voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 andCYP3A4 to a greater extent than that of CYP2C19.Therefore, there is potential for voriconazole and its majormetabolite to increase the sytemic exposure (plasmaconcentrations) of other drugs metabolized by theseCYP450 enzymes.

The systemic exposure of the following drugs issignificantly increased or is expected to be significantlyincreased by coadministration of voriconazole and their

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use is contraindicated:

Sirolimus (CYP3A4 substrate): Repeat doseadministration of oral voriconazole (400 mg Q12hfor 1 day, then 200 mg Q12h for 8 days) increasedthe Cmax and AUC of sirolimus (2 mg single dose)an average of 7-fold (90% CI: 5.7, 7.5) and 11-fold (90% CI: 9.9, 12.6), respectively, in healthysubjects. Coadministration of voriconazole andsirolimus is contraindicated (seeCONTRAINDICATIONS, PRECAUTIONS -Drug Interactions).

Terfenadine, astemizole, cisapride, pimozide andquinidine (CYP3A4 substrates): Although notstudied in vitro or in vivo, concomitantadministration of voriconazole with terfenadine,astemizole, cisapride, pimozide or quinidine mayresult in inhibition of the metabolism of thesedrugs. Increased plasma concentrations of thesedrugs can lead to QT prolongation and rareoccurrences of torsade de pointes.Coadministration of voriconazole andterfenidine, astemizole, cisapride, pimozide andquinidine is contraindicated (seeCONTRAINDICATIONS, PRECAUTIONS -Drug Interactions).

Ergot alkaloids: Although not studied in vitro orin vivo, voriconazole may increase the plasmaconcentration of ergot alkaloids (ergotamine anddihydroergotamine) and lead to ergotism.Coadministration of voriconazole with ergotalkaloids is contraindicated (seeCONTRAINDICATIONS, PRECAUTIONS -Drug Interactions).

Coadministration of voriconazole with the followingagents results in increased exposure or is expected toresult in increased exposure to these drugs. Therefore,careful monitoring and/or dosage adjustment of thesedrugs is needed:

Cyclosporine (CYP3A4 substrate): In stable renaltransplant recipients receiving chronic cyclosporinetherapy, concomitant administration of oral

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voriconazole (200 mg Q12h for 8 days) increasedcyclosporine Cmax and AUCτ an average of 1.1times (90% CI: 0.9, 1.41) and 1.7 times (90% CI:1.5, 2.0), respectively, as compared to whencyclosporine was administered withoutvoriconazole. When initiating therapy withvoriconazole in patients already receivingcyclosporine, it is recommended that thecyclosporine dose be reduced to one-half of theoriginal dose and followed with frequentmonitoring of the cyclosporine blood levels.Increased cyclosporine levels have been associatedwith nephrotoxicity. When voriconazole isdiscontinued, cyclosporine levels should befrequently monitored and the dose increased asnecessary (see PRECAUTIONS-DrugInteractions).

Tacrolimus (CYP3A4 substrate): Repeat oraldose administration of voriconazole (400 mg Q12hx 1 day then 200 mg Q12h x 6 days) increasedtacrolimus (0.1 mg/kg single dose) Cmax and AUCt

(in healthy subjects by an average of 2-fold (90%CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8),respectively. When initiating therapy withvoriconazole in patients already receivingtacrolimus, it is recommended that the tacrolimusdose be reduced to one-third of the original doseand followed with frequent monitoring of thetacrolimus blood levels. Increased tacrolimus levelshave been associated with nephrotoxicity. Whenvoriconazole is discontinued, tacrolimus levelsshould be carefully monitored and the doseincreased as necessary (see PRECAUTIONS -Drug Interactions).

Warfarin (CYP2C9 substrate): Coadministrationof voriconazole (300 mg Q12h x 12 days) withwarfarin (30 mg single dose) significantly increasedmaximum prothrombin time by approximately 2-times that of placebo in healthy subjects. Closemonitoring of prothrombin time or other suitableanti-coagulation tests is recommended if warfarinand voriconazole are coadministered and thewarfarin dose adjusted accordingly (seePRECAUTIONS-Drug Interactions).

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Oral Coumarin Anticoagulants (CYP2C9,CYP3A4 substrates): Although not studied invitro or in vivo, voriconazole may increase theplasma concentrations of coumarin anticoagulantsand therefore may cause an increase in prothrombintime. If patients receiving coumarin preparationsare treated simultaneously with voriconazole, theprothrombin time or other suitable anti-coagulationtests should be monitored at close intervals and thedosage of anticoagulants adjusted accordingly (seePRECAUTIONS-Drug Interactions).

Statins (CYP3A4 substrates): Although notstudied clinically, voriconazole has been shown toinhibit lovastatin metabolism in vitro (human livermicrosomes). Therefore, voriconazole is likely toincrease the plasma concentrations of statins that aremetabolized by CYP3A4. It is recommended thatdose adjustment of the statin be considered duringcoadministration. Increased statin concentrations inplasma have been associated with rhabdomyolysis(see PRECAUTIONS-Drug Interactions).

Benzodiazepines (CYP3A4 substrates): Althoughnot studied clinically, voriconazole has been shownto inhibit midazolam metabolism in vitro (humanliver microsomes). Therefore, voriconazole is likelyto increase the plasma concentrations ofbenzodiazepines that are metabolized by CYP3A4(e.g., midazolam, triazolam, and alprazolam) andlead to a prolonged sedative effect. It isrecommended that dose adjustment of thebenzodiazepine be considered duringcoadministration (see PRECAUTIONS-DrugInteractions).

Calcium Channel Blockers (CYP3A4 substrates):Although not studied clinically, voriconazole hasbeen shown to inhibit felodipine metabolism in vitro(human liver microsomes). Therefore, voriconazolemay increase the plasma concentrations of calciumchannel blockers that are metabolized by CYP3A4.Frequent monitoring for adverse events and toxicityrelated to calcium channel blockers is recommendedduring coadministration. Dose adjustment of the

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calcium channel blocker may be needed (seePRECAUTIONS-Drug Interactions).

Sulfonylureas (CYP2C9 substrates): Although notstudied in vitro or in vivo, voriconazole mayincrease plasma concentrations of sulfonylureas(e.g., tolbutamide, glipizide, and glyburide) andtherefore cause hypoglycemia. Frequent monitoringof blood glucose and appropriate adjustment (i.e.,reduction) of the sulfonylurea dosage isrecommended during coadministration (seePRECAUTIONS-Drug Interactions).

Vinca Alkaloids (CYP3A4 substrates): Althoughnot studied in vitro or in vivo, voriconazole mayincrease the plasma concentrations of the vincaalkaloids (e.g., vincristine and vinblastine) and leadto neurotoxicity. Therefore, it is recommended thatdose adjustment of the vinca alkaloid be considered.

No significant pharmacokinetic interactions wereobserved when voriconazole was coadministered with thefollowing agents. Therefore, no dosage adjustment forthese agents is recommended.

Prednisolone (CYP3A4 substrate): Voriconazole(200 mg Q12h x 30 days) increased Cmax and AUCof prednisolone (60 mg single dose) by an averageof 11% and 34%, respectively in healthy subjects.

Digoxin (P-glycoprotein mediated transport):Voriconazole (200 mg Q12h x 12 days) had nosignificant effect on steady state Cmax and AUCτ ofdigoxin (0.25 mg once daily for 10 days) in healthysubjects.

Mycophenolic acid (UDP-glucuronyl transferasesubstrate): Voriconazole (200 mg Q12h x 5 days)had no significant effect on the Cmax and AUCt ofmycophenolic acid and its major metabolite,mycophenolic acid glucuronide after administrationof a 1 g single oral dose of mycophenolate mofetil.

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Two-way Interactions

Concomitant use of the following agent with voriconazoleis contraindicated:

Rifabutin (potent CYP450 inducer): Rifabutin(300 mg once daily) decreased the Cmax and AUCτ ofvoriconazole at 200 mg twice daily by an average of67% (90% CI: 58%, 73%) and 79% (90% CI:71%, 84%), respectively, in healthy subjects. Duringcoadministration with rifabutin (300 mg once daily),the steady state Cmax and AUCτ of voriconazolefollowing an increased dose of 400 mg twice dailywere on average approximately 2-times higher,compared with voriconazole alone at 200 mg twicedaily. Coadministration of voriconazole at 400 mgtwice daily with rifabutin 300 mg twice dailyincreased the Cmax and AUCτ of rifabutin by anaverage of 3-times (90% CI: 2.2, 4.0) and 4-times(90% CI: 3.5, 5.4), respectively, compared torifabutin given alone. Coadministration ofvoriconazole and rifabutin is contraindicated.

Significant drug interactions that may require dosageadjustment, frequent monitoring of drug levels and/orfrequent monitoring of drug-related adverseevents/toxicity:

Phenytoin (CYP2C9 substrate and potentCYP450 inducer): Repeat dose administration ofphenytoin (300 mg once daily) decreased the steadystate Cmax and AUCτ of orally administeredvoriconazole (200 mg Q12h x 14 days) by anaverage of 50% and 70%, respectively, in healthysubjects. Administration of a higher voriconazoledose (400 mg Q12h x 7 days) with phenytoin (300mg once daily) resulted in comparable steady statevoriconazole Cmax and AUCτ estimates as comparedto when voriconazole was given at 200 mg Q12hwithout phenytoin.

Phenytoin may be coadministered with voriconazoleif the maintenance dose of voriconazole is increasedfrom 4 mg/kg to 5 mg/kg intravenously every 12hours or from 200 mg to 400 mg orally, every 12

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hours (100 mg to 200 mg orally, every 12 hours inpatients less than 40 kg) (see DOSAGE ANDADMINISTRATION).

Repeat dose administration of voriconazole (400 mgQ12h x 10 days) increased the steady state Cmax andAUCτ of phenytoin (300 mg once daily) by anaverage of 70% and 80%, respectively, in healthysubjects. The increase in phenytoin Cmax and AUCwhen coadministered with voriconazole may beexpected to be as high as 2-times the Cmax and AUCestimates when phenytoin is given withoutvoriconazole. Therefore, frequent monitoring ofplasma phenytoin concentrations and phenytoin-related adverse effects is recommended whenphenytoin is coadministered with voriconazole (seePRECAUTIONS-Drug Interactions).

Omeprazole (CYP2C19 inhibitor; CYP2C19 andCYP3A4 substrate): Coadminstration ofomeprazole (40 mg once daily x 10 days) with oralvoriconazole (400 mg Q12h x 1 day, then 200 mgQ12h x 9 days) increased the steady state Cmax andAUCτ of voriconazole by an average of 15% (90%CI: 5%, 25%) and 40% (90% CI: 29%, 55%),respectively in healthy subjects. No dosageadjustment of voriconazole is recommended.

Coadministration of voriconazole (400 mg Q12h x 1day, then 200 mg x 6 days) with omeprazole (40 mgonce daily x 7 days) to healthy subjects significantlyincreased the steady state Cmax and AUCτ ofomeprazole an average of 2-times (90% CI: 1.8,2.6) and 4-times (90% CI: 3.3, 4.4), respectively, ascompared to when omeprazole is given withoutvoriconazole. When initiating voriconazole inpatients already receiving omeprazole doses of 40mg or greater, it is recommended that theomeprazole dose be reduced by one-half (seePRECAUTIONS-Drug Interactions).

The metabolism of other proton pump inhibitors thatare CYP2C19 substrates may also be inhibited byvoriconazole and may result in increased plasmaconcentrations of these drugs.

No significant pharmacokinetic interaction was seen and

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no dosage adjustment of these drugs is recommended:

Indinavir (CYP3A4 inhibitor and substrate):Repeat dose administration of indinavir (800 mg tidfor 10 days) had no significant effect onvoriconazole Cmax and AUC following repeat doseadministration (200 mg Q12h for 17 days) in healthysubjects.

Repeat dose administration of voriconazole (200 mgQ12h for 7 days) did not have a significant effect onsteady state Cmax and AUCτ of indinavir followingrepeat dose administration (800 mg TID for 7 days)in healthy subjects.

Other Two-Way Interactions Expected to be SignificantBased on In Vitro Findings:

Other HIV Protease Inhibitors (CYP3A4substrates and inhibitors): In vitro studies (humanliver microsomes) suggest that voriconazole mayinhibit the metabolism of HIV protease inhibitors(e.g. saquinavir, amprenavir and nelfenavir). Invitro studies (human liver microsomes) also showthat the metabolism of voriconazole may beinhibited by HIV protease inhibitors (e.g., ritonavir,saquinavir, and amprenavir). Patients should befrequently monitored for drug toxicity during thecoadministration of voriconazole and HIV proteaseinhibitors (see PRECAUTIONS-Drug Interactions).

Non-Nucleoside Reverse Transcriptase Inhibitors(NNRTI) (CYP3A4 substrates, inhibitors orCYP450 inducers): In vitro studies (human livermicrosomes) show that the metabolism ofvoriconazole may be inhibited by an NNRTI (e.g.,delavirdine and efavirenz). Although not studied invitro or in vivo, the metabolism of voriconazole maybe induced by an NNRTI, such as efavirenz ornevirapine. In vitro studies (human livermicrosomes) show that voriconazole may alsoinhibit the metabolism of an NNRTI (e.g.,delavirdine). Patients should be frequentlymonitored for drug toxicity during the co-administration of voriconazole and an NNRTI (seePRECAUTIONS-Drug Interactions).

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MICROBIOLOGY

Mechanism Of Action

Voriconazole is a triazole antifungal agent. The primarymode of action of voriconazole is the inhibition of fungalcytochrome P-450-mediated 14 alpha-lanosteroldemethylation, an essential step in fungal ergosterolbiosynthesis. The accumulation of 14 alpha-methyl sterolscorrelates with the subsequent loss of ergosterol in thefungal cell wall and may be responsible for the antifungalactivity of voriconazole. Voriconazole has been shown tobe more selective for fungal cytochrome P-450 enzymesthan for various mammalian cytochrome P-450 enzymesystems.

Activity In Vitro And In Vivo

Voriconazole has demonstrated in vitro activity againstAspergillus fumigatus isolates as well as A. flavus, A. nigerand A. terreus. Variable in vitro activity againstScedosporium apiospermum and Fusarium spp., includingFusarium solani, has been seen. Most of the speciatedisolates from clinical studies were Aspergillus fumigatusbut clinical efficacy was also seen in a small number ofspecies other than A. fumigatus (see INDICATIONS ANDUSAGE and CLINICAL STUDIES - InvasiveAspergillosis).

In vitro susceptibility testing was performed according tothe National Committee for Clinical Laboratory Standards(NCCLS) proposed method (M38-P). Voriconazolebreakpoints have not been established for any fungi. Therelationship between clinical outcome and in vitrosusceptibility results remains to be elucidated.

Voriconazole has demonstrated in vivo activity in normaland immunocompromised guinea pigs with establishedsystemic A. fumigatus infections in which the endpointswere prolonged survival of infected animals and reductionof mycological burden from target organs. Activity has alsobeen shown in immunocompromised guinea pigs withpulmonary A. fumigatus infections. Voriconazoledemonstrated activity in immunocompromised guinea pigswith systemic infections produced by an A. fumigatusisolate with reduced susceptibility to itraconazole

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(itraconazole MIC 3.1 µg/mL). The exact mechanism ofresistance was not identified for that particular isolate. Inone experiment, voriconazole exhibited activity againstScedosporium apiospermum infections in immunecompetent guinea pigs.

Drug Resistance

Voriconazole drug resistance development has not beenadequately studied in vitro against the filamentous fungi,including Aspergillus, Scedosporium and Fusarium species.The frequency of drug resistance development for thevarious fungi for which this drug is indicated is not known.

Fungal isolates exhibiting reduced susceptibility tofluconazole or itraconazole may also show reducedsusceptibility to voriconazole, suggesting cross-resistancecan occur among these azoles. The relevance of cross-resistance and clinical outcome has not been fullycharacterized. Clinical cases where azole cross-resistance isdemonstrated may require alternative antifungal therapy.

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INDICATIONS AND USAGE

VFEND is indicated for use in the treatment of thefollowing fungal infections:

Treatment of invasive aspergillosis.In clinical trials, the majority of isolatesrecovered were Aspergillus fumigatus. Therewas a small number of cases of culture-provendisease due to species of Aspergillus other thanA. fumigatus (see CLINICAL STUDIES andMICROBIOLOGY sections).

Treatment of serious fungal infections causedby Scedosporium apiospermum (asexual formof Pseudallescheria boydii) and Fusarium spp.including Fusarium solani, in patientsintolerant of, or refractory to, other therapy.

Specimens for fungal culture and other relevantlaboratory studies (including histopathology) should beobtained prior to therapy to isolate and identifycausative organism(s). Therapy may be institutedbefore the results of the cultures and other laboratorystudies are known. However, once these resultsbecome available, antifungal therapy should beadjusted accordingly.

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CLINICAL STUDIES

Voriconazole, administered orally orparenterally, has been evaluated as primary orsalvage therapy in 520 patients aged 12 yearsand older with infections caused by Aspergillusspp., Fusarium spp., and Scedosporium spp.

Invasive Aspergillosis

Voriconazole was studied in patients for primarytherapy of invasive aspergillosis (randomized,controlled study 307/602), for primary andsalvage therapy of aspergillosis (non-comparative study 304) and for treatment ofpatients with invasive aspergillosis who wererefractory to, or intolerant of, other antifungaltherapy (non-comparative study 309/604).

Study 307/602The efficacy of voriconazole compared toamphotericin B in the primary treatment of acuteinvasive aspergillosis was demonstrated in 277patients treated for 12 weeks in Study 307/602.The majority of study patients had underlyinghematologic malignancies, including bonemarrow transplantation. The study also includedpatients with solid organ transplantation, solidtumors, and AIDS. The patients were mainlytreated for definite or probable invasiveaspergillosis of the lungs. Other aspergillosisinfections included disseminated disease, CNSinfections and sinus infections. Diagnosis ofdefinite or probable invasive aspergillosis wasmade according to criteria modified from thoseestablished by the National Institute of Allergyand Infectious Diseases Mycoses Study Group/European Organisation for Research andTreatment of Cancer (NIAID MSG/EORTC).

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Voriconazole was administered intravenouslywith a loading dose of 6mg/kg every 12 hoursfor the first 24 hours followed by a maintenancedose of 4 mg/kg every 12 hours for a minimumof seven days. Therapy could then be switchedto the oral formulation at a dose of 200 mgQ12h. Median duration of IV voriconazoletherapy was 10 days (range 2-90 days). AfterIV voriconazole therapy, the median duration ofPO voriconazole therapy was 76 days (range 2-232 days).

Patients in the comparator group receivedconventional amphotericin B as a slow infusionat a daily dose of 1.0-1.5 mg/kg/day. Medianduration of IV amphotericin therapy was 12days (range 1-85 days). Treatment was thencontinued with other licensed antifungal therapy(OLAT), including itraconazole and lipidamphotericin B formulations. Although initialtherapy with conventional amphotericin B wasto be continued for at least two weeks, actualduration of therapy was at the discretion of theinvestigator. Patients who discontinued initialrandomized therapy due to toxicity or lack ofefficacy were eligible to continue in the studywith OLAT treatment.

A satisfactory global response at 12 weeks(complete or partial resolution of all attributablesymptoms, signs, radiographic/bronchoscopicabnormalities present at baseline) was seen in53% of voriconazole treated patients comparedto 32% of amphotericin B treated patients(Table 4). A benefit of voriconazole comparedto amphotericin B on patient survival at Day 84was seen with a 71% survival rate onvoriconazole compared to 58% on amphotericinB (Table 4).

Table 4 also summarizes the response (success)based on mycological confirmation and species.

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Table 4Overall Efficacy and Success by Species in the PrimaryTreatment of Acute Invasive AspergillosisStudy 307/602

Voriconazole Ampho B c Stratified Difference(95% CI) d

n/N (%) n/N (%)Efficacy as PrimaryTherapy Satisfactory Global

Response a76/144 (53) 42/133 (32) 21.8%

(10.5%, 33.0%)p<0.0001

Survival at Day 84 b 102/144 (71) 77/133 (58) 13.1%( 2.1%, 24.2%)

Success by SpeciesSuccess n/N (%)

Overall success 76/144 (53) 42/133 (32)

Mycologicallyconfirmed e

37/84 (44) 16/67 (24)

Aspergillus spp.f

A. fumigatus 28/63 (44) 12/47 (26)A. flavus 3/6 4/9A. terreus 2/3 0/3A. niger 1/4 0/9A. nidulans 1/1 0/0

a Assessed by independent Data Review Committee (DRC)b Proportion of subjects alivec Amphotericin B followed by other licensed antifungal therapyd Difference and corresponding 95% confidence interval are stratified by protocole Not all mycologically confirmed specimens were speciatedf Some patients had more than one species isolated at baseline

Study 304The results of this comparative trial (Study 307/602)confirmed the results of an earlier trial in the primary andsalvage treatment of patients with acute invasiveaspergillosis (Study 304). In this earlier study, an overallsuccess rate of 52 % (26/50) was seen in patients treatedwith voriconazole for primary therapy. Success was seen in17/29 (59%) with Aspergillus fumigatus infections and 3/6(50%) patients with infections due to non-fumigatus species[A. flavus (1/1); A. nidulans (0/2); A. niger (2/2); A. terreus(0/1)]. Success in patients who received voriconazole assalvage therapy is presented in Table 5.

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Study 309/604

Additional data regarding response rates in patients whowere refractory to, or intolerant of, other antifungal agentsare also provided in Table 5. Overall mycologicaleradication for culture-documented infections due tofumigatus and non-fumigatus species of Aspergillus was36/82 (44%) and 12/30 (40%), respectively, in voriconazoletreated patients. Patients had various underlying diseasesand species other than A. fumigatus contributed to mixedinfections in some cases.

For patients who were infected with a single pathogen andwere refractory to, or intolerant of, other antifungal agents,the satisfactory response rates for voriconazole in studies304 and 309/604 are presented in Table 5.

Table 5 Combined Response Data in Salvage Patients with Single Aspergillus Species(Studies 304 and 309/604)

Successn/N

A. fumigatus 43/97 (44%)A. flavus 5/12A. nidulans 1/3A. niger 4/5A. terreus 3/8A. versicolor 0/1

Nineteen patients had more than one species of Aspergillusisolated. Success was seen in 4/17 (24%) of these patients.

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Other Serious Fungal Pathogens

In pooled analyses of patients, voriconazole was shown tobe effective against the following additional fungalpathogens:

Scedosporium apiospermum - Successful response tovoriconazole therapy was seen in 15 of 24 patients (63%).Three of these patients relapsed within 4 weeks, including 1patient with pulmonary, skin and eye infections, 1 patientwith cerebral disease, and 1 patient with skin infection. Tenpatients had evidence of cerebral disease and 6 of these hada successful outcome (1 relapse). In addition, a successfulresponse was seen in one of three patients with mixedorganism infections.

Fusarium spp.- Nine of 21 (43%) patients were successfullytreated with voriconazole. Of these nine patients, three hadeye infections, one had an eye and blood infection, one hada skin infection, one had a blood infection alone, two hadsinus infections, and one had disseminated infection(pulmonary, skin, hepatosplenic). Three of these patients(one with disseminated disease, one with an eye infectionand one with a blood infection) had Fusarium solani andwere complete successes. Two of these patients relapsed,one with a sinus infection and profound neutropenia andone post surgical patient with blood and eye infections.

CONTRAINDICATIONS

VFEND is contraindicated in patients with knownhypersensitivity to voriconazole or its excipients. There isno information regarding cross-sensitivity between VFEND(voriconazole) and other azole antifungal agents. Cautionshould be used when prescribing VFEND to patients withhypersensitivity to other azoles.

Coadministration of the CYP3A4 substrates, terfenadine,astemizole, cisapride, pimozide or quinidine with VFENDare contraindicated since increased plasma concentrations ofthese drugs can lead to QT prolongation and rareoccurrences of torsade de pointes (see CLINICALPHARMACOLOGY - Drug Interactions,PRECAUTIONS-Drug Interactions).

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Coadministration of VFEND with sirolimus iscontraindicated because VFEND significantly increasessirolimus concentrations in healthy subjects (see CLINICALPHARMACOLOGY - Drug Interactions,PRECAUTIONS-Drug Interactions).

Coadministration of VFEND with rifampin, carbamazepineand long-acting barbiturates is contraindicated since thesedrugs are likely to decrease plasma voriconazoleconcentrations significantly (see CLINICALPHARMACOLOGY - Drug Interactions, PRECAUTIONS- Drug Interactions).

Coadministration of VFEND with rifabutin iscontraindicated since VFEND significantly increasesrifabutin plasma concentrations and rifabutin alsosignificantly decreases voriconazole plasma concentrations(see CLINICAL PHARMACOLOGY - Drug Interactions,PRECAUTIONS-Drug Interactions).

Coadministration of VFEND with ergot alkaloids(ergotamine and dihydroergotamine) is contraindicatedbecause VFEND may increase the plasma concentration ofergot alkaloids, which may lead to ergotism.

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WARNINGS

VISUAL DISTURBANCES : The effect of VFEND onvisual function is not known if treatment continuesbeyond 28 days. If treatment continues beyond 28 days,visual function including visual acuity, visual field and colorperception should be monitored (see PRECAUTIONS –Information for Patients and ADVERSE EVENTS –Visual Disturbances).

HEPATIC TOXICITY: In clinical trials, there havebeen uncommon cases of serious hepatic reactionsduring treatment with VFEND (including clinicalhepatitis, cholestasis and fulminant hepatic failure,including fatalities). Instances of hepatic reactions werenoted to occur primarily in patients with serious underlyingmedical conditions (predominantly hematologicalmalignancy). Hepatic reactions, including hepatitis andjaundice, have occurred among patients with no otheridentifiable risk factors. Liver dysfunction has usually beenreversible on discontinuation of therapy (seePRECAUTIONS – Laboratory Tests and ADVERSEEVENTS – Clinical Laboratory Values.

Monitoring of hepatic function: Liver function testsshould be evaluated at the start of and during the course ofVFEND therapy. Patients who develop abnormal liverfunction tests during VFEND therapy should be monitoredfor the development of more severe hepatic injury. Patientmanagement should include laboratory evaluation of hepaticfunction (particularly liver function tests and bilirubin).Discontinuation of VFEND must be considered if clinicalsigns and symptoms consistent with liver disease developthat may be attributable to VFEND (see PRECAUTIONS-Laboratory Tests, DOSAGE AND ADMINISTRATION-Dosage Adjustment, ADVERSE EVENTS-ClinicalLaboratory Tests).

Pregnancy Category D: Voriconazole can cause fetalharm when administered to a pregnant woman.

Voriconazole was teratogenic in rats (cleft palates,hydronephrosis/hydroureter) from 10 mg/kg (0.3 times therecommended maintenance dose (RMD) on a mg/m2 basis)and embryotoxic in rabbits at 100 mg/kg (6 times the

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RMD). Other effects in rats included reduced ossification ofsacral and caudal vertebrae, skull, pubic and hyoid bone,super numerary ribs, anomalies of the sternebrae anddilatation of the ureter/renal pelvis. Plasma estradiol inpregnant rats was reduced at all dose levels. Voriconazoletreatment in rats produced increased gestational length anddystocia, which were associated with increased perinatalpup mortality at the 10 mg/kg dose. The effects seen inrabbits were an increased embryomortality, reduced fetalweight and increased incidences of skeletal variations,cervical ribs and extra sternebral ossification sites.

If this drug is used during pregnancy, or if the patientbecomes pregnant while taking this drug, the patient shouldbe apprised of the potential hazard to the fetus.

Galactose intolerance: VFEND tablets contain lactose andshould not be given to patients with rare hereditaryproblems of galactose intolerance, Lapp lactase deficiencyor glucose-galactose malabsorption.

PRECAUTIONS

General

(See WARNINGS, DOSAGE AND ADMINISTRATION)

Infusion Related Reactions

During infusion of the intravenous formulation ofvoriconazole in healthy subjects, anaphylactoid-typereactions, including flushing, fever, sweating, tachycardia,chest tightness, dyspnea, faintness, nausea, pruritus and rash,have occurred uncommonly. Symptoms appearedimmediately upon initiating the infusion. Considerationshould be given to stopping the infusion should thesereactions occur.

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Information For Patients

Patients should be advised:• that VFEND Tablets should be taken at least one

hour before, or one hour following, a meal.• that they should not drive at night while taking

VFEND. VFEND may cause changes to vision,including blurring and/or photophobia.

• that they should avoid potentially hazardoustasks, such as driving or operating machinery ifthey perceive any change in vision.

• that strong, direct sunlight should be avoided duringVFEND therapy.

Laboratory Tests

Patient management should include laboratory evaluationof renal (particularly serum creatinine) and hepatic function(particularly liver function tests and bilirubin).

Drug Interactions

Tables 6 and 7 provide a summary of significant druginteractions with voriconazole that either have been studiedin vivo (clinically) or that may be expected to occur basedon results of in vitro metabolism studies with human livermicrosomes. For more details, see CLINICALPHARMACOLOGY - Drug Interactions.

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Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics

Drug/Drug Class(Mechanism of Interaction by the Drug)

Voriconazole Plasma Exposure(Cmax and AUCττττ after

200 mg Q12h)

Recommendations for VoriconazoleDosage Adjustment/Comments

Rifampin* and Rifabutin*(CYP450 Induction)

Significantly Reduced Contraindicated

Carbamazepine(CYP450 Induction)

Not Studied In Vivo or In Vitro, but Likelyto Result in Significant Reduction

Contraindicated

Long Acting BarbituratesCYP450 Induction

Not Studied In Vivo or In Vitro, but Likelyto Result in Significant Reduction

Contraindicated

Phenytoin*(CYP450 Induction)

Significantly Reduced Increase voriconazole maintenance dosefrom 4 mg/kg to 5 mg/kg IV every 12hrs or from 200 mg to 400 mg orallyevery 12 hrs (100 mg to 200 mg orallyevery 12 hrs in patients weighing lessthan 40 kg)

HIV Protease Inhibitors(CYP3A4 Inhibition)

In Vivo Studies Showed No SignificantEffects of Indinavir on Voriconazole

Exposure

In Vitro Studies Demonstrate Potential forInhibition of Voriconazole Metabolism

(Increased Plasma Exposure)

No dosage adjustment in thevoriconazole dosage needed whencoadministered with indinavir

Frequent monitoring for adverse eventsand toxicity related to voriconazolewhen coadministered with other HIVprotease inhibitors

NNRTI**(CYP3A4 Inhibition or CYP450Induction)

In Vitro Studies Demonstrate Potential forInhibition of Voriconazole Metabolism


Not Studied In Vitro or In Vivo, butMetabolism of Voriconazole May also be

Induced(Decreased Plasma Exposure)

Frequent monitoring for adverse eventsand toxicity related to voriconazole

Careful assessment of voriconazoleeffectiveness

*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg Q12h voriconazole tohealthy subjects** Non-Nucleoside Reverse Transcriptase Inhibitors

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Table 7 Effect of Voriconazole on Pharmacokinetics of Other Drugs

Drug/Drug Class(Mechanism of Interaction by

Voriconazole)

Drug Plasma Exposure(Cmax and AUCττττ)

Recommendations for Drug DosageAdjustment/Comments

Sirolimus*(CYP3A4 Inhibition)

Significantly Increased Contraindicated

Rifabutin*(CYP3A4 Inhibition)

Significantly Increased Contraindicated

Terfenadine, Astemizole, Cisapride,Pimozide, Quinidine(CYP3A4 Inhibition)

Not Studied In Vivo or In Vitro, but DrugPlasma Exposure Likely to be Increased

Contraindicated because of potentialfor QT prolongation and rare

occurrence of torsade de pointesErgot Alkaloids(CYP450 Inhibition)


Contraindicated

Cyclosporine*(CYP3A4 Inhibition)

AUCτ Significantly Increased; NoSignificant Effect on Cmax

When initiating therapy with VFENDin patients already receivingcyclosporine, reduce the cyclosporinedose to one-half of the starting dose andfollow with frequent monitoring ofcyclosporine blood levels. Increasedcyclosporine levels have beenassociated with nephrotoxicity. WhenVFEND is discontinued, cyclosporineconcentrations must be frequentlymonitored and the dose increased asnecessary.

Tacrolimus*(CYP3A4 Inhibition)

Significantly Increased When initiating therapy with VFENDin patients already receiving tacrolimus,reduce the tacrolimus dose to one-thirdof the starting dose and follow withfrequent monitoring of tacrolimus bloodlevels. Increased tacrolimus levelshave been associated withnephrotoxicity. When VFEND isdiscontinued, tacrolimus concentrationsmust be frequently monitored and thedose increased as necessary.

Phenytoin*(CYP2C9 Inhibition)

Significantly Increased Frequent monitoring of phenytoinplasma concentrations and frequentmonitoring of adverse effects related tophenytoin

Warfarin*(CYP2C9 Inhibition)

Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment ofwarfarin dosage may be needed.

Omeprazole*(CYP2C19/3A4 Inhibition)

Significantly Increased When initiating therapy with VFENDin patients already receivingomeprazole doses of 40 mg or greater,reduce the omeprazole dose by one-half. The metabolism of other protonpump inhibitors that are CYP2C19substrates may also be inhibited byvoriconazole and may result inincreased plasma concentrations ofother proton pump inhibitors.

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Drug/Drug Class(Mechanism of Interaction by

Voriconazole)

Drug Plasma Exposure(Cmax and AUCττττ)

Recommendations for Drug DosageAdjustment/Comments

HIV Protease Inhibitors(CYP3A4 Inhibition)

In Vivo Studies showed No SignificantEffects on Indinavir Exposure

In Vitro Studies Demonstrate Potential forVoriconazole to Inhibit Metabolism


No dosage adjustment for indinavirwhen coadministered with VFEND

Frequent monitoring for adverse eventsand toxicity related to other HIVprotease inhibitors

NNRTI**(CYP3A4 Inhibition)



Frequent monitoring for adverse eventsand toxicity related to NNRTI

Benzodiazepines(CYP3A4 Inhibition)



Frequent monitoring for adverse eventsand toxicity (i.e., prolonged sedation)related to benzodiazepines metabolizedby CYP3A4 (e.g., midazolam,triazolam, alprazolam). Adjustment ofbenzodiazepine dosage may be needed.

HMG-CoA Reductase Inhibitors (Statins)(CYP3A4 Inhibition)



Frequent monitoring for adverse eventsand toxicity related to statins.Increased statin concentrations inplasma have been associated withrhabdomyolysis. Adjustment of thestatin dosage may be needed.

Dihydropyridine Calcium ChannelBlockers(CYP3A4 Inhibition)



Frequent monitoring for adverse eventsand toxicity related to calcium channelblockers. Adjustment of calciumchannel blocker dosage may be needed.

Sulfonylurea Oral Hypoglycemics(CYP2C9 Inhibition)


Frequent monitoring of blood glucoseand for signs and symptoms ofhypoglycemia. Adjustment of oralhypoglycemic drug dosage may beneeded.

Vinca Alkaloids(CYP3A4 Inhibition)


Frequent monitoring for adverse eventsand toxicity (i.e., neurotoxicity) relatedto vinca alkaloids. Adjustment of vincaalkaloid dosage may be needed.

*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole tohealthy subjects** Non-Nucleoside Reverse Transcriptase Inhibitors10

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Patients with Hepatic Insufficiency

It is recommended that the standard loading doseregimens be used but that the maintenance dose behalved in patients with mild to moderate hepaticcirrhosis (Child-Pugh Class A and B) receivingVFEND (see CLINICAL PHARMACOLOGY-Hepatic Insufficiency, DOSAGE andADMINISTRATION - Hepatic Insufficiency).

VFEND has not been studied in patients withsevere cirrhosis (Child-Pugh Class C). VFEND hasbeen associated with elevations in liver functiontests and clinical signs of liver damage, such asjaundice, and should only be used in patients withsevere hepatic insufficiency if the benefitoutweighs the potential risk. Patients with hepaticinsufficiency must be carefully monitored for drugtoxicity.

Patients With Renal Insufficiency

In patients with moderate to severe renaldysfunction (creatinine clearance <50 mL/min),accumulation of the intravenous vehicle, SBECD,occurs. Oral voriconazole should be administeredto these patients, unless an assessment of thebenefit/risk to the patient justifies the use ofintravenous voriconazole. Serum creatinine levelsshould be closely monitored in these patients, andif increases occur, consideration should be given tochanging to oral voriconazole therapy (seeCLINICAL PHARMACOLOGY-RenalInsufficiency, DOSAGE ANDADMINISTRATION- Renal Insufficiency).

Renal adverse events

Acute renal failure has been observed in severely illpatients undergoing treatment with VFEND.Patients being treated with voriconazole are likelyto be treated concomitantly with nephrotoxicmedications and have concurrent conditions thatmy result in decreased renal function.

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Monitoring of renal function

Patients should be monitored for the developmentof abnormal renal function. This should includelaboratory evaluation, particularly serumcreatinine.

Dermatological Reactions

Patients have rarely developed serious cutaneousreactions, such as Stevens-Johnson syndrome,during treatment with VFEND. If patients developa rash, they should be monitored closely andconsideration given to discontinuation of VFEND.VFEND has been infrequently associated withphotosensitivity skin reaction, especially duringlong-term therapy. It is recommended that patientsavoid strong, direct sunlight during VFENDtherapy.

Carcinogenesis, Mutagenesis, ImpairmentOf Fertility

Two-year carcinogenicity studies were conductedin rats and mice. Rats were given oral doses of 6,18 or 50 mg/kg voriconazole, or 0.2, 0.6, or 1.6times the recommended maintenance dose (RMD)on a mg/m2 basis. Hepatocellular adenomas weredetected in females at 50 mg/kg and hepatocellularcarcinomas were found in males at 6 and 50mg/kg. Mice were given oral doses of 10, 30 or100 mg/kg voriconazole, or 0.1, 0.4, or 1.4 timesthe RMD on a mg/m2 basis. In mice, hepatocellularadenomas were detected in males and females andhepatocellular carcinomas were detected in malesat 1.4 times the RMD of voriconazole.

Voriconazole demonstrated clastogenic activity(mostly chromosome breaks) in human lymphocytecultures in vitro. Voriconazole was not genotoxicin the Ames assay, CHO assay, the mousemicronucleus assay or the DNA repair test(Unscheduled DNA Synthesis assay).

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Voriconazole produced a reduction in thepregnancy rates of rats dosed at 50 mg/kg, or 1.6times the RMD. This was statistically significantonly in the preliminary study and not in a largerfertility study.

Teratogenic Effects

Pregnancy category D. See WARNINGS

Women Of Child-bearing Potential

Women of childbearing potential should useeffective contraception during treatment.

Nursing Mothers

The excretion of voriconazole in breast milk hasnot been investigated. VFEND should not be usedby nursing mothers unless the benefit clearlyoutweighs the risk.

Pediatric Use

Safety and effectiveness in pediatric patients belowthe age of 12 years have not been established.

A total of 22 patients aged 12-18 years withinvasive aspergillosis were included in thetherapeutic studies. Twelve out of 22 (55%)patients had successful response after treatmentwith a maintenance dose of voriconazole 4 mg/kgQ12h.

Sparse plasma sampling for pharmacokinetics inadolescents was conducted in the therapeuticstudies (see CLINICAL PHARMACOLOGY -Pharmacokinetics, General PharmacokineticCharacteristics).

Geriatric Use

In multiple dose therapeutic trials of voriconazole,9.2% of patients were ≥ 65 years of age and 1.8%of patients were ≥ 75 years of age. In a study inhealthy volunteers, the systemic exposure (AUC)and peak plasma concentrations (Cmax) were

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increased in elderly males compared to youngmales. Pharmacokinetic data obtained from 552patients from 10 voriconazole therapeutic trialsshowed that voriconazole plasma concentrations inthe elderly patients were approximately 80% to90% higher than those in younger patients aftereither IV or oral administration. However, theoverall safety profile of the elderly patients wassimilar to that of the young so no dosageadjustment is recommended (see CLINICALPHARMACOLOGY - Pharmacokinetics in SpecialPopulations).

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ADVERSE REACTIONS

Overview

The most frequently reported adverse events (allcausalities) in the therapeutic trials were visualdisturbances, fever, rash, vomiting, nausea,diarrhea, headache, sepsis, peripheral edema,abdominal pain, and respiratory disorder. Thetreatment-related adverse events which most oftenled to discontinuation of voriconazole therapywere elevated liver function tests, rash, and visualdisturbances (see hepatic toxicity underWARNINGS and discussion of ClinicalLaboratory Values and dermatological and visualadverse events below).

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Discussion Of Adverse Reactions

The data described in the table below reflectexposure to voriconazole in 1493 patients in thetherapeutic studies. This represents aheterogeneous population, includingimmunocompromised patients, e.g., patients withhematological malignancy or HIV and non-neutropenic patients. This subgroup does notinclude healthy volunteers and patients treated inthe compassionate use and non-therapeutic studies.This patient population was 62% male, had a meanage of 45.1 years (range 12-90, including 49patients aged 12-18 years), and was 81% whiteand 9% black. Five hundred sixty-one patients hada duration of voriconazole therapy of greater than12 weeks, with 136 patients receiving voriconazolefor over six months. Table 8 includes all adverseevents which were reported in therapeutic studiesat an incidence of ≥1% as well as events ofconcern which occurred at an incidence of <1%during voriconazole therapy.

In study 307/602, 381 patients (196 onvoriconazole, 185 on amphotericin B) were treatedto compare voriconazole to amphotericin Bfollowed by other licensed antifungal therapy in theprimary treatment of patients with acute invasiveaspergillosis. Study 305 evaluated the effects oforal voriconazole (200 patients) and oralfluconazole (191 patients) for another indication inimmunocompromised (primarily HIV) patients.Laboratory test abnormalities for these studies arediscussed under Clinical Laboratory Values below.

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Table 8

TREATMENT- EMERGENT ADVERSE EVENTSRate ≥ 1% or Adverse Events of Concern in All Therapeutic StudiesPossibly Related to Therapy or Causality Unknown

All TherapeuticStudies

Protocol 305(oral therapy)

Protocol 307/602(IV/ oral therapy)

VoriconazoleN=1493

VoriconazoleN = 200

FluconazoleN =191

VoriconazoleN =196

Ampho B**N = 185

N (%) N (%) N (%) N (%) N (%)

Special senses*Abnormal vision 307 (20.6) 31 (15.5) 8 (4.2) 55 (28.1) 1 (0.5)Photophobia 36 (2.4) 5 (2.5) 2 (1.0) 7 (3.6) 0Chromatopsia 20 (1.3) 2 (1.0) 0 2 (1.0) 0Eye hemorrhage 3 (0.2) 0 0 0 0

Body as a WholeFever 93 (6.2) 0 0 7 (3.6) 25 (13.5)Chills 61 (4.1) 1 (0.5) 0 0 36 (19.5)Headache 48 (3.2) 0 1 (0.5) 7 (3.6) 8 (4.3)Abdominal pain 25 (1.7) 0 0 5 (2.6) 6 (3.2)Chest pain 13 (0.9) 0 0 4 (2.0) 2 (1.1)

Cardiovascular systemTachycardia 37 (2.5) 0 0 5 (2.6) 5 (2.7)Hypertension 29 (1.9) 0 0 1 (0.5) 2 (1.1)Hypotension 26 (1.7) 1 (0.5) 0 1 (0.5) 3 (1.6)Vasodilatation 23 (1.5) 0 0 2 (1.0) 2 (1.1)

Digestive systemNausea 88 (5.9) 2 (1.0) 3 (1.6) 14 (7.1) 29 (15.7)Vomiting 71 (4.8) 2 (1.0) 1 (0.5) 11 (5.6) 18 (9.7)Liver function tests abnormal 41 (2.7) 6 (3.0) 2 (1.0) 9 (4.6) 4 (2.2)Diarrhea 16 (1.1) 0 0 3 (1.5) 6 (3.2)Cholestatic jaundice 16 (1.1) 3 (1.5) 0 4 (2.0) 0Dry mouth 15 (1.0) 0 1 (0.5) 3 (1.5) 0Jaundice 3 (0.2) 1 (0.5) 0 0 0

Hemic and lymphatic systemThrombocytopenia 7 (0.5) 0 1 (0.5) 2 (1.0) 2 (1.1)Anemia 2 (0.1) 0 0 0 5 (2.7)Leukopenia 4 (0.3) 0 0 1 (0.5) 0Pancytopenia 1 (0.1) 0 0 0 0

Metabolic and NutritionalSystemsAlkaline phosphatase increased 54 (3.6) 10 (5.0) 3 (1.6) 6 (3.1) 4 (2.2)Hepatic enzymes increased 28 (1.9) 3 (1.5) 0 7 (3.6) 5 (2.7)SGOT increased 28 (1.9) 8 (4.0) 2 (1.0) 1 (0.5) 0SGPT increased 27 (1.8) 6 (3.0) 2 (1.0) 3 (1.5) 1 (0.5)Hypokalemia 24 (1.6) 0 0 1 (0.5) 36 (19.5)Peripheral edema 16 (1.1) 1 (0.5) 0 7 (3.6) 9 (4.9)Hypomagnesemia 16 (1.1) 0 0 2 (1.0) 10 (5.4)

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All TherapeuticStudies

Protocol 305(oral therapy)

Protocol 307/602(IV/ oral therapy)

VoriconazoleN=1493

VoriconazoleN = 200

FluconazoleN =191

VoriconazoleN =196

Ampho B**N = 185

N (%) N (%) N (%) N (%) N (%)Bilirubinemia 12 (0.8) 1 (0.5) 0 1 (0.5) 3 (1.6)Creatinine increased 4 (0.3) 1 (0.5) 0 0 59 (31.9)

Nervous systemHallucinations 37 (2.5) 0 0 10 (5.1) 1 (0.5)Dizziness 20 (1.3) 0 2 (1.0) 5 (2.6) 0

Skin and AppendagesRash 86 (5.8) 3 (1.5) 1 (0.5) 13 (6.6) 7 (3.8)Pruritus 16 (1.1) 0 0 2 (1.0) 2 (1.1)Maculopapular rash 17 (1.1) 3 (1.5) 0 1 (0.5) 0

UrogenitalKidney function abnormal 8 (0.5) 1 (0.5) 1 (0.5) 4 (2.0) 40 (21.6)Acute kidney failure 7 (0.5) 0 0 0 11 (5.9)

* See WARNINGS – Visual Disturbances, PRECAUTIONS – Information For Patients**Amphotericin B followed by other licensed antifungal therapy

VISUAL DISTURBANCES: Voriconazoletreatment-related visual disturbances are common.In clinical trials, approximately 30% of patientsexperienced altered/enhanced visual perception,blurred vision, color vision change and/orphotophobia. The visual disturbances weregenerally mild and rarely resulted indiscontinuation. Visual disturbances may beassociated with higher plasma concentrationsand/or doses.

The mechanism of action of the visual disturbanceis unknown, although the site of action is mostlikely to be within the retina. In a study in healthyvolunteers investigating the effect of 28-daytreatment with voriconazole on retinal function,voriconazole caused a decrease in theelectroretinogram (ERG) waveform amplitude, adecrease in the visual field, and an alteration incolor perception. The ERG measures electricalcurrents in the retina. The effects were noted earlyin administration of voriconazole and continuedthrough the course of study drug dosing.

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Fourteen days after end of dosing, ERG, visualfields and color perception returned to normal(see WARNINGS, PRECAUTIONS –Information For Patients).

Dermatological Reactions: Dermatologicalreactions were common in the patients treatedwith voriconazole. The mechanism underlyingthese dermatologic adverse events remainsunknown. In clinical trials, rashes consideredrelated to therapy were reported by 6% (86/1493)of voriconazole-treated patients. The majority ofrashes were of mild to moderate severity. Casesof photosensitivity reactions appear to be morelikely to occur with long-term treatment. Patientshave rarely developed serious cutaneous reactions,including Stevens-Johnson syndrome, toxicepidermal necrolysis and erythema multiformeduring treatment with VFEND. If patientsdevelop a rash, they should be monitored closelyand consideration given to discontinuation ofVFEND. It is recommended that patients avoidstrong, direct sunlight during VFEND therapy.

Less Common Adverse Events

The following adverse events occurred in <1% ofall voriconazole-treated patients, including healthyvolunteers and patients treated undercompassionate use protocols (total N = 2090).This listing includes events where a causalrelationship to voriconazole cannot be ruled outor those which may help the physician inmanaging the risks to the patients. The list doesnot include events included in Table 8 above anddoes not include every event reported in thevoriconazole clinical program.

Body as a whole: abdomen enlarged, allergicreaction, anaphylactoid reaction (seePRECAUTIONS), ascites, asthenia, back pain,cellulitis, edema, face edema, flank pain, flusyndrome, graft versus host reaction, granuloma,infection, bacterial infection, fungal infection,injection site pain, injection site

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infection/inflammation, mucous membranedisorder, multi-organ failure, pain, pelvic pain,peritonitis, sepsis, substernal chest pain

Cardiovascular: atrial arrhythmia, atrialfibrillation, AV block complete, bigeminy,bradycardia, bundle branch block, cardiomegaly,cardiomyopathy, cerebral hemorrhage, cerebralischemia, cerebrovascular accident, congestiveheart failure, deep thrombophlebitis, endocarditis,extrasystoles, heart arrest, myocardial infarction,nodal arrhythmia, palpitation, phlebitis, posturalhypotension, pulmonary embolus, QT intervalprolonged, supraventricular tachycardia, syncope,thrombophlebitis, vasodilatation, ventriculararrhythmia, ventricular fibrillation, ventriculartachycardia (including possible torsade de pointes)

Digestive: anorexia, cheilitis, cholecystitis,cholelithiasis, constipation, duodenal ulcerperforation, duodenitis, dyspepsia, dysphagia,esophageal ulcer, esophagitis, flatulence,gastroenteritis, gastrointestinal hemorrhage,GGT/LDH elevated, gingivitis, glossitis, gumhemorrhage, gum hyperplasia, hematemesis,hepatic coma, hepatic failure, hepatitis, intestinalperforation, intestinal ulcer, enlarged liver,melena, mouth ulceration, pancreatitis, parotidgland enlargement, periodontitis, proctitis,pseudomembranous colitis, rectal disorder, rectalhemorrhage, stomach ulcer, stomatitis, tongueedema

Endocrine: adrenal cortex insufficiency, diabetesinsipidus, hyperthyroidism, hypothyroidism

Hemic and lymphatic: agranulocytosis, anemia(macrocytic, megaloblastic, microcytic,normocytic), aplastic anemia, hemolytic anemia,bleeding time increased, cyanosis, DIC,ecchymosis, eosinophilia, hypervolemia,lymphadenopathy, lymphangitis, marrowdepression, petechia, purpura, enlarged spleen,thrombotic thrombocytopenic purpura

Metabolic and Nutritional: albuminuria, BUN

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increased, creatine phosphokinase increased,edema, glucose tolerance decreased,hypercalcemia, hypercholesteremia,hyperglycemia, hyperkalemia, hypermagnesemia,hypernatremia, hyperuricemia, hypocalcemia,hypoglycemia, hyponatremia, hypophosphatemia,uremia

Musculoskeletal: arthralgia, arthritis, bonenecrosis, bone pain, leg cramps, myalgia,myasthenia, myopathy, osteomalacia, osteoporosis

Nervous system: abnormal dreams, acute brainsyndrome, agitation, akathisia, amnesia, anxiety,ataxia, brain edema, coma, confusion, convulsion,delirium, dementia, depersonalization, depression,diplopia, encephalitis, encephalopathy, euphoria,Extrapyramidal Syndrome, grand mal convulsion,Guillain-Barré syndrome, hypertonia, hypesthesia,insomnia, intracranial hypertension, libidodecreased, neuralgia, neuropathy, nystagmus,oculogyric crisis, paresthesia, psychosis,somnolence, suicidal ideation, tremor, vertigo

Respiratory system: cough increased, dyspnea,epistaxis, hemoptysis, hypoxia, lung edema,pharyngitis, pleural effusion, pneumonia,respiratory disorder, respiratory distresssyndrome, respiratory tract infection, rhinitis,sinusitis, voice alteration

Skin and Appendages: alopecia, angioedema,contact dermatitis, discoid lupus erythematosis,eczema, erythema multiforme, exfoliativedermatitis, fixed drug eruption, furunculosis,herpes simplex, melanosis, photosensitivity skinreaction, psoriasis, skin discoloration, skindisorder, skin dry, Stevens-Johnson syndrome,sweating, toxic epidermal necrolysis, urticaria

Special senses: abnormality of accommodation,blepharitis, color blindness, conjunctivitis, cornealopacity, deafness, ear pain, eye pain, dry eyes,keratitis, keratoconjunctivitis, mydriasis, nightblindness, optic atrophy, optic neuritis, otitisexterna, papilledema, retinal hemorrhage, retinitis,

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scleritis, taste loss, taste perversion, tinnitus,uveitis, visual field defect

Urogenital: anuria, blighted ovum, creatinineclearance decreased, dysmenorrhea, dysuria,epididymitis, glycosuria, hemorrhagic cystitis,hematuria, hydronephrosis, impotence, kidneypain, kidney tubular necrosis, metrorrhagia,nephritis, nephrosis, oliguria, scrotal edema,urinary incontinence, urinary retention, urinarytract infection, uterine hemorrhage, vaginalhemorrhage

Clinical Laboratory Values

The overall incidence of clinically significanttransaminase abnormalities in the voriconazoleclinical program was 13.4% (200/1493) ofpatients treated with voriconazole. Increasedincidence of liver function test abnormalities maybe associated with higher plasma concentrationsand/or doses. The majority of abnormal liverfunction tests either resolved during treatmentwithout dose adjustment or following doseadjustment, including discontinuation of therapy.

Voriconazole has been infrequently associatedwith cases of serious hepatic toxicity includingcases of jaundice and rare cases of hepatitis andhepatic failure leading to death. Most of thesepatients had other serious underlying conditions.

Liver function tests should be evaluated at thestart of and during the course of VFEND therapy.Patients who develop abnormal liver function testsduring VFEND therapy should be monitored forthe development of more severe hepatic injury.Patient management should include laboratoryevaluation of hepatic function (particularly liverfunction tests and bilirubin). Discontinuation ofVFEND must be considered if clinical signs andsymptoms consistent with liver disease developthat may be attributable to VFEND (seeWARNINGS and PRECAUTIONS-LaboratoryTests).

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Acute renal failure has been observed in severelyill patients undergoing treatment with VFEND.Patients being treated with voriconazole are likelyto be treated concomitantly with nephrotoxicmedications and have concurrent conditions thatmay result in decreased renal function. It isrecommended that patients are monitored for thedevelopment of abnormal renal function. Thisshould include laboratory evaluation, particularlyserum creatinine.

Tables 9 and 10 show the number of patients withhypokalemia and clinically significant changes inrenal and liver function tests in two randomized,comparative multicenter studies. In study 305,patients were randomized to either oralvoriconazole or oral fluconazole to evaluate anindication other than invasive aspergillosis inimmunocompromised patients. In study 307/602,patients with definite or probable invasiveaspergillosis were randomized to eithervoriconazole or amphotericin B therapy.

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Table 9PROTOCOL 305Clinically Significant Laboratory Test Abnormalities

Criteria* VORICONAZOLE FLUCONAZOLEn/N (%) n /N (%)

T. Bilirubin >1.5x ULN 8/185 (4.3) 7/186 (3.8)AST >3.0x ULN 38/187 (20.3) 15/186 (8.1)ALT >3.0x ULN 20/187 (10.7) 12/186 (6.5)Alk phos >3.0x ULN 19/187 (10.2) 14/186 (7.5)

* Without regard to baseline valuen number of patients with a clinically significant abnormality while on study therapyN total number of patients with at least one observation of the given lab test while on study therapyULN upper limit of normal

Table 10PROTOCOL 307/602Clinically Significant Laboratory Test Abnormalities

Criteria* VORICONAZOLE AMPHOTERICIN B**n/N (%) n/N (%)

T. Bilirubin >1.5x ULN 35/180 (19.4) 46/173 (26.6)AST >3.0x ULN 21/180 (11.7) 18/174 (10.3)ALT >3.0x ULN 34/180 (18.9) 40/173 (23.1)Alk phos >3.0x ULN 29/181 (16.0) 38/173 (22.0)Creatinine >1.3x ULN 39/182 (21.4) 102/177 (57.6)Potassium <0.9x LLN 30/181 (16.6) 70/178 (39.3)

* Without regard to baseline value** Amphotericin B followed by other licensed antifungal therapyn number of patients with a clinically significant abnormality while on study therapyN total number of patients with at least one observation of the given lab test while on study therapyULN upper limit of normalLLN lower limit of normal10

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OVERDOSE

In clinical trials, there were three cases ofaccidental overdose. All occurred in pediatricpatients who received up to five times therecommended intravenous dose of voriconazole.A single adverse event of photophobia of 10minutes duration was reported.

There is no known antidote to voriconazole.

Voriconazole is hemodialyzed with clearance of121 mL/min. The intravenous vehicle, SBECD, ishemodialyzed with clearance of 55 mL/min. In anoverdose, hemodialysis may assist in the removalof voriconazole and SBECD from the body.

The minimum lethal oral dose in mice and rats was300 mg/kg (equivalent to 4 and 7 times therecommended maintenance dose (RMD), based onbody surface area). At this dose, clinical signsobserved in both mice and rats included salivation,mydriasis, titubation (loss of balance whilemoving), depressed behavior, prostration, partiallyclosed eyes, and dyspnea. Other signs in micewere convulsions, corneal opacification andswollen abdomen.

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DOSAGE AND ADMINISTRATION

Administration

VFEND Tablets should be taken at least one hourbefore, or one hour following, a meal.

VFEND I.V. for Injection requires reconstitutionto 10 mg/mL and subsequent dilution to 5 mg/mLor less prior to administration as an infusion, at amaximum rate of 3 mg/kg per hour over 1-2 hours(see Intravenous Administration).NOT FOR IV BOLUS INJECTION

Use In Adults

Therapy must be initiated with the specifiedloading dose regimen of intravenous VFEND toachieve plasma concentrations on Day 1 that areclose to steady state. On the basis of high oralbioavailability, switching between intravenous andoral administration is appropriate when clinicallyindicated (see CLINICAL PHARMACOLOGY).

For the treatment of adults with invasiveaspergillosis and infections due to Fusarium spp.and Scedosporium apiospermum, therecommended dosing regimen of VFEND is asfollows:

Loading dose of 6 mg/kg VFEND I.V. every 12hours for two doses, followed by a maintenancedose of 4 mg/kg VFEND I.V. every 12 hours.

Once the patient can tolerate medication given bymouth, the oral tablet form of voriconazole maybe utilized. Patients who weigh more than 40 kgshould receive an oral maintenance dose of 200mg VFEND tablet every 12 hours. Adult patientswho weigh less than 40 kg should receive an oralmaintenance dose of 100 mg every 12 hours.

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Dosage Adjustment

If patient response is inadequate, the oralmaintenance dose may be increased from 200 mgevery 12 hours to 300 mg every 12 hours. Foradult patients weighing less than 40 kg, the oralmaintenance dose may be increased from 100 mgevery 12 hours to 150 mg every 12 hours.

If patients are unable to tolerate treatment, reducethe intravenous maintenance dose to 3 mg/kgevery 12 hours and the oral maintenance dose by50 mg steps to a minimum of 200 mg every 12hours (or to100 mg every 12 hours for adultpatients weighing less than 40 kg).

Phenytoin may be coadministered with VFEND ifthe maintenance dose of VFEND is increased to 5mg/kg I.V. every 12 hours, or from 200 mg to400 mg every 12 hours orally (100 mg to 200 mgevery 12 hours orally in adult patients weighingless than 40kg) (see CLINICALPHARMACOLOGY, PRECAUTIONS-DrugInteractions).

Duration of therapy should be based on theseverity of the patient’s underlying disease,recovery from immunosuppression, and clinicalresponse.

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Use In Geriatric Patients

No dose adjustment is necessary for geriatricpatients.

Use In Patients With Hepatic Insufficiency

In the clinical program, patients were includedwho had baseline liver function tests (ALT, AST)up to 5 times the upper limit of normal. No doseadjustment is necessary in patients with thisdegree of abnormal liver function, but continuedmonitoring of liver function tests for furtherelevations is recommended (see WARNINGS).

It is recommended that the standard loading doseregimens be used but that the maintenance dose behalved in patients with mild to moderate hepaticcirrhosis (Child-Pugh Class A and B).

VFEND has not been studied in patients withsevere hepatic cirrhosis (Child-Pugh Class C) or inpatients with chronic hepatitis B or chronichepatitis C disease. VFEND has been associatedwith elevations in liver function tests and clinicalsigns of liver damage, such as jaundice, andshould only be used in patients with severe hepaticinsufficiency if the benefit outweighs the potentialrisk. Patients with hepatic insufficiency must becarefully monitored for drug toxicity.

Use In Patients With Renal Insufficiency

The pharmacokinetics of orally administeredVFEND are not significantly affected by renalinsufficiency. Therefore, no adjustment isnecessary for oral dosing in patients with mild tosevere renal impairment (see CLINICALPHARMACOLOGY - Special Populations)

In patients with moderate or severe renalinsufficiency (creatinine clearance <50 mL/min),accumulation of the intravenous vehicle, SBECD,occurs. Oral voriconazole should be administeredto these patients, unless an assessment of thebenefit/risk to the patient justifies the use of

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intravenous voriconazole. Serum creatinine levelsshould be closely monitored in these patients, and,if increases occur, consideration should be givento changing to oral voriconazole therapy (seeDOSAGE and ADMINISTRATION).

Voriconazole is hemodialyzed with clearance of121 mL/min. The intravenous vehicle, SBECD, ishemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove asufficient amount of voriconazole to warrant doseadjustment.

Intravenous Administration

VFEND I.V. For Injection:

Reconstitution

The powder is reconstituted with 19 mL of Waterfor Injection to obtain an extractable volume of 20mL of clear concentrate containing 10 mg/mL ofvoriconazole. It is recommended that a standard20 mL (non-automated) syringe be used to ensurethat the exact amount (19.0 mL) of water forinjection is dispensed. Discard the vial if a vacuumdoes not pull the diluent into the vial. Shake thevial until all the powder is dissolved.

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Dilution

VFEND must be infused over 1–2 hours, at aconcentration of 5 mg/mL or less. Therefore, therequired volume of the 10 mg/mL VFENDconcentrate should be further diluted as follows(appropriate diluents listed below):

1. Calculate the volume of 10 mg/mL VFENDconcentrate required based on the patient'sweight (see Table 11).

2. In order to allow the required volume ofVFEND concentrate to be added, withdrawand discard at least an equal volume of diluentfrom the infusion bag or bottle to be used. Thevolume of diluent remaining in the bag orbottle should be such that when the 10 mg/mLVFEND concentrate is added, the finalconcentration is not less than 0.5 mg/mL norgreater than 5 mg/mL.

3. Using a suitable size syringe and aseptictechnique, withdraw the required volume ofVFEND concentrate from the appropriatenumber of vials and add to the infusion bag orbottle. DISCARD PARTIALLY USEDVIALS.

The final VFEND solution must be infused over1-2 hours at a maximum rate of 3 mg/kg per hour.

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Table 11 RequiredVolumes of 10mg/mL VFEND Concentrate

Volume of VFEND Concentrate (10 mg/mL) required for:Body Weight

(kg)3 mg/kg dose

(number of vials)4 mg/kg dose

(number of vials)6 mg/kg dose

(number of vials)

30 9.0 mL (1) 12 mL (1) 18 mL (1)35 10.5 mL (1) 14 mL (1) 21 mL (2)40 12.0 mL (1) 16 mL (1) 24 mL (2)45 13.5 mL (1) 18 mL (1) 27 mL (2)50 15.0 mL (1) 20 mL (1) 30 mL (2)55 16.5 mL (1) 22 mL (2) 33 mL (2)60 18.0 mL (1) 24 mL (2) 36 mL (2)65 19.5 mL (1) 26 mL (2) 39 mL (2)70 21.0 mL (2) 28 mL (2) 42 mL (3)75 22.5 mL (2) 30 mL (2) 45 mL (3)80 24.0 mL (2) 32 mL (2) 48 mL (3)85 25.5 mL (2) 34 mL (2) 51 mL (3)90 27.0 mL (2) 36 mL (2) 54 mL (3)95 28.5 mL (2) 38 mL (2) 57 mL (3)100 30.0 mL (2) 40 mL (2) 60 mL (3)

VFEND is a single dose unpreserved sterile lyophile.Therefore, from a microbiological point of view,once reconstituted, the product should be usedimmediately. If not used immediately, in-use storagetimes and conditions prior to use are theresponsibility of the user and should not be longerthan 24 hours at 2° to 8°C (37° to 46°F). Thismedicinal product is for single use only and anyunused solution should be discarded. Only clearsolutions without particles should be used.

The reconstituted solution can be diluted with:

9 mg/mL (0.9%) Sodium Chloride USPLactated Ringers USP5% Dextrose and Lactated Ringers USP5% Dextrose and 0.45% Sodium Chloride, USP5% Dextrose USP5% Dextrose and 20 mEq Potassium Chloride, USP0.45% Sodium Chloride USP5% Dextrose and 0.9% Sodium Chloride, USP

The compatibility of VFEND I.V. with diluents otherthan those described above is unknown (seeIncompatibilities below).

Parenteral drug products should be inspectedvisually for particulate matter and discoloration priorto administration, whenever solution and container

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permit.

Incompatibilities:

VFEND I.V. must not be infused into the sameline or cannula concomitantly with other druginfusions, including parenteral nutrition, e.g.,Aminofusin 10% Plus. Aminofusin 10% Plus isphysically incompatible, with an increase in sub-visible particulate matter after 24 hours storage at4ºC.

Infusions of blood products and any electrolytesupplementation must not occur simultaneously withVFEND I.V.

VFEND I.V. must not be diluted with 4.2% SodiumBicarbonate Infusion. The mildly alkaline nature ofthis diluent caused slight degradation of VFENDafter 24 hours storage at room temperature.Although refrigerated storage is recommendedfollowing reconstitution, use of this diluent is notrecommended as a precautionary measure.Compatibility with other concentrations is unknown.

Stability

VFEND Tablets: Store at controlled roomtemperature 15° - 30°C (59° - 86°F).

VFEND I.V. for Injection: Store at controlled roomtemperature 15° - 30°C (59° - 86°F).10

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HOW SUPPLIED

Tablets

VFEND 50 mg tablets - white, film-coated, round,debossed with “Pfizer” on one side and “VOR50” onthe reverse.Bottles of 30 (NDC XXXX-3170-30)

VFEND 200 mg tablets – white, film coated, capsuleshaped, debossed with “Pfizer” on one side and“VOR200” on the reverse.Bottles of 30 (NDC XXXX-3180-30)

Powder for Solution for Injection

VFEND I.V. for injection is supplied in a single usevial as a sterile lyophilized powder equivalent to 200mg VFEND and 3200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).

Individually packaged vials of 200 mg VFEND I.V.(NDC XXXX-3190-XX)

Storage

VFEND Tablets should be stored at controlled roomtemperature 15° - 30°C (59° - 86°F).

Unreconstituted vials should be stored at controlledroom temperature 15° - 30°C (59° - 86°F). VFEND isa single dose unpreserved sterile lyophile. From amicrobiological point of view, following reconstitutionof the lyophile with Water for Injection, thereconstituted solution should be used immediately. Ifnot used immediately, in-use storage times andconditions prior to use are the responsibility of the userand should not be longer than 24 hours at 2°to 8°C(37° to 46°F). Chemical and physical in-use stabilityhas been demonstrated for 24 hours at 2° to 8°C (37°to 46°F). This medicinal product is for single use onlyand any unused solution should be discarded. Onlyclear solutions without particles should be used (seeDOSAGE AND ADMINISTRATION - IntravenousAdministration).

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REFERENCES

1. National Committee for Clinical LaboratoryStandards. Reference method for broth dilutionantifungal susceptibility testing of conidium-forming filamentous fungi. Approved StandardM38-P. National Committee for ClinicalLaboratory Standards, Villanova, Pa.

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---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------------------------------------------------------------------------------------------------------------------- /s/---------------------Mark Goldberger5/24/02 12:29:27 PMNDA 21266, NDA 21267

proposed us package insert vfend i.v. (voriconazole) for … · 2009-03-31 · cmax* (µg/ml) (cv%)...

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