`
`
`
`NDA 21-266/S-032 SUPPLEMENTS APPROVAL
`
`NDA 21-267/S-036
`
`NDA 21-630/S-023
`
`
`
`
`Pfizer, Inc.
`
`Attention: Maureen Garvey, Ph.D.
`
`
`Senior Director
`235 East 42nd Street
`New York, NY 10017-5755
`
`
`Dear Dr. Garvey:
`
`Please refer to your supplemental new drug applications (sNDAs) submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act for the following:
`
`Drug Product Name
`
`
`
`
`NDA
`Number
`21-266
`
`Supplement
`Number
`S-032
`
`Date of
`Supplement
`
`July 22, 2010
`
`Date of Receipt
`
`
`July 22, 2010
`
`21-267
`
`21-630
`
`S-036
`
`S-023
`
`July 22, 2010
`
`July 22, 2010
`
`July 22, 2010
`
`July 22, 2010
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`VFEND® (voriconazole)
`Tablets, 50 mg and 200 mg
`VFEND® I.V. (voriconazole)
`for Injection, 10 mg/mL
`VFEND® (voriconazole) for
`Oral Suspension, 45 mg/mL
`
`
`We acknowledge receipt of your amendments to all three supplements dated November 2 and 5,
`2010.
`
`
`
`SUMMARY OF LABELING SUPPLEMENTS
`
`On July 22, 2010, Pfizer submitted Prior Approval Labeling Supplements that propose adding
`safety information to the package inserts (PI) related to the concomitant and sequential use of
`voriconazole and fluconazole. The patient package insert (PPI) was also submitted, but no
`changes were proposed.
`
`
`
`
`Reference ID: 2866932
`
`

`

`
`
`
` NDA 21-266/S-032
`
` NDA 21-267/S-036
`
` NDA 21-630/S-023
`Page 2
`
`
` REVISIONS TO THE PACKAGE INSERT
`
`The additions to the package insert (PI) that were agreed upon for the above three supplements
`
`are noted with underline:
`
`1. Under the CLINICAL PHARMACOLOGY/ Drug Interactions/Effects of Other Drugs
`on Voriconazole subsection, the following two paragraphs were added between paragraghs
`
`beginning with “Carbamazepine and long-acting barbiturates (potent CYP450 inducers)”
`and “Minor or no significant pharmacokinetic interactions that do not require dosage
`adjustment” heading:
`
`
`
`
`
`Significant drug interactions that may require voriconazole dosage adjustment, or
`
`
`frequent monitoring of voriconazole-related adverse events/toxicity:
`
`
`
`Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent administration of
`oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral
`
`fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects
`resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI:
`
`20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study
`involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and
`fluconazole did not eliminate or diminish this effect. Concomitant administration of
`voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse
`events related to voriconazole is recommended if voriconazole is used sequentially after
`fluconazole, especially within 24 hours of the last dose of fluconazole. (see PRECAUTIONS
`
`- Drug Interactions).
`
`
`2. In Table 11: Effect of Other Drugs on Voriconazole Pharmacokinetics safety information
`regarding Fluconazole was added:
`
`Recommendations for Voriconazole
`Dosage Adjustment/Comments
`
`Contraindicated
`
`When voriconazole is coadministered
`
`with efavirenz, voriconazole
`
`maintenance dose should be increased to
`
`
`400 mg Q12h and efavirenz should be
`
`decreased to 300 mg Q24h (See
`CLINICAL PHARMACOLOGY and
`DOSAGE AND
`
`ADMINISTRATION-Dosage
`Adjustment)
`Contraindicated
`
`
`
`Coadministration of voriconazole and
`
`low-dose ritonavir (100 mg Q12h)
`
`
`
`Drug/Drug Class
`(Mechanism of Interaction by the Drug)
`
`
`Rifampin*, and Rifabutin*
`(CYP450 Induction)
`Efavirenz**
`(CYP450 Induction)
`
`Voriconazole Plasma Exposure
`(Cmax and AUCτ after
`200 mg Q12h)
`Significantly Reduced
`
`Significantly Reduced
`
`High-dose Ritonavir (400mg Q12h)**
`(CYP450 Induction)
`
`
`
`
`
`Significantly Reduced
`
`
`
`
`
`
`Reference ID: 2866932
`
`

`

`
` NDA 21-266/S-032
`
` NDA 21-267/S-036
`
` NDA 21-630/S-023
`Page 3
`
`
`
`Drug/Drug Class
`
`(Mechanism of Interaction by the Drug)
`
`
`Low-dose Ritonavir (100mg Q12h)**
`(CYP450 Induction)
`Carbamazepine
`(CYP450 Induction)
`Long Acting Barbiturates
`(CYP450 Induction)
`Phenytoin*
`(CYP450 Induction)
`
`Voriconazole Plasma Exposure
`(Cmax and AUCτ after
`200 mg Q12h)
`
`Reduced
`
`Not Studied In Vivo or In Vitro, but Likely
`
`
`
`to Result in Significant Reduction
`Not Studied In Vivo or In Vitro, but Likely
`
`
`
`to Result in Significant Reduction
`Significantly Reduced
`
`St. John’s Wort
`
`(CYP450 inducer; P-gp inducer)
`
`Oral Contraceptives**
`containing ethinyl estradiol and
`
`norethindrone (CYP2C19 Inhibition)
`
`Fluconazole**(CYP2C9, CYP2C19 and
`CYP3A4 Inhibition)
`
`
`Significantly Reduced
`
`Increased
`
`Significantly Increased
`
`
`Other HIV Protease Inhibitors
`(CYP3A4 Inhibition)
`
`In Vivo Studies Showed No Significant
`Effects of Indinavir on Voriconazole
`Exposure
`
`In Vitro Studies Demonstrated Potential for
`
`
`Inhibition of Voriconazole Metabolism
`
`(Increased Plasma Exposure)
`
`Other NNRTIs***
`(CYP3A4 Inhibition or CYP450 Induction)
`
`In Vitro Studies Demonstrated Potential for
`
`Inhibition of Voriconazole Metabolism by
`
`Delavirdine and Other NNRTIs (Increased
`
`Plasma Exposure)
`
`A Voriconazole-Efavirenz Drug Interaction
`
`Study Demonstrated the Potential for the
`
`Metabolism of Voriconazole to be Induced
`by Efavirenz and Other NNRTIs
`
`(Decreased Plasma Exposure)
`
`
`Recommendations for Voriconazole
`Dosage Adjustment/Comments
`
`should be avoided, unless an assessment
`of the benefit/risk to the patient justifies
`
`the use of voriconazole
`Contraindicated
`
`Contraindicated
`
`Increase voriconazole maintenance dose
`
`from 4 mg/kg to 5 mg/kg IV every 12
`
`hrs or from 200 mg to 400 mg orally
`
`every 12 hrs (100 mg to 200 mg orally
`
`every 12 hrs in patients weighing less
`than 40 kg)
`Contraindicated
`
`
`Monitoring for adverse events and
`
`toxicity related to voriconazole is
`
`recommended when coadministered
`with oral contraceptives
`Avoid concomitant administration of
`voriconazole and fluconazole.
`Monitoring for adverse events and
`toxicity related to voriconazole is
`
`recommended especially if voriconazole
`
`
`is started within 24 h after the last dose
`of fluconazole.
`
`No dosage adjustment in the
`
`voriconazole dosage needed when
`
`coadministered with indinavir
`
`Frequent monitoring for adverse events
`and toxicity related to voriconazole
`when coadministered with other HIV
`
`protease inhibitors
`
`Frequent monitoring for adverse events
`and toxicity related to voriconazole
`
`
`
`Careful assessment of voriconazole
`effectiveness
`
`
`
`*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg Q12h voriconazole to healthy
`
`
`subjects
`**Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least
`
`
`
`2 days voriconazole to healthy subjects
`*** Non-Nucleoside Reverse Transcriptase Inhibitors
`
`
`
`
`Reference ID: 2866932
`
`

`

`
` NDA 21-266/S-032
`
` NDA 21-267/S-036
`
` NDA 21-630/S-023
`Page 4
`
`
`We have completed our review of these supplemental applications, as amended. They are
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text, including minor editorial revisions.
`
`
`CONTENT OF LABELING
`
`
` As soon as possible, but no later than 14 days from the date of this letter, submit, using the FDA
`
`automated drug registration and listing system (eLIST), the content of labeling [21 CFR
`314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling (text for the package insert) and include the labeling changes
`proposed in any pending “Changes Being Effected” (CBE) supplements. Information on
`submitting SPL files using eLIST may be found in the guidance for industry titled “SPL
`
`Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`
`The SPL will be accessible from publicly available labeling repositories. Also within 14 days,
`amend all pending supplemental applications for these NDAs, including pending “Changes
`Being Effected” (CBE) supplements, for which FDA has not yet issued an action letter, with the
`content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format that includes the changes
`approved in these supplemental applications.
`
`
`LABELING
`
`
`Submit final printed labeling as soon as they are available, but no more than 30 days after they
`are printed. The final printed labeling (FPL) must be identical to the package insert.
`
`The final printed labeling should be submitted electronically according to the guidance for
`industry titled “Providing Regulatory Submissions in Electronic Format – Human
`Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
`
`(October 2005)”. Alternatively, you may submit 12 paper copies, with 6 of the copies
`individually mounted on heavy-weight paper or similar material. For administrative purposes,
`designate these submissions “Final Printed Labeling for approved NDA 21-266/S-032; NDA
`21-267/S-036; NDA 21-630/S-023.” Approval of these submissions by FDA is not required
`before the labeling is used.
`
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`
`If you decide to issue a letter communicating important safety-related information about these
`drug products (i.e., a “Dear Health Care Professional” letter), we request that you submit, at least
`
`Reference ID: 2866932
`
`

`

`
` NDA 21-266/S-032
`
` NDA 21-267/S-036
`
` NDA 21-630/S-023
`Page 5
`
`
`24 hours prior to issuing the letter, an electronic copy of the letter to these NDAs, to
`CDERMedWatchSafetyAlerts@fda.hhs.gov, and to the following address:
`
`
`MedWatch
`
`Food and Drug Administration
`
`Suite 12B-05
`
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for approved NDAs
`(21 CFR 314.80 and 314.81).
`
`
`
`If you have any questions, call Jacquelyn Smith, M.A., Regulatory Project Manager, at (301)
`796-1600.
`
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
` Ozlem Belen, M.D.
`Deputy Director of Safety
` Division of Special Pathogen and Transplant Products
` Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`
`
`Enclosure: Package Insert (PI)
` Patient Package Insert (PPI)
`
`
`
`
`
`
`Reference ID: 2866932
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`OZLEM A BELEN
`11/21/2010
`
`Reference ID: 2866932
`
`