`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`
`
`NDA 21-266/S-025, S-027, S-029, S-030 SUPPLEMENTS APPROVAL
`
`NDA 21-267/S-025, S-029, S-032, S-033
`
`NDA 21-630/S-014, S-018, S-020, S-021
`
`
`
`
`Pfizer, Inc.
`
`Attention: Ms. Anne Palestroni
`
`
` Director, US Regulatory Affairs
`235 East 42nd Street 685/19/05
`New York, NY 10017-5755
`
`
`Dear Ms. Palestroni:
`
`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:
`
`
`
`
`Receipt Date of
`Supplement
`
`December 20, 2007
`July 1, 2009
`December 17, 2009
`March 31, 2010
`December 20, 2007
`July 1, 2009
`December 17, 2009
`March 31, 2010
`December 20, 2007
`July 1, 2009
`December 17, 2009
`March 31, 2010
`
`
`Letter Date of
`Supplement
`
`December 19, 2007
`July 1, 2009
`December 17, 2009
`March 31, 2010
`December 19, 2007
`July 1, 2009
`December 17, 2009
`March 31, 2010
`December 19, 2007
`July 1, 2009
`December 17, 2009
`March 31, 2010
`
`
`NDA Number
`Name of Drug Product
`and Formulation Strengths
`21-266
`VFEND® (voriconazole)
`Tablets, 50 mg and
`200 mg
`
`21-267
`VFEND® I.V.
`(voriconazole) for
`Injection, 10 mg/mL
`21-630
`VFEND® (voriconazole)
`for Oral Suspension, 45
`mg/mL
`
`Supplement
`Number
`
`S-025
`S-027
`S-029
`S-030
`S-025
`S-029
`S-032
`S-033
`S-014
`S-018
`S-020
`S-021
`
`
`
`
`We acknowledge receipt of your amendments dated April 10, 2008, December 17, 2009, April 8,
`April 29, and June 11 and June 17, 2010.
`
`

`

`
` NDA 21-266/S-025, S-027, S-029, S-030
`
`
` NDA 21-267/S-025, S-029, S-032, S-033
`
` NDA 21-630/S-014, S-018, S-020, S-021
`
`Page 2
`
`
` SUMMARY OF LABELING SUPPLEMENTS
`
`(1)
`
`
`
`Visual Adverse Events - CBE Supplements
`NDA 21-266/S-025, NDA 21-267/S-025, and NDA 21-630/S-014
`
`
`In letters dated December 19, 2007, “Changes Being Effected” (CBE) supplements
`NDA 21-266/S-025, NDA 21-267/S-025, and NDA 21-630/S-014 were submitted that proposed
`revisions to the WARNINGS and ADVERSE EVENTS sections, to the VISUAL
`DISTURBANCES sub-section of the package insert and to the “What are possible side effects
`of VFEND? Eyesight (vision) changes” section of the Patient Package Insert.
`
`
`(2)
`
`Drug-Drug Interactions Between Voriconazole And Long-Acting Opiates
`Supplements
`NDA 21-266/S-027, NDA 21-267/S-029, and NDA 21-630/S-018
`
`
`
`In letters dated July 1, 2009, “Prior Approval Supplements” NDA 21-266/S-027,
`NDA 21-267/S-029, and NDA 21-630/S-018 were submitted that proposed revisions to the
`CLINICAL PHARMACOLOGY and the PRECAUTIONS sections of the package insert to
`add information regarding drug interactions between voriconazole and fentanyl, voriconazole
`and oxycodone, and voriconazole and non-steroidal anti-inflammatory drugs (NSAIDs).
`
`
`(3)
`
`Squamous Cell Carcinoma Adverse Events - CBE Supplements
`NDA 21-266/S-029, NDA 21-267/S-032, and NDA 21-630/S-020
`
`
`In letters dated December 17, 2009, CBE labeling supplements NDA 21-266/
`S-029, NDA 21-267/S-032, and NDA 21-630/S-020 were submitted to revise the VFEND label
`to update the PRECAUTIONS/ Dermatological Reactions subsection to reference several
`recently reported cases of squamous skin carcinoma that had developed in immunocompromised
`patients (primarily post-lung transplant) receiving long-term treatment with voriconazole.
`
`
`(4) Melanoma Adverse Events – CBE Supplements
`NDA 21-266/S-030, NDA 21-267/S-033, and NDA 21-630/S-021
`
`
`In letters dated March 31, 2010, CBE labeling supplements NDA 21-266/S-030, NDA 21-267/
`S-033, and NDA 21-630/S-021 were submitted to revise the VFEND label to update the
`PRECAUTIONS/ Dermatological Reactions subsection to include melanoma.
`
`
`
`

`

`
` NDA 21-266/S-025, S-027, S-029, S-030
`
`
` NDA 21-267/S-025, S-029, S-032, S-033
`
` NDA 21-630/S-014, S-018, S-020, S-021
`
`Page 3
`
`
` REVISIONS TO THE PACKAGE INSERT
`
`The revisions to the package insert (PI) that were agreed upon for the above twelve supplements
`
`are as follow (additions are noted with underline and deletions with strikethrough):
`
`(1)
`
`
`Visual Adverse Events - CBE Supplements
`
`a. Under the WARNINGS/VISUAL DISTURBANCES subsection, a new sentence
`was added:
`
`
`
`VISUAL DISTURBANCES: The effect of VFEND on visual function is not
`known if treatment continues beyond 28 days. There have been post-marketing
`
`
` reports of prolonged visual adverse events, including optic neuritis and papilledema.
`
`If treatment continues beyond 28 days, visual function including visual acuity, visual
`field and color perception should be monitored (see PRECAUTIONS – Information
`
`for Patients and ADVERSE REACTIONS – Visual Disturbances).
`
`
`b. Under the ADVERSE REACTIONS section, the font for the heading VISUAL
`DISTURBANCES was changed and a new second paragraph was added:
`
`
`
`
`VISUAL DISTURBANCES Visual Disturbances: Voriconazole treatment-related
`
`visual disturbances are common. In therapeutic trials, approximately 21% of patients
`experienced abnormal vision, color vision change and/or photophobia. The visual
`disturbances were generally mild and rarely resulted in discontinuation. Visual
`disturbances may be associated with higher plasma concentrations and/or doses.
`
`There have been post-marketing reports of prolonged visual adverse events, including
`
`optic neuritis and papilledema (see WARNINGS).
`
`
`c. In the Patient Package Insert, under the What are possible side effects of VFEND?
`section and the Eyesight (vision) changes subsection, the second paragraph was
`revised:
`
`
`
`These changes include blurred vision, color vision change, and being sensitive to light
`while you are taking VFEND. These changes are generally mild. Vision side effects
`lasting for more than one month have been reported by some patients. Your doctor
`should monitor your eyesight if you take VFEND for more than 28 days.
`
`Drug-Drug Interactions Between Voriconazole And Long-Acting Opiates - Prior
`Approval Supplements
`
`
`a. Under the CLINICAL PHARMACOLOGY/Drug Interactions/Effect of
`
`Voriconazole on Other Drugs subsection, three new paragraphs were added:
`
`
`
`
`
`
`
`
`
`
`
`
`(2)
`
`
`
`
`
`
`

`

`
` NDA 21-266/S-025, S-027, S-029, S-030
`
`
` NDA 21-267/S-025, S-029, S-032, S-033
`
` NDA 21-630/S-014, S-018, S-020, S-021
`
`Page 4
`
`
`
`
`
`
`
`
`
`
`
`
`
` Note: Information for Fentanyl and Oxycodone was added between Alfentanil and
`
`
` Cyclosporine in this subsection.
`
`
`Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use
`of voriconazole (400 mg Q12h on Day 1, then 200 mg Q12h on Day 2) with a single
`itravenous dose of fentanyl (5 μg/kg) resulted in an increase in the mean AUC0–∞ of
`fentanyl by 1.4-fold (range 0.81- to 2.04-fold). When voriconazole is co-administered
`with fentanyl IV, oral or transdermal dosage forms, extended and frequent monitoring
`of patients for respiratory depression and other fentanyl-associated adverse events is
`recommended, and fentanyl dosage should be reduced, if warranted. (see
`
`PRECAUTIONS – Drug Interactions).
`
`Oxycodone (CYP3A4 substrate): In an independent published study,
`
`coadministration of multiple doses of oral voriconazole (400 mg Q12h on Day 1
`followed by five doses of 200 mg Q12h on Days 2 to 4) with a single 10 mg oral dose
`of oxycodone on Day 3 resulted in an increase in the mean Cmax and AUC0–∞ of
`oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6-fold (range 2.7- to 5.6-fold),
`respectively. The mean elimination half-life of oxycodone was also increased by 2.0­
`fold (range 1.4- to 2.5-fold). Voriconazole also increased the visual effects
`
`(heterophoria and miosis) of oxycodone. A reduction in oxycodone dosage may be
`
`
`needed during voriconazole treatment to avoid opioid related adverse effects.
`Extended and frequent monitoring for adverse effects associated with oxycodone and
`other long-acting opiates metabolized by CYP3A4 is recommended. (see
`
`PRECAUTIONS – Drug Interactions).
`
`
`
`Note: Information for Non-Steroidal Anti-Inflammatory Drugs was added between
`
`Vinca Alkaloids and the paragraph beginning “No significant pharmacokinetic
`interactions were observed when voriconazole…”
`
`Non-Steroidal Anti-Inflammatory Drugs (NSAIDS; CYP2C9 substrates): In two
`independent published studies, single doses of ibuprofen (400 mg) and diclofenac (50
`mg) were coadministered with the last dose of voriconazole (400 mg Q12h on Day 1,
`followed by 200 mg Q12h on Day 2). Voriconazole increased the mean Cmax and
`AUC of the pharmacologically active isomer, S (+)-ibuprofen by 20% and 100%,
`respectively. Voriconazole increased the mean Cmax and AUC of diclofenac by
`114% and 78%, respectively. A reduction in ibuprofen and diclofenac dosage of
`NSAIDs may be needed during concomitant administration with voriconazole.
`Patients receiving voriconazole concomitantly with other NSAIDs (e.g., celecoxib,
`naproxen, lornoxicam, meloxicam) that are also metabolized by CYP2C9 should be
`carefully monitored for NSAID-related adverse events and toxicity, and dosage
`
`reduction should be made if warranted. (see PRECAUTIONS – Drug Interactions).
`
`
`
`
`b. Under the PRECAUTIONS/Drug Interactions subsection, Table 12 was updated:
`
`
`Note: Information on Fentanyl, Oxycodone and NSAIDs was added to Table 12
`
`
`
`

`

`
` NDA 21-266/S-025, S-027, S-029, S-030
`
`
` NDA 21-267/S-025, S-029, S-032, S-033
`
` NDA 21-630/S-014, S-018, S-020, S-021
`
`Page 5
`
`
`Table 12: Effect of Voriconazole on Pharmacokinetics of Other Drugs
`Recommendations for Drug Dosage
`Drug Plasma
`Drug/Drug
`Adjustment/Comments
`Exposure
`Class
`(Cmax and
`(Mechanism of
`AUCτ)
`Interaction by
`Voriconazole)
`Fentanyl
`(CYP3A4
`Inhibition)
`
`
`Increased
`
`
`Oxycodone
`(CYP3A4
`Inhibition)
`
`
`Reduction in the dose of fentanyl and other long-acting
`opiates metabolized by CYP3A4 should be considered when
`coadministered with VFEND. Extended and frequent
`monitoring for opiate-associated adverse events may be
`necessary (see CLINICAL PHARMACOLOGY-Drug
`
`Interactions).
`
`Significantly Reduction in the dose of oxycodone and other long-acting
`Increased
`opiates metabolized by CYP3A4 should be considered when
`
`coadministered with VFEND. Extended and frequent
`monitoring for opiate-associated adverse events may be
`necessary (see CLINICAL PHARMACOLOGY-Drug
`Interactions).
`
`
`Frequent monitoring for adverse events and toxicity
`related to NSAIDs. Dose reduction of NSAIDs may be
`needed. (see CLINICAL PHARMACOLOGY - Drug
`
`Interactions).
`
`
`Increased
`
`
`
`
`
`
`
`NSAIDs ****
`including
`
`ibuprofen and
`
`diclofenac
`(CYP2C9
`
`Inhibition)
` *Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID 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
` *** Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 4
`
`days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg QD)
`
`**** Non-Steroidal Anti-Inflammatory Drugs
`
`***** Non-Nucleoside Reverse Transcriptase Inhibitors
`
`
`(3)
`
`Squamous Cell Carcinoma Adverse Events - CBE Supplements
`
`
`
`
` and
`
`
`(4) Melanoma Adverse Events – CBE Supplements
`
`
`
`
`a. Under the PRECAUTIONS/Dermatological Reactions subsection, the first
`paragraph was revised and a new second paragraph was added:
`
`
`
`
`
`
`
`
`
`

`

`
` NDA 21-266/S-025, S-027, S-029, S-030
`
`
` NDA 21-267/S-025, S-029, S-032, S-033
`
` NDA 21-630/S-014, S-018, S-020, S-021
`
`Page 6
`
`
`
`
`
` Dermatological Reactions Adverse Events
`
`Patients have rarely developed serious exfoliative cutaneous reactions, such as
`Stevens-Johnson syndrome, during treatment with VFEND. If a patients develops a
`rash, they should be monitored closely and consideration given to discontinuation of
`
`VFEND an exfoliative cutaneous reaction, VFEND should be discontinued. VFEND
`has been infrequently associated with photosensitivity skin reaction, especially during
`
`long-term therapy. It is recommended that patients avoid strong, direct sunlight
`
`
`during VFEND therapy.
`
`In addition, VFEND has been associated with photosensitivity skin reactions.
`Patients should avoid intesnse or prolonged exposure to direct sunlight during
`VFEND treatment. In patients with photosensitivity skin reactions, squamous cell
`carcinoma of the skin and melanoma have been reported during long-term therapy. If
`a patient develops a skin lesion consistent with squamous cell carcinoma or
`
`melanoma, VFEND should be discontinued.
`
`
`b. Under the ADVERSE REACTIONS/Dermatological Reactions subsection, the first
`paragraph was revised and reformatted, and a new third paragraph was added:
`
`
`
`Dermatological Reactions: Dermatological reactions were common in the patients
`treated with voriconazole. The mechanism underlying these dermatologic adverse
`events remains unknown. In clinical trials, rashes considered related to therapy were
`reported by 7% (110/1655) of voriconazole-treated patients. The majority of rashes
`were of mild to moderate severity. Cases of photosensitivity reactions appear to be
`
`
`more likely to occur with long-term treatment.
`
`
`Patients have rarely developed serious cutaneous reactions, including Stevens-
`Johnson syndrome, toxic epidermal necrolysis and erythema multiforme during
`treatment with VFEND. If patients develop a rash, they should be monitored closely
`
`and consideration given to discontinuation of VFEND. It is recommended that
`patients avoid strong, direct sunlight during VFEND therapy. If a patient develops an
`
`
`exfoliative cutaneous reaction, VFEND should be discontinued.
`
`In addition, VFEND has been associated with photosensitivity skin reactions.,
`Patients should avoid strong, direct sunlight during VFEND therapy. In patients with
`photosensitivity skin reactions, squamous cell carcinoma of the skin and melanoma
`
`have been reported during long-term therapy. If a patient develops a skin lesion
`
`consistent with squamous cell carcinoma or melanoma, VFEND should be
`discontinued.
`
`
`
`c. Under the ADVERSE REACTIONS/Less Common Adverse Events/Skin and
`
`Appendages subsection, new information was added:
`
`
`
`
`
`
`
`
`
`
`
`

`

`
` NDA 21-266/S-025, S-027, S-029, S-030
`
`
` NDA 21-267/S-025, S-029, S-032, S-033
`
` NDA 21-630/S-014, S-018, S-020, S-021
`
`Page 7
`
`
`
`Skin and Appendages: alopecia, angioedema, contact dermatitis, discoid lupus
`erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug
`eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis,
`photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration,
`skin disorder, skin dry, squamous cell carcinoma, Stevens-Johnson syndrome,
`sweating, toxic epidermal necrolysis, urticaria
`
`
`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 this NDA, 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 this supplemental application.
`
`
`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-025, S-027,
`S-029, S-030; NDA 21-267/S-025, S-029, S-032, S-033; NDA 21-630/S-014, S-018, S-020,
`
`
`
`
`
`

`

`
` NDA 21-266/S-025, S-027, S-029, S-030
`
`
` NDA 21-267/S-025, S-029, S-032, S-033
`
` NDA 21-630/S-014, S-018, S-020, S-021
`
`Page 8
`
`
`S-021.” 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 this
`drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit, at least
`24 hours prior to issuing the letter, an electronic copy of the letter to this NDA, 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 an approved NDA
`(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}
`
`
` Renata Albrecht, M.D.
` Director
`
` 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)
`
`
`
`
`
`
`
`
`

`

`Application
`Type/Number
`--------------------
`NDA-21630
`
`Submission
`Type/Number
`--------------------
`SUPPL-21
`
`--------------------
`PFIZER INC
`
`Submitter Name
`
`Product Name
`
`------------------------------------------
`VFEND (VORICONAZOLE)
`ORAL SUSPENSION
`VFEND (VORICONAZOLE)
`ORAL SUSPENSION
`VFEND (VORICONAZOLE)
`ORAL SUSPENSION
`VFEND (VORICONAZOLE)
`ORAL SUSPENSION
`VFEND (VORICONAZOLE)
`200MG IV
`VFEND (VORICONAZOLE)
`200MG IV
`VFEND (VORICONAZOLE)
`200MG IV
`VFEND (VORICONAZOLE)
`200MG IV
`VFEND (VORICONAZOLE)
`50/200MG TABLETS
`VFEND (VORICONAZOLE)
`50/200MG TABLETS
`VFEND (VORICONAZOLE)
`50/200MG TABLETS
`VFEND (VORICONAZOLE)
`50/200MG TABLETS
`
`NDA-21630
`
`SUPPL-20
`
`PFIZER INC
`
`NDA-21630
`
`SUPPL-18
`
`PFIZER INC
`
`NDA-21630
`
`SUPPL-14
`
`PFIZER INC
`
`NDA-21267
`
`SUPPL-33
`
`PFIZER INC
`
`NDA-21267
`
`SUPPL-32
`
`PFIZER INC
`
`NDA-21267
`
`SUPPL-29
`
`PFIZER INC
`
`NDA-21267
`
`SUPPL-25
`
`PFIZER INC
`
`NDA-21266
`
`SUPPL-30
`
`PFIZER INC
`
`NDA-21266
`
`SUPPL-29
`
`PFIZER INC
`
`NDA-21266
`
`SUPPL-27
`
`PFIZER INC
`
`NDA-21266
`
`SUPPL-25
`
`PFIZER INC
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RENATA ALBRECHT
`06/17/2010
`
`