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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`
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`
`
`NDA 21-083/S-049
`NDA 21-110/S-059
`
`Wyeth Pharmaceuticals, Inc.
`
`Attention:
`Sharon Pfleger, M.S., RAC
`
`Manager, Global Regulatory Affairs
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`SUPPLEMENTS APPROVAL
`
`
`
`PO Box 8299
`Philadelphia, PA 19101-8299
`
`
`Dear Ms. Pfleger:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated and received on
`January 13, 2011, and submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act (FDCA) for the following:
`
`
`Name of Drug Product
`RAPAMUNE® (sirolimus) Oral Solution,
`1 mg/mL
`RAPAMUNE® (sirolimus) Tablets,
`
`1 mg, 2 mg, and 5 mg
`
`NDA Number
`21-083
`
`Supplement Number
`S-049
`
`21-110
`
`S-059
`
`
`We acknowledge receipt of your amendments dated June 3 and June 30, 2011.
`
`These prior approval supplemental new drug applications provide for revisions to the
`Instructions for Use section of the package insert and the carton label to enhance safe use of
`Rapamune® (sirolimus) and ensure consistency with the Medication Guide.
`
`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.
`
`The revisions to the package insert including the Instructions for Use section and carton label
`were as follows (additions are noted with underline and deletions noted with strikethrough):
`
`
`
`1. The RECENT MAJOR CHANGES subsection of the HIGHLIGHTS section of the
`package insert was revised as follows:
`
`Dosage and Administration
`
`Therapeutic Drug Monitoring (2.3)
`
`
`04/2010
`
`
`
`
`Reference ID: 2972147
`
`

`

`
` NDA 21-083/S-049
`
` NDA 21-110/S-059
`Page 2
`
`
`
`Warnings and Precautions
`
`
`• Fluid Accumulation and Wound
`Healing (5.6)
`
`
`• Hyperlipidemia (5.7)
`
`
`• Latent Viral infections (5.10)
`
`• Assay for Sirolimus Therapeutic
`
` Drug Monitoring (5.15)
`
`04/2010
`
`
` 09/2010
`
`07/2010
`
` 04/2010
`
`
`
`2. Please see the revisions in the enclosed marked-up version of the Instructions for Use
`
`section of the package insert.
`
`
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`3. The carton label was revised to include the same revisions as those made in the
`
`Instructions for Use section of the package insert and is also enclosed.
`
`
`
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`4. The carton label was also revised as follows:
`
`
`
`• DISPENSE WITH MEDICATION GUIDE ENCLOSED OR PROVIDED
`SEPARATELY was added.
`
`
`•
`
`
`
`
`"Patient Instructions for RAPAMUNE Administration" was revised to
`
`Instructions for Use for RAPAMUNE (sirolimus) Oral Solution.
`
`
`
`• PROTECT FROM LIGHT was added.
`
`
`• U.S. Patents: See package insert was removed.
`
`
`• The following was revised:
`
`
` Patient Kit contains:
`
`1 bottle of 60 mL oral solution
`
`
`1 bottle adapter assembly
`
`
`30 disposable syringes and caps
`
`
`1 syringe carrying case
`
`
`Package Insert
`
`
`Medication Guide
`
`
`
`to:
`
` Each RAPAMUNE Oral Solution carton contains:
`
`a) a 2 oz. (60 mL fill) amber glass bottle of sirolimus
`
` (concentration of 1 mg/mL
`b) 1 oral syringe adapter for fitting into the neck of the bottle
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`c) enough disposable amber oral syringes and caps for daily dosing
`
`
` d) 1 carrying case
`
`
`
`
`
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`Reference ID: 2972147
`
`

`

`
` NDA 21-083/S-049
`
` NDA 21-110/S-059
`Page 3
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`
`
`
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` Also contains: Package Insert and Medication Guide
`
` You will also need:
`
`• glass or plastic cup
`
` • 6 oz. of water or orange juice only
`
`
`5. Minor editorial and formatting changes were made throughout all sections of the package
`insert.
`
`
`
`
`
`
` CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, Medication
`Guide, and Instructions for Use), with the addition of any labeling changes in pending “Changes
`Being Effected” (CBE) supplements, as well as annual reportable changes not included in the
`enclosed labeling.
`
`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
`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, as well as annual reportable changes and annotate each change. To
`facilitate review of your submissions, provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement numbers and annual report date(s).
`
`
`CARTON LABEL
`
`We acknowledge your June 30, 2011 submissions containing final printed carton label.
`
`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 Hyun J. Son, Pharm.D., Safety Regulatory Project Manager, at
`(301) 796-1600.
`
`
`
`
`Reference ID: 2972147
`
`

`

`
` NDA 21-083/S-049
`
` NDA 21-110/S-059
`Page 4
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`ENCLOSURES:
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Ozlem Belen, M.D., MPH
`Deputy Director for Safety
`Division of Transplant and Ophthalmology Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`Edited versions of the Instructions for Use section of package insert and carton label
`Revised Content of Labeling
`Revised Carton Label
`
`
`
`
`Reference ID: 2972147
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`07/11/2011
`
`Reference ID: 2972147
`
`