DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
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`Food and Drug Administration
`Rockville, MD 20857
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`NDA 21-083/S-046
`NDA 21-110/S-056
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`Wyeth Pharmaceuticals, Inc.
`Attention: Sharon Pfleger
` Manager, Worldwide Regulatory Affairs
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`P. O. Box 8299
`Philadelphia, PA 19101-8299
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`Dear Ms. Pfleger:
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`Please refer to your Supplemental New Drug Applications dated and received May 18, 2010,
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`under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Rapamune (sirolimus)
`Oral Solution (NDA 21-083) and Rapamune (sirolimus) Tablets (NDA 21-110).
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`We also refer to your amendments dated June 30, 2010.
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`These Prior Approval Supplemental New Drug Applications, submitted in response to the
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`Division’s Supplement Request letter dated February 10, 2010, provide for the following
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`revisions to the package insert (additions are underlined):
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`1. The following two paragraphs were added at the end of the 5.10 Latent Viral Infections
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`section of the package insert:
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`Immunosuppressed patients are at increased risk for opportunistic infections, including
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`activation of latent viral infections. These include BK virus-associated nephropathy, which
`has been observed in patients receiving immunosuppressants, including Rapamune. This
`infection may be associated with serious outcomes, including deteriorating renal function and
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` renal graft loss [see Adverse Reactions (6.6)]. Patient monitoring may help detect patients at
`risk for BK virus-associated nephropathy. Reduction in immunosuppression should be
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`considered for patients who develop evidence of BK virus-associated nephropathy.
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`Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been
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`reported in patients treated with immunosuppressants, including Rapamune. PML commonly
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`presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors
`for PML include treatment with immunosuppressant therapies and impairment of immune
`function. In immunosuppressed patients, physicians should consider PML in the differential
`diagnosis in patients reporting neurological symptoms and consultation with a neurologist
`should be considered as clinically indicated. Consideration should be given to reducing the
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`amount of immunosuppression in patients who develop PML. In transplant patients,
`physicians should also consider the risk that reduced immunosuppression represents to the
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`graft.
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`NDA 21-083/S-046
`NDA 21-110/S-056
`Page 2
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`2. The following sentence was added in the 6.6 Postmarketing Experience, Infections section:
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`ƒ
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`Infections – Tuberculosis. BK virus associated nephropathy has been observed in
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`patients receiving immunosuppressants, including Rapamune. This infection may be
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`associated with serious outcomes, including deteriorating renal function and renal graft
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`loss. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have
`been reported in patients treated with immunosuppressants, including Rapamune [see
`Warnings and Precautions (5.10)].
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`We have completed the review of these supplemental new drug applications, and have concluded
`that adequate information has been presented to demonstrate that the drug products are safe and
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`effective for use as recommended in the agreed upon labeling text (enclosed). Accordingly,
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`these supplemental applications are approved effective on the date of this letter.
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, please submit 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
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`identical to the enclosed content of labeling (text for the package insert), which was submitted on
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`June 30, 2010. For administrative purposes, please designate this submission, “SPL for
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`NDA 21-083/S-046 and NDA 21-110/S-056.”
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`Also, within 14 days from the date of this letter, please amend all pending supplemental
`applications for these NDAs, including pending "Changes Being Effected" (CBE) supplements
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`for which FDA has not yet issued an action letter, with the content of labeling [21 CFR
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`314.50(l)(1)(i)] in structured product labeling (SPL) format that includes the changes approved
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`in these supplemental applications.
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`PROMOTIONAL MATERIALS
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`All promotional materials for your drug product that include representations about your drug
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`product must be promptly revised to make it consistent with the labeling changes approved in
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`this supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions to
`your promotional materials should include prominent disclosure of the important new safety
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`information that appears in the revised package labeling. Within 7 days of receipt of this letter,
`submit your statement of intent to comply with 21 CFR 314.70(a)(4) to the following address or
`by facsimile at 301-847-8444:
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`Food and Drug Administration
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`2
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`NDA 21-083/S-046
`NDA 21-110/S-056
`Page 3
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` In addition, as required under 21 CFR 314.81(b)(3)(i), you must submit your updated final
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` promotional materials, and the package insert(s), at the time of initial dissemination or
`publication, accompanied by a Form FDA-2253, directly to the above address. For instruction on
`completing the Form FDA 2253, see page 2 of the Form. For more information about submission
`of promotional materials to the Division of Drug Marketing, Advertising, and Communications
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`(DDMAC), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`If you issue a letter communicating important safety related information about this drug product
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`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
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`the letter to both this NDA and to the following address:
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`MedWatch
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`Food and Drug Administration
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`5600 Fishers Lane, Room 12B05
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`Rockville, MD 20857
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
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`(21 CFR 314.80 and 314.81).
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`If you have any questions, please call Diana Willard, Chief Project Manager at (301) 796-1600.
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`Sincerely,
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`{See appended electronic signature page}
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`Ozlem Belen, MD, MPH
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`Deputy Director for Safety
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`Division of Special Pathogen and Transplant
`Products
`Office of Antimicrobial Products
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`Center for Drug Evaluation and Research
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`ENCLOSURE: LABELING
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`3
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`Application
`Type/Number
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`NDA-21110
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`Submission
`Type/Number
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`SUPPL-56
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`NDA-21083
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`SUPPL-46
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`Submitter Name
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`Product Name
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`------------------------------------------
`--------------------
`RAPAMUNE (SIROLIMUS) 1MG
`WYETH
`PHARMACEUTICA TABLETS
`LS INC
`RAPAMUNE
`WYETH
`PHARMACEUTICA (SIROLIMUS)1MG/ML ORAL
`LS INC
`SOLUTION
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`OZLEM A BELEN
`07/02/2010
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