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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 21083/S-062
`NDA 21110/S-081
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`PF PRISM C.V.
`c/o Pfizer, Inc.
`Attention: Deneen Stewart, PhD
` Director, Worldwide Safety and Regulatory
`500 Arcola Road
`Collegeville, PA 19426
`
`
`Dear Dr. Stewart:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated and received
`December 15, 2017, and your amendment January 8, 2018, submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act (FDCA) for the following:
`
`
`NDA
`Number
`NDA 21083
`NDA 21110
`
`Supplement
`Number
`S-062
`S-081
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`Name of Drug Product
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`Rapamune® (sirolimus) Oral Solution, 1 mg/mL
`Rapamune® (sirolimus) Tablets, 1 mg, 2 mg, and 5 mg
`
`
`We also refer to our letter dated November 15, 2017, notifying you, under Section 505(o)(4) of
`the FDCA, of new safety information that we believe should be included in the labeling for the
`class of mammalian target of rapamycin (m-TOR) inhibitors. This information pertains to the
`risk of embryo-fetal toxicities in animals, at exposures near or below those achieved in human
`transplant patients.
`
`These supplemental new drug applications provides for revisions to the labeling for Rapamune.
`The agreed upon changes to the language included in our November 15, 2017, letter is as
`follows: (additions are noted by underline and deletions are noted by strikethrough)
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`
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`1. In the HIGHLIGHTS OF PRESCRIBING INFORMATION: the WARNINGS
`AND PRECAUTIONS section, is revised to add a new bulleted title at the end of the
`list as follows:
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`
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`• Embryo-Fetal Toxicity (5.15, 8.1)
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`Reference ID: 4206874
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`

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`NDA 21083/S-062
`NDA 21110/S-081
`Page 2
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`2. In the HIGHLIGHTS OF PRESCRIBING INFORMATION: the USE IN
`SPECIFIC POPULATIONS section, is revised as follows:
`
` •
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` Pregnancy: Use only if the potential benefit outweights the potential risk to
`the embryo/fetus (8.1) Based on animal data may cause fetal harm (5.15, 8.1)
`
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`3. In the Full Prescribing Information: Contents, the title “Embryo-Fetal Toxicity”
`section 5.15 has been added and all numbering and references have been updated
`throughout the labeling accordingly.
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`In the FULL PRESCRIBING INFORMATION:
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`4. In the 5 WARNINGS AND PRECAUTIONS section, a new the subsection 5.15
`titled “Embryo-Fetal Toxicity” is be added as follows:
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`5.15 Embryo-Fetal Toxicity
`Based on animal studies and the mechanism of action [see Clinical Pharmacology
`(12.1)], Rapamune may cause fetal harm when administered to a pregnant
`woman. In animal studies, mTOR inhibitors caused embryo-fetal toxicity when
`administered during the period of organogenesis at maternal exposures that were
`equal to or less than human exposures at the recommended lowest starting dose.
`Advise pregnant women of the potential risk to a fetus. Advise women of
`childbearing potential to avoid becoming pregnant and to use effective
`contraception while using Rapamune and for 12 weeks after ending treatment.
`[see Use in Specific Populations (8.1)]
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`
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`5. The 8 USE IN SPECIFIC POPULATIONS/PREGNANCY subsection is revised
`as follows:
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`8.1
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`Pregnancy
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`Pregnancy Category C: Sirolimus was embryo/fetotoxic in rats when given in
`doses approximately 0.2 to 0.5 the human doses (adjusted for body surface area).
`Embryo/fetotoxicity was manifested as mortality and reduced fetal weights (with
`associated delays in skeletal ossification). However, no teratogenesis was evident.
`In combination with cyclosporine, rats had increased embryo/feto mortality
`compared with sirolimus alone. There were no effects on rabbit development at a
`maternally toxic dosage approximately 0.3 to 0.8 times the human doses (adjusted
`for body surface area). There are no adequate and well- controlled studies in
`pregnant women. Effective contraception must be initiated before Rapamune
`therapy, during Rapamune therapy, and for 12 weeks after Rapamune therapy has
`been stopped. Rapamune should be used during pregnancy only if the potential
`benefit outweighs the potential risk to the embryo/fetus.
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`Reference ID: 4206874
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`

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`NDA 21083/S-062
`NDA 21110/S-081
`Page 3
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`6. The MEDICATION GUIDE is revised for consistency with the package insert, as
`well as administrative changes and/or editorial changes. See attached medication
`guide.
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`APPROVAL & LABELING
`
`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 submitted on January 8, 2018.
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`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), 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.
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications that include labeling changes
`for this NDA, 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 this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, 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 number(s) and annual report
`date(s).
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`Reference ID: 4206874
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`

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`NDA 21083/S-062
`NDA 21110/S-081
`Page 4
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`PROMOTIONAL MATERIALS
`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`should include prominent disclosure of the important new safety 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 address above, by fax to 301-847-8444, or
`electronically in eCTD format. For more information about submitting promotional materials in
`eCTD format, see the draft guidance for industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
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`If you have any questions, call Ms. June Germain, Safety Regulatory Project Manager, at (301)
`796-4024.
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`Sincerely,
`
`{See appended electronic signature page}
`
`Ozlem Belen, MPH, MD
`Deputy Director for Safety
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
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`ENCLOSURE: Content of Labeling, Medication guide
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`Reference ID: 4206874
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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/
`----------------------------------------------------
`
`OZLEM A BELEN
`01/12/2018
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`Reference ID: 4206874
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`