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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 21083/S-058
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` NDA 21110/S-075
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` PF PRISM C.V.
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` c/o Pfizer, Inc.
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` Attention: Deneen Stewart, PhD
` Director, Worldwide Safety and Regulatory
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` 500 Arcola Road
` Collegeville, PA 19426
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` Dear Dr. Stewart:
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` Please refer to your Supplemental New Drug Applications (sNDAs) dated and received August
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` 14, 2015, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA)
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` for Rapamune (sirolimus) Oral Solution and Rapamune (sirolimus) Tablets.
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` We acknowledge receipt of your amendments dated October 16, 2015.
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` We also refer to our letter dated July 14, 2015, notifying you, under Section 505(o)(4) of the
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` 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 of which Rapamune (sirolimus) Oral
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` Solution and Rapamune (sirolimus) Tablets are members. This information pertains to the
` serious risk of pulmonary hypertension (PH), including pulmonary arterial hypertension (PAH),
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` that suggest an association with the use of sirolimus.
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` These supplemental new drug applications provide for revisions to the labeling for Rapamune
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` (sirolimus) Oral Solution and Rapamune (sirolimus) Tablets, consistent with our July 14, 2015,
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` letter and agreed upon labeling revisions through electronic mail correspondence dated October
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` 2, 2015 as follows (additions are noted by underline and deletions are noted by strikethrough):
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`The 5 WARNINGS AND PRECAUTIONS/5.11 Interstitial Lung Disease section is
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`revised as follows:
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`Interstitial Lung Disease/Non-Infectious Pneumonitis
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`Cases of interstitial lung disease [ILD] (including pneumonitis, bronchiolitis obliterans
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`organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified
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`infectious etiology have occurred in patients receiving immunosuppressive regimens
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`including Rapamune. In some cases, the ILD was reported with pulmonary hypertension
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`(including pulmonary arterial hypertension [PAH]) as a secondary event. In some cases,
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`the interstitial lung disease ILD has resolved upon discontinuation or dose reduction of
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`Reference ID: 3843454
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` NDA 21083/S-058
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` NDA 21110/S-075
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` Page 2
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` Rapamune. The risk may be increased as the trough sirolimus concentration increases
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` [see Adverse Reactions (6.7)].
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`APPROVAL & LABELING
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` We have completed our review of these supplemental applications, as amended. They are
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`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text.
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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, submit the content of
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` 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
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` http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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` of labeling must be identical to the enclosed labeling (text for the package insert), with the
` addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as
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`well as annual reportable changes not included in the enclosed labeling.
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` 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:
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`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
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` 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 includes labeling changes
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` for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
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` with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
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` changes approved in these supplemental applications, as well as annual reportable changes and
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` annotate each change. To facilitate review of your submission, provide a highlighted or marked-
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` up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
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` should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
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`Reference ID: 3843454
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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 Transplant and Ophthalmology Products
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`Office of Antimicrobial Products
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`Center for Drug Evaluation and Research
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` NDA 21083/S-058
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` NDA 21110/S-075
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` Page 3
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` PROMOTIONAL MATERIALS
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` All promotional materials that include representations about your drug product must be promptly
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` revised to be consistent with the labeling changes approved in thesesupplements, including any
` new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
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` 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
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` 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
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` eCTD format, see the draft Guidance for Industry (available at:
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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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, call Ms. June Germain, MS., Safety Regulatory Project Manager, at
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`(301) 796-4024.
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`ENCLOSURE: Content of Labeling
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`Reference ID: 3843454
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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
`11/05/2015
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`Reference ID: 3843454
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