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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 21083/S061
`NDA 21110/S080
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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, Ph.D.
` Director, Worldwide Safety and Regulatory
`500 Arcola Road
`Collegeville, PA 19426
`
`
`Dear Dr. Stewart:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received November
`29, 2017, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA or the Act) for the following:
`
`
`
`Supplement #
`
`
`Product Description
`
`
`NDA #
`
`
`21083
`
`
`21110
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`
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`S-061
`
`
`S-080
`
`
`Rapamune® (sirolimus) Oral Solution 1mg/mL
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`Rapamune® (sirolimus) Tablet, 0.5 mg, 1 mg, and 2 mg.
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`
`
`These Prior Approval supplemental new drug applications provide for the following revisions to
`the package insert for these two products (additions are underlined text; deletions are in
`strikethrough text):
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`
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`1. In the 6.4 Conversion from Calcineurin Inhibitors to Rapamune in Maintenance
`Renal Transplant Population, a new paragraph is added at the end of the subsection to
`read:
`
`In a second study evaluating the safety and efficacy of conversion from tacrolimus to
`Rapamune 3 to 5 months post kidney transplant, a higher rate of adverse events,
`discontinuations due to adverse events, acute rejection, and new onset diabetes mellitus
`was observed following conversion to Rapamune. There was also no benefit with respect
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`Reference ID: 4267399
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`

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`NDA 21083/S061
`NDA 21110/S080
`Page 2
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`to renal function and a greater incidence of proteinuria was observed after conversion to
`sirolimus [(see Clinical Studies (14.4)].
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`2. In the 12 CLINICAL PHARMACOLOGY/Drug-Drug Interactions/Verapamil, the
`second sentence is revised as follows:
`
`The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg
`q 12h of verapamil at steady state to 26 25 healthy volunteers significantly affected the
`bioavailability of sirolimus and verapamil.
`
`
`3. In the 14 CLINICAL STUDIES/14.4 Conversion from Calcineurin Inhibitors to
`Rapamune in maintenance Renal Transplant Patients, the following two paragraphs
`are added at the end of the subsection:
`
`In an open-label, randomized, comparative, multicenter study where kidney transplant
`patients were either converted from tacrolimus to sirolimus 3 to 5 months post-transplant
`(sirolimus group) or remained on tacrolimus, there was no significant difference in renal
`function at 2 years post-transplant. Overall, 44/131 (33.6%) discontinued treatment in the
`sirolimus group versus 12/123 (9.8%) in the tacrolimus group. More patients reported
`adverse events 130/131 (99.2%) versus 112/123 (91.1%) and more patients reported
`discontinuations from the treatment due to adverse events 28/131 (21.4%) versus 4/123
`(3.3%) in the sirolimus group compared to the tacrolimus group.
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`The incidence of biopsy-confirmed acute rejection was higher for patients in the
`sirolimus group 11/131 (8.4%) compared to the tacrolimus group 2/123 (1.6%) through 2
`years post-transplant. The rate of new-onset diabetes mellitus post-randomization,
`defined as 30 days or longer of continuous or at least 25 days non-stop (without gap) use
`of any diabetic treatment after randomization, a fasting glucose ≥126 mg/dL or a non-
`fasting glucose ≥200 mg/dL, was higher in the sirolimus group 15/82 (18.3%) compared
`to the tacrolimus group 4/72 (5.6%). A greater incidence of proteinuria, was seen in the
`sirolimus group 19/131 (14.5%) versus 2/123 (1.6%) in the tacrolimus group.
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`APPROVAL & LABELING
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`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, which is identical to the package insert submitted on May 21, 2018.
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`
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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
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`Reference ID: 4267399
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`

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`NDA 21083/S061
`NDA 21110/S080
`Page 3
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`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.
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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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`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 Judit Milstein, Chief, Project Management Staff at 301-796-0763.
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`Sincerely,
`
`{See appended electronic signature page}
`
`Renata Albrecht, MD
`Director
`Division of Transplant and Ophthalmology Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
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`ENCLOSURE(S): Content of Labeling
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`Reference ID: 4267399
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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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`RENATA ALBRECHT
`05/23/2018
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`Reference ID: 4267399
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`