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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`
`
`NDA 21083/S-051
`NDA 21110/S-065
`
`Wyeth Pharmaceuticals, Inc.,
`a subsidiary of Pfizer, Inc.
`Attention: Nhu Debi Tran, Pharm.D.
` Director, Worldwide Regulatory Strategy
`PO Box 8299
`Philadelphia, PA 19101-8299
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`Name of Drug Product
`
`NDA
`Number
`021083 Rapamune® (sirolimus) Oral
`Solution, 1 mg/mL
`021110 Rapamune® (sirolimus) Tablets,
`1 mg, 2 mg, and 5 mg
`
`Supplement
`Number
`S-051
`
`S-065
`
`
`Date of
`Submission
`June 29, 2012
`
`June 29, 2012
`
`
`Date of
`Receipt
`June 29, 2012
`
`June 29, 2012
`
`
`Dear Dr. Tran:
`
`Please refer to your Supplemental New Drug Application (sNDA) submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for the following:
`
`
`
`These “Prior Approval” supplemental new drug applications propose revisions to section 7.4
`Inducers or Inhibitors of CYP3A4 and P-gp and section 12.3 Pharmacokinetics Other Drug-Drug
`Interactions to include hepatitis C protease inhibitors (e.g., boceprevir and telaprevir) as drugs
`that could potentially increase sirolimus blood concentrations as described below (added text is
`underlined, and deleted text is strikethrough.)
`
`A) The RECENT MAJOR CHANGES subsection of the HIGHLIGHTS section of the
`
`package insert has been deleted as follows:
`
`----------------- RECENT MAJOR CHANGES ---------------------------------­
`
`
` Warnings and Precautions
`
`
`
`
`
`
` • Hyperlipidemia (5.7)
`
` • Latent Viral infections (5.10)
`
`
`
`
`
`09/2010
`
`07/2010
`
`
`
`Reference ID: 3228232
`
`

`

`
` NDA 21083/S-051
`
` NDA 21110/S-065
`Page 2
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` B) 7.4 Inducers or Inhibitors of CYP3A4 and P-gp
`
`
`
`
`
`Exercise caution when using sirolimus with drugs or agents that are modulators of CYP3A4 and
`P-gp. The dosage of Rapamune and/or the co-administered drug may need to be adjusted [see
`Clinical Pharmacology (12.3)].
`  Drugs that could increase sirolimus blood concentrations:
`
`
`Bromocriptione, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole,
`
`protease inhibitors (e.g., for HIV and protesase inhibitors hepatitis C that include drugs
`such as (e.g., ritonavir, indinavir, boceprevir, and telaprevir), metoclopramide,
`nicardipine, troleandomycin, verapamil
`  Drugs and other agents that could decrease sirolimus concentrations:
`
`
`Carbamazepine, phenobarbital, phenytoin, rifapentine, St. John’s Wort (Hypericum
`perforatum)
`  Drugs with concentrations that could increase when given with Rapamune:
`
`Verapamil
`
`
`
`
`C) 12.3 Pharmacokinetics/Other Drug-Drug Interactions
`
`Co-administration of Rapamune with other known strong inhibitors of CYP3A4 and/or P-gp
`(such as voriconazole, itraconazole, telithromycin, or clarithromycin) or other known strong
`inducers of CYP3A4 and/or P-gp (such as rifabutin) is not recommended [see Warnings and
`Precautions (5.17), Drug Interactions (7.2)]. In patients in whom strong inhibitors or inducers of
`CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or
`induction of CYP3A4 should be considered.
`
`Care should be exercised when drugs or other substances that are substrates and/or inhibitors or
`inducers of CYP3A4 are administered concomitantly with Rapamune. Other drugs that have the
`potential to increase sirolimus blood concentrations include (but are not limited to):
`Calcium channel blockers: nicardipine.
`
`
`Antifungal agents: clotrimazole, fluconazole.
`
`
`Antibiotics: troleandomycin.
`
`
`Gastrointestinal prokinetic agents: cisapride, metoclopramide.
`
`
`Other drugs: bromocriptine, cimetidine, danazol, protease inhibitors (e.g., for HIV and
`
`hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir). HIV
`
`
`protease inhibitors (e.g. ritonavir, indinavir)
`
`
`D) Medication Guide, under the section Tell your doctor about all the medicines you take,
`
`
`Especially tell your doctor if you take:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a medicine to lower your cholesterol or triglycerides
`cyclosporine (including Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf) or other
`medicines that suppress the immune system
`
`
`
` an antibiotic
`
`an antifungal medicine
`
`
`Reference ID: 3228232
`
`

`

`
` NDA 21083/S-051
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` NDA 21110/S-065
`Page 3
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` a medicine for high blood pressure or heart problems
`
`
`an anti-seizure medicine
`
`
`  medicines used to treat stomach acid, ulcers, or other gastrointestinal problems
`
` bromocriptine mesylate (Parlodel, Cycloset)
`
` danazol
`
`  medicines to treat HIV or hepatitis C an anti HIV medicine
`
` St. John’s Wort
`
`
`
`
`
`
`We have completed our review of these supplemental applications. They are approved, effective
`on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling text.
`
`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 and 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.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications 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).
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`
`
`
`Reference ID: 3228232
`
`

`

`
` NDA 21083/S-051
`
` NDA 21110/S-065
`Page 4
`
`
`If you have any questions, call Hyun Son, Pharm.D., Regulatory Project Manager, at
`(301) 796-1600.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Ozlem Belen, MD, MPH
`Deputy Director for Safety
`Division of Transplant and Ophthalmology Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE: Content of Labeling
`
`Reference ID: 3228232
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`12/10/2012
`
`Reference ID: 3228232
`
`