CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Packagefor:
`
`Application Number: 021083
`
`Trade Name: RAPAMUNEORAL SOLUTION Itmg/mL
`
`Generic Name: SIROLIMUS
`
`Sponsor: WYETH-AYERST RESEARCH
`
`Approval Date: 09/15/99
`
`INDICATION(s): PROPHYLAXIS OF ORGAN
`REJECTION IN PATIENTS RECEIVING RENAL
`TRANSPLANTS
`
`West-Ward Pharm.
`Exhibit 1008
`Page 001
`
`West-Ward Pharm.
`Exhibit 1008
`Page 001
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION: 021083
`
`CONTENTS
`
`Included
`
`Pending
`Completion
`
`Not
`Not
`Prepared Required
`
`x
`
`Ars
`
`
`
`Kir|X|X
`
`X
`xX
`X
`
`xX
`
`|
`
`ApprovalLetter
`Tenative ApprovalLetter
`Approvable Letter
`Printed Labeling
`Medical Review(s)
`Chemistry Review(s)
`EA/FONSI
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology
`Biopharmaceutics Review(s)
`Bioequivalence Review(s)
`Administrative/
`Correspondence Document(s)
`
` West-Ward Pharm.
`
`x
`
`Exhibit 1008
`Page 002
`
`West-Ward Pharm.
`Exhibit 1008
`Page 002
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Application Number: 021083
`
`APPROVAL LETTER
`
`West-Ward Pharm.
`Exhibit 1008
`Page 003
`
`West-Ward Pharm.
`Exhibit 1008
`Page 003
`
`

`

`NDA21-083
`
`Wyeth-Ayerst Research
`Attention: Maureen Skowronek
`Director, U.S. Regulatory Affairs
`_P.O. Box 8299
`Philadelphia, PA 19101-8299
`
`Dear Ms. Skowronek:
`
`SEP 15 199
`
`Please refer to your new drugapplication (NDA), dated and received on December15, 1998,
`submitted undersection 505(b) ofthe Federal Food, Drug, and Cosmetic Act for Rapamune®
`(sirolimus) Oral Solution, Img/mL.
`
`We acknowledge receipt of your submissions dated:
`
`January 6, 1999
`January 14,1999
`February 17,1999 _
`February 19, 1999
`March 11, 1999
`March15, 1999
`March 17, 1999
`‘ March 22, 1999
`March 23, 1999
`March 29, 1999
`March 31, 1999
`April 1, 1999
`April 8, 1999 (2)
`
`April 12, 1999
`April 13, 1999
`April 15, 1999
`April 21, 1999
`April 26, 1999
`April 28, 1999
`April 29, 1999
`April 30, 1999
`May4, 1999
`May7, 1999
`May 13, 1999
`May 17, 1999
`May 21, 1999
`
`May24, 1999 -
`_ May 26, 1999
`May 28, 1999 (2)
`June 1, 1999
`June 4, 1999
`June 10, 1999
`June 11, 1999.
`June14, 1999(2)
`June 18, 1999
`June 21, 1999
`June 25, 1999
`June 29, 1999
`July 9, 1999
`
`July 13, 1999
`July 14, 1999
`July 28, 1999
`August 5, 1999
`August 6, 1999 (3)
`August 9, 1999
`August 17, 1999
`August 19, 1999
`August 24, 1999 (4)
`August 25, 1999 (2)
`August 30, 1999
`September9, 1999
`‘-. September 14, 1999
`
`This new drugapplication provides for the use ofRapamune® (sirolimus) OralSolution forthe
`prophylaxis of organ rejection in patients receiving renal transplants.
`
`Wehave completed the review ofthis application, as amended, and have concluded that adequate
`information has been presented to demonstrate that the drug product is-safe and effective for use
`as. recommended in the agreed upon labeling text. Accordingly,the application is approved
`effective on the dateofthisletter.
`
`Thefinal printed labeling (FPL) must be identical to the package insert submitted September14,
`1999, the patient package insert submitted September 14, 1999, and the immediate container and
`carton labels submitted August 5, 1999. Marketing the product with FPLthatis not identical to
`the approved labeling text may render the product misbranded and an unapproved new drug.
`
`Please submit 20 copies ofthe FPL as soonas it is available, in no case more than 30 daysafterit
`is printed. Individually mount ten ofthe copies on heavy-weight paper or similar material. For
`administrative purposes, this submission should be designated “FPL for approved NDA 21-083.”
`_ Approval ofthis submission by FDAis not required before the labeling is used.
`
`West-Ward Pharm.
`Exhibit 1008
`
`
` Page 004
`
`West-Ward Pharm.
`Exhibit 1008
`Page 004
`
`

`

`NDA 21-083
`
`Page 2
`
`Weremind you ofyour Phase 4 commitments specified in your submission dated August 30,
`1999. These commitments, along with any completion dates agreed upon,are listed below.
`
`Clinical
`
`1.
`
`In orderto evaluate the optimal dose ofsirolimus in renal transplantpatients, who are
`at high risk for acute rejection, you agree to conducta well-controlled, comparative
`study or studies,to further define the optimal dose or concentrationin this population.
`Patients from anyorall ofthe following groups mightbe included:
`
`e Black patients
`e Patients with retransplants.
`e Patients with high panel-reactive antibodies.
`* Patients with greater than or equal to 4 human leukocyte antigen mismatches.
`e Patients with multiorgan (kidney-pancreas) transplants.
`
`2. Youwill conduct an appropriate study or studies to better define the type and duration
`of hyperlipidemia associated with the use ofsirolimus. In particular, you will measure
`and analyze total fasting serum cholesterol and triglycerides, as well as high-density
`lipids/low-density lipids, and lipoprotein A. Transplantrecipients with and without a
`lipid disorderpriorto transplant will be included, and the use oflipid-lowering agents
`and otherspecific interventionswill be evaluated.
`
`3. Youwill create a registry for collecting safety data on pregnanciesthat occur during the
`use of Rapamune®.
`
`4. You will collect and report long-term follow-up safety and efficacy data from the
`ongoing Phase 3 studies, studies 301 and 302. Data pertaining to glomerular filtration
`rate (GFR) and serum creatinine will be included as follow-up information. These data
`should be collected throughoutthe entire duration of the study whetheror not patients
`remain on study drug. Please note that study 301 is a 2-year study and study 302 is a 3-
`year study.
`
`5.
`
`6.
`
`Aspart of the continuing developmentofsirolimus, youwill assess its effect on long-
`term renal function using GFR in patients receiving kidney or other solid organ
`transplants.
`
`-
`
`In your ongoing and future studies ofsirolimus, you will evaluate the impact ofthis
`drugon liver functiontests in recipients of kidney or liver transplants who may have
`hepatitis B virus and/or hepatitis C virus infection.
`
`Clinical Pharmacology
`
`7.
`
`Ina crossover study with healthy volunteers, you will evaluate the drug-drug
`interaction potential of sirolimus when co-administered with SangCya® and
`Sandimmune®. Furthermore, you will evaluate the various administration times of
`sirolimus and cyclosporine (Neoral®), in order to determine the magnitude ofthe
`sirolimus concentration increase when patients do not take sirolimus 4 hours after the
`cyclosporine dose.
`
`West-Ward Pharm.
`Exhibit 1008
`Page 005
`
`West-Ward Pharm.
`Exhibit 1008
`Page 005
`
`

`

`NDA 21-083.
`
`Page 3
`
`8. You will evaluate the optimum therapeutic concentration range for sirolimus and the
`value of reduced cyclosporine concentrations in combination with sirolimus. Youwill
`employ therapeutic drug monitoring andlogistic regression modeling in both high- and
`low-risk patients.
`
`~
`
`9. Youwill evaluate the sirolimus-erythromycin pharmacokinetic interaction in a
`crossover study with healthy volunteers.
`
`10. You will conduct a study or studies to evaluate the effect of ethnicity on the
`pharmacokinetics ofsirolimussoas to facilitate the determination of the optimum
`dosing regimen amongotherethnic origins. Such a determination will be made using a
`population pharmacokinetics analysis, preferably using mixed effects modeling.
`
`11. You will evaluate the interactions between sirolimus and verapamil.
`
`Preclinical
`
`12. You will submit the report for the second carcinogenicity study in mice to the Agency
`upon issuance. This is projected for the first quarter of 2000.
`
`13. In order to qualify the degradation product WAY-126792 (seco-rapamycin), you will
`conductthe following studies: a 3-month study in monkeys, a segmentII reproductive
`study, the standard ICH battery of genotoxicity assays, and studies to further evaluate
`the immunosuppressive activity of seco-rapamycin.
`
`14, You will conduct a combination study with sirolimus and cyclosporinethatwill
`incorporate physiologic and morphologic parameters of nephrotoxicity and a recovery
`period.
`,
`
`15. a) Youwill provide us with the data published in the literature and/or data generated
`from additional studies to better define the effect of the p-glycoprotein efflux system on
`sirolimus pharmacokinetics.
`
`b) Studies are ongoing using a subclone of the human intestinal Caco-2 cell line with
`induced CYP3A4activity to examine the combined effects of metabolism and efflux on
`sirolimus disposition. To gain a better understanding oftheroles ofintestinal
`metabolism and efflux, you agree to complete this in vitro study and submit the data for
`our review.
`
`Protocols, data, and final reports should be submitted to your IND forthis product and a copy of
`the coverletter sent to this NDA. If an IND is not required to meet yourPhase 4 commitments,
`please submit protocols, data, and final reports to this NDA as correspondence. In addition, as
`per 21 CFR 314.82(b)(2)\vii), we request that you include a status summary of each commitment
`in your annual report to this NDA. Thestatus summary should include the numberof patients
`entered in each study, expected completion and submission dates, and any changesin plans since
`the last annual report. For administrative purposes,all submissions, including labeling
`supplements,relating to these Phase 4 commitments must be clearly designated “Phase 4
`Commitments.”
`
`West-Ward Pharm.
`Exhibit 1008
`Page 006
`
`West-Ward Pharm.
`Exhibit 1008
`Page 006
`
`

`

`NDA 21-083
`
`Page 4
`
`Validation ofthe regulatory methods has not been completed. At the presenttime,it is the policy
`ofthe Center not to withhold approval because the methods are being validated. Nevertheless,
`we expect your continued cooperation to resolve any problemsthat may beidentified.
`Be advised that, as ofApril 1, 1999,all applications for new active ingredients, new dosage
`forms, new indications, new routes ofadministration, and new dosing regimensare required to
`contain an assessmentofthe safety andeffectiveness ofthe productin pediatric patients unless
`this requirementis waived or deferred (63 FR 66632). We note that you havenotfulfilled the
`requirements of21 CFR 314.55. We are deferring submission ofyour pediatric studies until
`December 31, 2004. However,in the interim, please submit your pediatric drug development
`plans within 120 days from the date ofthis letter unless you believe a waiver is appropriate.
`Ifyou believe that this drug qualifies for a waiverofthe pediatric study requirements, you should
`submit a request for a waiver with supporting information and documentation in accordance with
`the provisions of 21 CFR 314.55 within 60 days from the date ofthis letter. We will notify you
`within 120 daysofreceipt ofyour response whether a waiveris granted. If a waiver is not
`granted, we will ask you to submit yourpediatric drug developmentplans within 120 days from
`the date of denial of the waiver.
`
`Pediatric studies conducted under the terms ofsection 505A ofthe Federal Food, Drug, and
`Cosmetic Act mayresult in additional marketing exclusivity for certain products (pediatric
`exclusivity). FDA does not necessarily ask a sponsorto complete the same scopeofstudiesto
`qualify for pediatric exclusivity as it does to fulfill the requirements ofthe pediatric rule
`
`We remind you that you must comply with the requirements for an approved NDAsetforth under
`21 CFR 314.80 and 314.81.
`
`~
`
`In addition, once the package insert has been finalized, please submit three copies ofthe
`introductory promotional materials that you proposeto use for this/these product(s). All proposed
`materials should be submitted in draft or mock-up form,notfinal print. Please send one copyto
`the Division of Special Pathogen and Immunologic Drug Products and two copies of both the
`promotional materials and the package insert(s) directly to:
`
`Division of Drug Marketing, Advertising,
`and Communications, HFD-40
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`-
`
`Please submit one market packageofthe drug product whenit is available.
`
`Ifyou have any questions, contact Matthew A. Bacho, Regulatory Project Managerat (301) 827-
`2127.
`
`
`
`
`. Kweder, M.D.
`Acting Director
`Office of Drug Evaluation IV
`Center for Drug Evaluation and Research
`
`_
`
`~
`
`
`
`West-Ward Pharm.
`Exhibit 1008
`Page 007
`
`West-Ward Pharm.
`Exhibit 1008
`Page 007
`
`