CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`Application Number: 021083
`
`Trade Name: RAPAMUNE ORAL SOLUTION lmg/mL
`
`Generic Name: SIROLIMUS
`
`Sponsor: WYETH—AYERST RESEARCH
`
`Approval Date: 09/15/99
`
`INDICATION§s}: PROPHYLAXIS OF ORGAN
`
`REJECTION IN PATIENTS RECEIVING RENAL
`
`TRANSPLANTS
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 001
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 001
`
`

`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION: 021083
`
`CONTENTS
`
`Included
`
`Pending
`Completion
`
`Not
`Not
`Pregared Reguired
`
`Apgroval Letter
`Tenative Apgroval Letter
`Apgrovable Letter
`Printed Labeling
`Medical Reviewgsg
`Chemist1_'y Reviewjsg
`EA/FONSI
`
`Pharmacology Reviewgsg
`Statistical Reviewgsg
`Microbiology Reviews}
`Clinical Pharmacology
`Biogharmaceutics Reviewg s g
`Bioeguivalence Reviewgsg
`Administrative/
`
`X
`
`><><><><><><><
`
`Correspondence Documentgsg
`
`X
`
`P
`
`X
`>4
`
`X
`
`X
`
`
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 002
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 002
`
`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Application Number: 021083
`
`APPROVAL LETTER
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 003
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 003
`
`

`
`NDA 2l-083
`
`Wyeth-Ayerst Research
`Attention: Maureen Skowronek
`Director, U.S. Regulatory Aflairs
`, P.O. Box 8299
`Philadelphia, PA 19101-8299
`
`Dear Ms. Skowronek:
`
`SEP 15999
`
`Please refer to your new drug application (NDA), dated and received on December 15, 1998,
`submitted under section 505(b) ofthe Federal Food, Drug, and Cosmetic Act for Rapamune®
`(sirolirnus) Oral Solution, lmg/mL.
`.
`
`We acknowledge receipt of your submissions dated:
`
`January 6, 1999
`January 14,1999
`February 17, 1999 .
`February 19, 1999
`March 11, 1999
`March 15, 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
`May 4, 1999
`May 7, 1999
`May 13, 1999
`May 17, 1999
`May 21, 1999
`
`May 24, 1999 ~
`_ May 26, 1999
`May 28, 1999(2)
`June 1, 1999
`June 4, 1999
`June 10, 1999
`June 11, 1999.
`June 14, 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
`September 9, 1999
`'- September 14, 1999
`
`This new drug application provides for the use of Rapamune® (sirolimus) Oral “Solution for the
`prophylaxis of organ rejection in patients receiving renal transplants.
`
`We have completed the review ofthis application, as amended, and have concluded that adequate
`information has been presented to demonstrate that the drug product issafe and effective for use
`as recommended in the agreed upon labeling text. Accordingly, the application is approved
`effective on the date of this letter.
`
`The finalprinted labeling (FPL) must be identical to the package insert submitted September 14,
`1999, the patient package insert submitted September 14, 1999, and the irrunediate container and
`carton labels submitted August 5, 1999. Marketing the product with FPL that is not identical to
`the approved labeling text may render the product misbranded and an unapproved new drug.
`
`Please submit 20 copies ofthe FPL as soon as it is available, in no case more than 30 days afier it
`is printed. Individually mount ten of the copies on heavy-weight paper or similar material. For
`administrative purposes, this_ submission should be designated “FPL for approved NDA 21-083.”
`8 Approval of this submission by FDA is not required before the labeling is used.
`’
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 004
`
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 004
`
`

`
`NDA 21-083
`
`Page 2
`
`We remind you of your 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 order to evaluate the optimal dose of sirolimus in renal transplant patients, who are
`at high risk for acute rejection, you agree to conduct a well-controlled, comparative
`study or studies,'to further define the optimal dose or concentration in this population.
`Patients from any or all ofthe following groups might be included:
`
`0 Black patients
`0 Patients with retransplants.
`0 Patients with high panel-reactive antibodies.
`0 Patients with greater than or equal to 4 human leukocyte antigen mismatches.
`0 Patients with multiorgan (kidney-pancreas) transplants.
`
`You will conduct an appropriate study or studies to better define the type and duration
`of hyperlipidemia associated with the use of sirolimus. 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. Transplant recipients with and without a
`lipid disorder prior to transplant will be included, and the use of lipid-lowering agents
`and other specific interventions will be evaluated.
`
`You will create a registry for collecting safety data on pregnancies that occur during the
`use of Raparnune®.
`
`You will collect and report long-term follow-up safety and efficacy data from the
`ongoing Phase 3 studies, studies 30] and 302. Data pertaining to glomerular filtration
`rate (GFR) and serum creatinine will be included as follow-up information. These data
`should be collected throughout the entire duration of the study whether or not patients
`remain on study drug. Please note that study 301 is a 2-year study and study 302 is a 3-
`year study.
`
`As part of the continuing development of sirolimus, you will assess its efiect on long-
`tenn renal function using GFR in patients receiving kidney or other solid organ
`transplants.
`
`In your ongoing and future studies of sirolimus, you will evaluate the impact of this
`drug on liver function tests in recipients of kidney or liver transplants who may have
`hepatitis B virus and/or hepatitis C virus infection.
`
`Clinical Pharmacology
`
`7.
`
`In a crossover study with healthy volunteers, you will evaluate the drug-drug
`interaction potential of sirolimus when co-administered with Sang(b'a® and
`Sandimmune®. Furthermore, you will evaluate the various administration times of
`sirolimus and cyclosporine (Neoral®), in order to determine the magnitude of the
`sirolimus concentration increase when patients do not take sirolimus 4 hours afier the
`cyclosporine dose.
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 005
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 005
`
`

`
`
`
`Protocols, data, and final reports should be submitted to your MD for this product and a copy of
`the cover letter sent to this NDA. Ifan IND is not required to meet your. Phase 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. The status summary should include the number of patients
`entered in each study, expected completion and submission dates, and any changes in 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.”
`
`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. You will
`employ therapeutic drug monitoring and logistic regression modeling in both high- and
`low-risk patients.
`
`9. You will 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 of sirolimusso as to facilitate the determination of the optimum
`dosing regimen among other ethnic origins. Such a determination will be made using a
`population pharmacokinetics analysis, preferably using mixed effects modeling.
`
`1 1. You will evaluate the interactions between sirolimus and veraparnil.
`
`Preclinical
`
`12. You will submit the report for the second carcinogenicity
`upon issuance. This is projected for the first quarter of 2000.
`
`mice to the Agency
`
`13. In order to qualify the degradation product WAY-126792 (seco-rapamycin), you will
`conduct the following studies: a 3-month study in monkeys, a segment I] reproductive
`study, the standard ICI-I battery of genotoxicity assays, and studies to further evaluate
`the irnmunosuppressive activity of seco-rapamycin.
`
`14. You will conduct a combination study with sirolimus and cyclosporine that will
`incorporate physiologic ‘and morphologic parameters of nephrotoxicity and a recovery
`period.
`'
`
`15. a) You will provide us with the data published in the literature and/or data generated
`from additional studies to better define the efiect of the p-glycoprotein efilux system on
`sirolimus pharmacokinetics.
`
`b) Studies are ongoing using a subclone of the human intestinal Caco-2 cell line with
`induced CYP3A4 activity to examine the combined effects of metabolism and efilux on
`sirolimus disposition. To gain a better understanding of the roles of intestinal
`metabolism and efflux, you agree to complete this in vitro study and submit the data for
`our review.
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 006
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 006
`
`

`
`NDA 21-083
`
`Page 4
`
`Validation ofthe regulatory methods has not been completed. At the present time, 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 problems that may be identified.
`
`Be advised that, as ofApril 1, 1999, all applications for new active ingredients, new dosage
`forms, new indications, new routes of administration, and new dosing regimens are required to
`contain an assessment ofthe safety and efiectiveness ofthe product in pediatric patients unless
`this requirement is waived or deferred (63 FR 66632). We note that you have not fulfilled the
`requirements of 21 CFR 314.55. We are deferring submission of your 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 waiver of the 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 days of receipt ofyour response whether a waiver is granted. If a waiver is not
`granted, we will ask you to submit your pediatric drug development plans within 120 days from
`the date of denial of the waiver.
`
`Pediatric studies conducted under the terms of section 505A ofthe Federal Food, Drug, and
`Cosmetic Act may result in additional marketing exclusivity for certain products (pediatric
`exclusivity). FDA does not necessarily ask a sponsor to complete the same scope of studies to
`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 NDA set forth 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 propose to use for this/these product(s). All proposed
`materials should be submitted in draft or mock-up form, not final print. Please send one copy to
`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, I-11-‘D-40
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`Please submit one market package of the drug product when it is available.
`
`If you have any questions, contact Matthew A. Bacho, Regulatory Project Manager at (301) 827-
`2127.
`
` /S/
`
`.
`
`. w er, M.
`Acting Director
`Ofiice of Drug Evaluation IV
`Center for Drug Evaluation and Research
`
`
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 007
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 007