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 1 S 1399
`
`Please refer to your new drug application (NDA), dated and received on December 15, 1998,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Raparnune®
`(sirolimus) Oral Solution, lmwmL.
`
`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
`May4, 1999
`May 7, 1999
`May 13, 1999
`May 17, 1999
`May 21, 1999
`
`May 24, 1999 -
`May26, 1999
`May 28, 1999 (2)
`June l, 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 ofRapamune® (sirolimus) Oral Solution for the
`prophylaxis of organ rejection in patients receiving renal transplants.
`
`We have completed the review of this 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 date of this letter.
`
`The final printed labeling (FPL) must be identical to the package insert submitted September 14,
`1999, the patient package insert submitted September 14, 1999, and the immediate 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 of the FPL as soon as it is available, in no case more than 30 days after 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."
`Approval of this submission by FDA is not required before the labeling is used.
`
`West-Ward Exhibit 1011
`Rapamune Approval
`Page 001
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`

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`NDA21-083
`
`Page2
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`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 of the following groups might be included:
`
`• Black patients
`• Patients with retransplants.
`• Patients with high panel-reactive antibodies.
`• Patients with greater than or equal to 4 human leukocyte antigen mismatches.
`• Patients with multiorgan (kidney-pancreas) transplants.
`
`2. You will conduct an appropriate study or studies to better define the type and duration
`ofhyperlipidemia 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.
`
`3. You will create a registry for collecting safety data on pregnancies that 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 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.
`
`5. As part of the continuing development of sirolimus, you will assess its effect on long(cid:173)
`term renal function using GFR in patients receiving kidney or other solid organ
`transplants.
`
`6.
`
`In your ongoing and future studies of sirolimus, you will evaluate the impact ofthis
`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 SangCya® and
`Sandimmune®. Furthennore, 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 after the
`cyclosporine dose.
`
`West-Ward Exhibit 1011
`Rapamune Approval
`Page 002
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`NDA21-083
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`Page3
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`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 sirolimus so 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.
`
`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 orcier to qualify the degradation product WAY-126792 (seco-rapamycin), you will
`conduct the following studies: a 3-month study in monkeys, a segment II 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 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 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 CYP3A4 activity to examine the combined effects of metabolism and efflux 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.
`
`Protocols, data, and final reports should be submitted to your IND for this product and a copy of
`the cover letter sent to this NDA. If an 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 21CFR314.82(bX2Xvii}, 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 labelirig
`supplements, relating to these Phase 4 commitments must be clearly designated "Phase 4
`Commitments."
`
`West-Ward Exhibit 1011
`Rapamune Approval
`Page 003
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`NDA21-083
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`Page4
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`Validation of the regulatory methods has not been completed. At the present time, it is the policy
`of the 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 of April 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 of the safety and effectiveness of the 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.SS. 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 of this letter unless you believe a waiver is appropriate.
`
`If you 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 of21CFR314.SS within 60 days from the date of this letter. We will notify you
`within 120 days of receipt of your 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 SOSA of the Federal Food, Drug, and
`Cosmetic Act may result in additional marketing exclusivity for certain products (pediatric
`excJusivity). 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 of the 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 finaliz.ed, please submit three copies of the
`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, HFD-40
`Food and Drug Administration
`S600 Fishers Lane
`Rockville, Maryland 208S7
`
`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>!llin~cerecrcrlv~/~S)UU2IS----~\~-~~
`~::-=-r--rr.:::::r=-iTn-_ _ _J 'J
`
`Sandra L. Kweder, M.D.
`Acting Director
`Office of Drug Evaluation N
`Center for Drug Evaluation and Research
`
`r
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