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` é DEPARTMENTOF HEALTH&HUMAN SERVICES
`
`{h
`
`PublicHealthService
`
`Food and Drug Administration
`Rockviile, MD 20857
`
`NDA 21-880
`
`Celgene Corporation
`86 Morris Avenue
`
`Summit, New Jersey 07901
`
`Attention:
`
`Gretchen Toolan
`
`Director, Regulatory Affairs
`
`Dear Ms. Toolan:
`
`Please refer to your new drug application (NDA) dated April 7, 2005, received April 7, 2005,
`submitted under section 505 (b) of the Federal Food, Drug, and Cosmetic Act for Revlimid®
`(lenalidomide) capsules 5 and 10 mg.
`
`We acknowledge receipt of your submissions dated December 22, 2004; May 17 and 31, 2005; June
`1,14, and 24, 2005; July 8, 12, 20, 27, and 28, 2005; August 3, 5, 9, 10, 12, 15, 22, 24, 25, 26, and 31,
`2005; September 5, 7, 22, and 30, 2005; October 4 and 19, 2005; and November 16 and 30, 2005;
`December 2, 5, 9, 15 and 21, 2005.
`
`This new drug application, considered for approval under 21 CFR 314.520 (Subpart H), at your
`request, provides for the use of Revlimid® 5 mg and 10 mg capsules for the treatment of patients with
`transfusion dependent anemia due to low or intermediate—1 risk myelodysplastic syndromes associated
`with a deletion 5 q cytogenetic abnormality with or without additional cytogenetic abnormalities.
`
`We have completed our review of this application, as amended. It is approved under the provisions of
`21 CFR 314.520 (Subpart H), effective on the date of this letter, for use as recommended in the agreed
`upon labeling text, required patient labeling, and the components of the RevAssistSM Risk
`Minimization Action Plan (RiskMAP).
`
`Under 21 CFR 314.520 (Subpart H), distribution of the drug is limited as described below and in the
`attached detailed RevAssistSM program. The primary goal of the RevAssistSM program is to prevent
`fetal exposures, pending complete and adequate characterization of the teratogenic potential of
`lenalidomide.
`
`Revlimid® RiskMAP:
`
`We remind you that your Revlimid® RiskMAP (called RevAssistSM) is an important part of the
`postmarketing risk management for Revlimid®, and must include each of the following components:
`
`1. Registration in the RevAssistSM program of prescribers, pharmacies, nurses, and patients who
`agree to specific responsibilities in order to distribute, prescribe, dispense, and use Revlimid®.
`
`

`

`NDA 21-880
`
`Page 2
`
`2.
`
`5”
`
`4.
`
`Implementation of a program and distribution of materials to educate prescribers, pharmacies,
`' nurses, and patients about the risks and benefits of Revlimid®, including materials which
`describe the roles of the RevAssistSM program participants.
`Implementation of a reporting and data collection system for safety surveillance. '
`Implementation of a plan to monitor, evaluate, and improve minimization of drug exposure
`during pregnancy and compliance with restrictions for safe use under the RevAssistSM program.
`
`The Revlimid® Risk Minimization Action Plan, as described in the attached documents adequately
`addresses each of these requirements. Any change to the program must be discussed with FDA prior
`to its institution and is subject to FDA‘s determination that the required components continue to be
`met. We expect your continued cooperation to resolve any problems regarding the RevAssistSM
`program that may be identified following approval of this application.
`
`We remind you of your December 15, 2005 submission and your commitment to establish a pregnancy
`registry to monitor for potential human teratogenicity even if animal teratogenicity testing indicates
`that the RevAssistSM program for monitoring fetal exposure is unnecessary.
`
`We also remind you of your post marketing study commitments specified in your submission dated
`December 21, 2005. These commitments, along with any completion dates agreed upon, are listed
`below.
`
`1. The embryo-fetal toxicity assessment of Revlimid has not been adequately addressed. You
`have agreed to provide adequate information for this assessment in appropriate models
`designed to fillly assesses the possible toxicity of Revlimid. You indicated you plan to
`conduct these studies in two different species that are appropriate to assess the full range of
`thalidomide embryo-fetal effects. As discussed, the rat is not an acceptable model. If the
`study with lenalidomide in the first species shows clear evidence of teratogenesis, than a
`confirmatory study will not be necessary. Although not generally considered “definitive”
`test systems for pharmaceutical products, additional studies of an exploratory nature on the
`embryo-fetal effects of lenalidomide (e.g.,
`assay; [ElassayL may be
`usefiil.
`
`Protocol Submission:
`
`Study Start:
`Final Report Submission:
`
`06/06
`
`09/06
`12/07
`
`2. You have agreed to submit the study report and data from the ongoing study, CC-5013-MDS-
`004, a randomized, double—blind, placebo-controlled, multicenter, 3-arm study of the efficacy
`and safety of‘2 doses of lenalidomide (5 mg daily versus 10 mg day 21 days of a 28 day cycle)
`versus placebo in red blood cell (RBC) transfiision—dependent patients with low-or
`intermediate-l-risk myelodysplastic syndromes (MDS) associated with a deletion 5q
`cytogenetic abnormality when completed.
`
`Protocol Submission:
`
`Study Start:
`Final Report Submission:
`
`03/05
`
`08/05
`12/08
`
`3. Following Revlimid dosing, approximately 2/3 of lenalidorrride is excreted as unchanged
`drug in urine. In multiple myeloma patients with mild renal impairment, exposure (plasma
`
`

`

`NDA 21-880
`
`Page 3
`
`AUC) was 56% higher than in similar patients with normal renal function who received the
`same dose. Based on these data, you have agreed to conduct a study to determine the
`pharmacokinetics of lenalidomide in subjects with renal impairment. To assist with the
`study design, please refer to the FDA Guidance, "Pharmacokinetics in Patients with
`Impaired Renal Function.”
`
`Protocol Submission:
`
`Study Start:
`Final Report Submission:
`
`1 1/04
`
`03/06
`12/07
`
`4. Regarding the Evaluation/Surveillance Plan:
`
`0 You have agreed to submit a Pregnancy Exposure follow—up plan which will document
`your plan to follow-up pregnancy exposures to their outcome. This plan may be submitted
`as a post-marketing commitment.
`
`Plan submission
`
`06/01/06
`
`0
`
`You have agreed to submit an Evaluation Plan of RevAssist to FDA within 3 to 6 months
`of approval. Please include, at a minimum, plans to study the Pharmacy Audit Plan,
`Outcomes of Pregnancy Exposures, and the Knowledge Surveys of physicians, nurses, and
`patients.
`
`Plan submission
`
`06/01/06
`
`5. You have agreed to submit all exposed pregnancies within 15 days of receipt as 15 day
`expedited reports.
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition,.under 21
`CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you must include a status summary of each commitment
`in your annual report to this NDA. The status summary should include expected summary completion
`and final report submission dates, any changes in plans since the last annual report, and, for clinical
`studies, number of patients entered into each study. All submissions, including supplements, relating
`to these postrnarketing study commitments should be prominently labeled “Postmarketing Study
`Commitment Protocol”, “Postmarketing Study Commitment Final Report”, or “Postmarketing
`Study Commitment Correspondence.”
`
`Pursuant to 21 CFR Part 208, FDA has determined that Revlimid poses a serious and significant public
`health concern requiringdistribution of a Medication Guide. The Medication Guide is necessary for
`patients' safe and effective use of Revlimid. FDA has determined that Revlimid is a product that has
`serious risks of which patients should be made aware because information concerning the risks could
`affect patients" decisions to use Revlimid. In addition, patient labeling could help prevent serious
`adverse events related to use of the product. Under 21 CFR 208, you are responsible for ensuring that
`the Medication Guide is available for distribution to patients who are dispensed Revlimid.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (package insert, Medication
`Guide and immediate container and carton labels). Marketing the product with FPL that is not identical
`to the approved labeling text may render the product misbranded and an unapproved new drug.
`
`

`

`NDA 21-880
`
`Page 4
`
`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15
`of the copies on heavy-weight paper or similar material. For administrative purposes, designate this
`submission “FPL for approved NDA 21-880.” Approval of this submission by FDA is not required
`before the labeling is used.
`
`As part of the approval under Subpart H, we acknowledge that you submitted to the Agency your
`promotional materials (both promotional labeling and advertisements) that are to be used within the
`first 120 days after approval. In addition, as required by 21 CFR 314.550, afier the initial 120 day
`period following this approval, you must submit all subsequent promotional labeling as well as
`advertisements at least 30 days before the intended time of initial distribution of the labeling or initial
`publication of the advertisement. Send one copy to the Division of Drug Oncology Products and two
`copies of the promotional materials and the package insert directly to:
`
`Food and Drug Administration
`-
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`Food and Drug Administration
`5901-B Ammendale Road
`
`Beltsville, MD 20705—1266
`
`We remind you that you must comply with the reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`The MedWatch—to-Manufacturer Program provides manufacturers with copies of serious adverse event
`reports that are received directly by the FDA. New molecular entities and important new biologics
`qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for
`this product. To participate in the program, please see the enrollment instructions and program
`description details at www.fda.gov/medwatch/report/mmphtm
`
`If you have any questions, call Carl Huntley, Regulatory Project Manager, at (301) 796-1372.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, MD.
`Director, Office of Oncology Drug Products
`Office of New Drugs
`Center for Drug Evaluation and Research
`Food and Drug Administration
`
`Enclosure
`
`