CENTER FOR DRUG EVALUATION AND RESEARCH
`APPROVAL PACKAGE FOR:
`APPLICATION NUMBER
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`21-549
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`Approval Letter(s)
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`HELSINN EXHIBIT 2002
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`Page 1 of 6 IPR2025-00945
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`SERVIC,
`*,.ul s, ¢
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`_( DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Ssrvice
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`")
`*
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`o WEALTY
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`2
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`O
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`Food and Drug Administration
`Rockville, MD 20857
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`NDA 21-549
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`Merck & Company, Inc. -
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`Attention: Steven A. Aurecchia, M.D.
`Sumneytown Pike
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`P.O. Box 4, BLA-20
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`West Point, PA 19486
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`Dear Dr. Aurecchia:
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`Please refer to your new drug application (NDA) dated September 27, 2002, received
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`September 27, 2002, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`EMEND® (aprepitant) Capsules.
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`We acknowledge receipt of your submissions dated November 5, November 19, November 25, and
`December 27, 2002 and January 6, January 7, January 8, January 15, January 16, January 22. Februar
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`12, February 14, February 27, March 11, March 14, March 17, March 18, March 19, March 20, <
`March 21. March 24, and March 26, 2003.
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`This new drug application provides for the use of EMEND® (aprepitant) Capsules in combination wizz
`other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with
`initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.
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`We completed our review of this application, as amended. It is approved, effective on the date of this
`letter, for use as recommended in the agreed-upon labeling text.
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`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the packa
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`packaze Inser.
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`and text for the patient package insert) and submitted labeling (immediate container and carton label:
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`submitted February 27, 2003). Marketing the product with FPL that is not identical to the approved
`labeling text may render the product misbranded and an unapproved new drug.
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`Please submit an electronic version of the FPL according to the guidance for industry titled Providinz
`Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copizs
`of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount =22
`of the copies on heavy-weight paper or similar material. For administrative purposes, designate this
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`submission “FPL for approved NDA 21-549.” Approval of this submission by FDA is not requirec
`before the labeling is used.
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`We remind you of your postmarketing study commitments in your submission dated March 24, 200>
`These commitments are listed below.
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`Page 2 of 6
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`NDA 21-549
`Page 2
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`1. Commitment #1
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`Merck will obtain pharmacokinetic interaction data on a total of 10 patients receiving
`concomitant aprepitant and docetaxel (an IV chemotherapy CYP3A4 subtrate), instead of
`the originally planned 20 patients (Protocol 051, Serial No. 242, IND
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`The timeline is as follows:
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`¢ Completion of patient portion (N = 10) 4™ Quarter 2003
`e Submission of Clinical Study Report 2" Quarter 2004
`2. Commitment #2
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`Merck will conduct a drug interaction study to evaluate the effect of aprepitant on either
`vinorelbine or irinotecan.
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`The timeline is as follows:
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`e Protocol Submission ' 1* Quarter 2004
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`¢ Completion of patient portion of study 4™ Quarte: 2005
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`¢ Submission of Clinical Study Report 3" Quarter 2006
`3. Commitment #3
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`Merck will conduct a drug interaction study in healthy subjects, including some who are
`CYP2D6 poor metabolizers, to evaluate the effect of aprepitant on dolasetron.
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`The timeline is as follows:
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`e Draft Clinical Study Protocol to FDA 4" Quarter 2003
`¢ Completion of patient portion of study 2" Quarter 2004
`e Submission of Clinical Study Report 4™ Quarter 2004
`4. Commitment #4
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`Merck will initiate a risk management program as outlined in the submission to NDA 21-549 dated
`March 18, 2003, to ensure that health care providers understand the approved indication for EMEND
`and precautions with its use and to address and minimize potential for confusion with AMEN or
`VFEND and EMEND. Merck will submit all medication error reports relating to tradename confusion.
`both potential and actual, that occur with EMEND for a period of one year following the date of
`approval. All actual and potential errors will be submitted as 15-day reports regardless of patient
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`outcome. Merck agrees to evaluate these data with FDA and, if needed, to implement intervention to
`further minimize risk of medication errors.
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`For the duration of the program, Merck also commits to providing the following: 1) reports on the
`proactive surveillance audit with retail pharmacists on a quarterly basis beginning no later that the
`fourth quarter of 2003; 2) an annual summary report beginning in the fourth quarter of 2004.
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`Page 3 of 6
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`NDA 21-549
`Page 3
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`S. Commitment #5
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`Merck will submit to FDA a report on the assessment of the inhibitory properties of
`aprepitant on CYP2C8 and CYP2B6 in vitro in human liver microsomes.
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`The timeline is as follows:
`¢ Submission of final report to FDA 2" Quarter 2003
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`6. Commitment #6
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`Merck commits to justify the use of . ~ —
`method, including studies on the . _— for he nanoparticle
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`formulation. Accordingly, based on the data presented in the response, the dissolution
`specification will be reviewed and, if warranted, revised.
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`The timeline is as follows:
`e Submission of information to FDA 2nd Quarter 2003
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`Submiit 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 should 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 postmarketing study commitments must be prominently labeled
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`“Postmarketing Study Protocol”, “Postmarketing Study Final Report”, or “Postmarketing Study
`Correspondence.” :
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`FDA's Pediatric Rule [at 21 CFR 314.55/21 CFR 601.27] was challenzed in court. On October 17.
`2002, the court ruled that FDA did not have the authority to issue the Pediatric Rule and has barred
`FDA trom enforcing it. Although the government decided not to pursue an appeal in the courts, it wii
`work with Congress in an effort to enact legislation requiring pharmaceutical manufacturers to condu2:
`appropriate pediatric clinical trials. In addition, third party interveners have decided to appeal the
`court's decision striking down the rule. Therefore, we encourage you to submit a pediatric plan tha:
`describes development of your product in the pediatric population where it may be used. Please be
`aware that whether or not this pediatric plan and subsequent submission of pediatric data will be
`required depends upon passage of legislation or the success of the third party appeal. In any event. w2
`hope you will decide to submit a pediatric plan and conduct the appropriate pediatric studies to provide
`important information on the safe and effective use of this drug in the relevant pediatric populations.
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`The pediatric exclusivity provisions of FDAMA as reauthorized by the Best Pharmaceuticals for
`Children Act are not affected by the court's ruling. Pediatric studies conducted under the terms of
`section 303A of the Federal Food, Drug, and Cosmetic Act may result in additional marketing
`exclusivity for certain products. You should refer to the Guidance for Industry on Qualifying for
`Pediatric Exclusivity (available on our web site at www.fda.gov/cder/pediatric) for details. If you wish
`to qualify for pediatric exclusivity you should submit a "Proposed Pediatric Study Request”. FDA
`generally does not consider studies submitted to an NDA before issuance of a Written Request as
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`Page 4 of 6
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`NDA 21-549
`Page 4
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`responsive to the Written Request. Applicants should obtain a Written Request before submitting
`pediatric studies to an NDA.
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`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to
`this division and two copies of both the promotional materials and the package insert directly to:
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`Division of Drug Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane ‘
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`Rockville, MD 20857
`Please submit one market package of the drug product when it is available.
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`We have not completed validation of the regulatory methods. However, we expect vour continued
`cooperation to resolve any problems that may be identified.
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`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
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`314.80 and 314.81).
`If you have any questions, call Brian Strongin, R.Ph., M.B.A., Regulatory Project Manager at (301) .
`827-7473.
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`Sincerely,
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`{See ap!r&/ electronic signarure page}
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`Florence Houn, M.D.
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`Director
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`Office of Drug Evaluation III
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`Center for Drug Evaluation and Research
`Enclosure
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`Page 5 of 6
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`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
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`Julie Beitz
`3/26/03 09:52:36 AM
`Julie Beitz MD signing for Florence Houn MD
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`Page 6 of 6
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