CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICA TION NUMBER:
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`2 1 -8 9 7
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`APPROVABLE LETTER ’
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
`Food and Drug Administration
`Rockviile, MD 20857
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`NDA 21—897
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`Alkermes, Inc.
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`88 Sidney Street
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`Cambridge, MA 02139-4136
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`Attention: Priya Jambhekar
`Global Vice President, Regulatory and Government Affairs
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`Dear Ms. Jambhekar:
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`Please refer to your new drug application (NDA) dated March 31, 2005, received March 31, 2005,
`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Vivitrol
`(naltrexone for extended—release injectable suspension).
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`We acknowledge receipt of your submissions dated May 6, 9, 12,16, 2111319, Iiine 17, 24 (3), 27, and
`29, July 6, 13, and 29(3), August 8, 12, 15, 16(2), 22, and 31, September 6, 7(2), 12(2), 14, 23, and 30,
`October 3, 5, 12, 14, and 27, November 3, 4, and 14, and December 14, 2005.
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`We have completed our review of this application, as amended, and it is approvable. Before the
`application may be approved, however, it will be necessary for you to address the following
`deficiencies
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`a5!
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`1. You have not provided evidence of efficacy of Vivitrol in alcohol-dependent patients who are
`"N —§~
`actively drinkingat the time of treatment initiation.
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`..............,I, propose labeling to restrict the use of the product to alcohol—
`dependent patients who have refrained from drinking -s- 1“ prior to treatment
`initiation.
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`Note that if you elect this latter option, we would expect you to conduct a post-approval study
`to determine whether Vivitrol is effective in patients whose pro—treatment abstinence is
`enforced (i.e. via hospitalization) rather than spontaneous (as was the case with the population
`studied in your efficacy trial, ALK21—OO3).
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`2. Provide pharmacokinetic/toxicokinetic exposure data in the appropriate species necessary for
`interpreting the existing carcinogenicity and reproductive toxicology data in the product
`labeling. In the absence of adequate bridging data, the following nonclinical studies would
`have to be conducted:
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`NDA 21—897
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`Page 2
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`a. a Segment I reproductive and developmental toxicology study including toxicokinetic
`data in a single species with the final drug product formulation;
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`b. Segment II reproductive and developmental toxicology studies in two species including
`toxicokinetic data with the final drug product formulation;
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`c.
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`a Segment III reproductive and developmental toxicology study including toxicokinetic
`data with the final drug product formulation; and
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`d. carcinogenicity assessment in two species using the final drug product formulation.
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`In addition, we have the following comments for your consideration, which are not approvability
`issues.
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`3. To further evaluate the allergenic pOtential of Vivitrol, conduct a trial to ascertain whether
`patients develop naltrexone—specific, naltrexone—carboxymethylcellulose-specific, and
`carboxymethylcellulose-specific antibodies (IgG, IgM, and IgG) following Vivitrol
`administration. Evaluate whether development of these specific antibodies is associated with
`adverse events of urticaria and angioedema.
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`Revise the drug release specifications to include Day 14 and Day 28 drug release information.
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`Conduct in vitro CYP inhibition studies using conventional CYP substrates and validated
`analytical methodology.
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`Conductm vitro studiesin human hepatocytes to evaluate the potential of naltrexone to induce
`CYP3A4 and CYP1A2.
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`The data provided in theNDA. M”
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`a?"
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`1.,Therefore provide additional data on percent crystallinity and in
`vitro drug release for all commercial scale batches of Vivitrol. Also, provide stability updates
`from the ongoing stability studies. Based these data, the need to revise them vitro drug release
`specifications and to establish a specification to control the percent crystallinity1n Vivitrol will
`be assessed.
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`In addition, it will be necessary for you to submit revised draft printed labeling as indicated in the
`attached, edited document. Note that these revisions are only preliminary draft comments. The
`labeling will be revised once the aforementioned deficiencies-are addressed.
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`NDA 21-897
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`Page 3
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`When you respond to the above deficiencies, include a safety update as described at 21 CFR
`314.50(d)(5)(vi)(b). The safety update should include data from all non—clinical and clinical studies of
`the drug under consideration regardless of indication, dosage form, or dose level.
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`1. Describe in detail any significant changes or findings in the safety profile.
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`2. When assembling the sections describing discontinuations due to adverse events, serious adverse
`events, and common adverse events, incorporate new safety data as follows.
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`0 Present new safety data from the studies for the proposed indication using the same format as the
`original NDA submission.
`0 Present tabulations of the new safety data combined with the original NDA data.
`0
`Include tables that compare frequencies of adverse events in the original NDA with the
`retabulated frequencies described1n the bullet above.
`0 For indications other than the proposed indication, provide separate tables for the frequencies of
`adverse events occurring in clinical trials.
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`3. Present a retabulation of the reasons for premature study discontinuation by incorporating the drop—
`outs from the newly completed studies. Describe any new trends or patterns identified.
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`4. Provide case report forms and narrative summaries for each patient whodied during a clinical
`study or who did not complete a study because of an adverse event. In addition, provide narrative
`summarles fOI‘ SCI‘lOllS adverse events.
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`5. Describe any information that suggests a substantial change in the incidence of common, but less
`serious, adverse events between the new data and the original NDA data.
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`6. Provide a summary of worldwide experience on the safety of this-drug. Include an updated
`estimate of use for drug marketed in other countries.
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`7. Provide English translations of current approved foreign labeling not previously submitted.
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`Within 10 days after the date of this letter, you are required to amend this application, notify us of your
`intent to file an amendment, or follow one of your other options under 21 CFR 314. l 10 Ifyou do not
`follow one of these options, we will consider your lack of response a request to withdraw the
`application under 21 CFR 314.65. Any amendment should respond to all the deficiencies listed. We
`will not process a partial reply as a major amendment nor will the review clock be reactivated until all
`deficiencies have been addressed.
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`Under 21 CFR 314.102(d), you may request an informal meeting or telephone conference with this
`division to discuss what steps need to be taken before the application may be approved.
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`The drug product may not be legally marketed until you have been notified1n writing that the
`application1s approved.
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`NDA 21-897
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`Page 4
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`If you have any questions, call Lisa Basham-Cruz, Regulatory Project Manager, at (301) 796—1175.
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`Sincerely,
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`{See appended elecn‘onic signature page}
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`Bob Rappaport, MD '
`Director
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`Division of Anesthesia, Analgesia, and
`Rheumatology Products
`Office of Drug Evaluation 11
`Center for Drug Evaluation and Research
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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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`_
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`7
`Bob Rappaport
`12/23/2005 04:13:16 PM
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