Alkermes, Inc.Lybalvi (olanzapine and samidorphan)

NDA 213378/Original 1 NDA 213378/Original 2 COMPLETE RESPONSE

Alkermes, Inc.

Attention: Lauren DiPetrillo, PhD Director, Regulatory Affairs

852 Winter Street

Waltham, MA 02451

Dear Dr. DiPettrillo:

Please refer to your new drug application (NDA) dated November 15, 2019, received November 15, 2019, and your amendments, submitted under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Lybalvi (olanzapine and samidorphan).

We have completed our review of this application and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

PRODUCT QUALITY Facility Inspections:

1. During a review of records requested under section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act, and provided by Alkermes, Inc./FEI: 1000142940, Wilmington, OH, USA manufacturing facility, the FDA noted objectionable conditions. These objectionable conditions will be conveyed to the representative of the facility within 10 business days of this Complete Response Letter. Satisfactory resolution of these objectionable conditions is required (e.g., preapproval inspection and adequate facility responses addressing these conditions) before this application may be approved.

If it is determined that an inspection is needed to approve your application, please note that FDA continues to monitor the public health situation as well as travel restrictions. We are actively working to define an approach for scheduling outstanding inspections, once safe travel may resume and based on public health need and other factors.

For more information, please see the FDA guidances related to COVID 19. These guidances can be found at hittps://www.fda.gov/emergency-preparedness-

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and-response/coronavirus-disease-2019-covid-19/covid-19-related-quidance- documents-industry-fda-staff-and-other-stakeholders.

Pharmaceutical Manufacturing Comment:

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2.

PRESCRIBING INFORMATION

3. We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information’ and Pregnancy and Lactation Labeling Final Rule? websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRP|)—a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 314.50(I)(1)(i)] in structured product labeling (SPL) format as described at FDA.gov.?

’ http:/Awww.fda.gov/Drugs/GuidanceComplianceRequlatoryInformation/LawsActsandRules/ucm08415 9.htm

2 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330 Zhtm

3 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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CARTON AND CONTAINER LABELING

4. The © lacks prominence. Uy

PROPRIETARY NAME

5. Please refer to correspondence dated, February 13, 2020, which addresses the proposed proprietary name, Lybalvi. This name was found acceptable, pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

SAFETY UPDATE

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 nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

(1) Describe in detail any significant changes or findings in the safety profile.

(2) When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

e Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the re-tabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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(3) Present a re-tabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

(4) Provide case report forms and narrative summaries for each patient who died during a Clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

(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 application data.

(6) Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

(7) Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

(8) Provide English translations of current approved foreign labeling not previously submitted.

OTHER

Within 1 year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under

21 CFR 314.65. You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider

his resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to ‘ake before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

The drug product may not be legally marketed until you have been notified in writing hat this application is approved.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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If you have any questions, call Jasmeet (Mona) Kalsi, Regulatory Project Manager, at (240) 402-8977 or email Jasmeet.Kalsi@fda.hhs.gov.

Sincerely,

{See appended electronic signature page}

Eric Bastings, MD

Deputy Director

Office of Neuroscience

Office of New Drugs

Center for Drug Evaluation and Research

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

ERIC P BASTINGS 11/13/2020 05:57:10 PM

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