Teva Pharmaceuticals USAbuprenorphine and naloxone sublingual film, 16 mg/4 mg

NDA 208042

Food and Drug Administration Silver Spring MD 20993

COMPLETE RESPONSE

Teva Pharmaceuticals USA 425 Privet Road Horsham, PA 19044

Attention: Scott D. Tomsky Vice President, Regulatory Affairs

Dear Mr. Tomsky:

Please refer to your New Drug Application (NDA) dated and received November 30, 2015, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA), for buprenorphine and naloxone sublingual film, 16 mg/4 mg.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reason for this action below.

FACILITY INSPECTIONS

Our field investigator could not complete inspection of the Lohmann Therapy Systems

(FEI 1000121692) manufacturing facility at West Caldwell, New Jersey, because the facility was not ready for inspection. Satisfactory inspection is required before this application may be approved. Please notify us in writing when this facility is ready for inspection.

PRESCRIBING INFORMATION

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 (SRPI) — 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(1)(1)(i) in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm

Based on the USP salt policy, the product name throughout the package insert, all labeling pouches and cartons should use the active base only. Furthermore, the strengths should be expressed as the base and not the salt, with a corresponding equivalency statement to the salt

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form of the APIs, placed in all labeling (i.e., 16 mg of buprenorphine is equivalent to 17.25 mg of buprenorphine hydrochloride. 4 mg of naloxone is equivalent to 4.89 mg of naloxone hydrochloride dihydrate). See our Guidance for Industry, Naming of Drug Products Containing Salt Drug Substances, available at http://www.fda.gov/downloads/drugs/guidance complianceregulatoryinformation/guidances/ucm379753.pdf

MEDICATION GUIDE

Add the following bolded statement or appropriate alternative to the carton and container labels per 21 CFR 208.24(d): "ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide."

RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS

Section 505-1 of the FDCA authorizes FDA to require the submission of a risk evaluation and mitigation strategy (REMS) if FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks [section 505-1(a)].

We acknowledge receipt of your proposed REMS, included in your submission dated November 30, 2015, and amended on August 22, and September 13, 2016, which contains a Medication Guide, elements to assure safe use, an implementation system and a timetable for submission of assessments of the REMS. In accordance with section 505-1 of the FDCA, we agree that a REMS will be necessary for buprenorphine and naloxone sublingual film if it is approved, to ensure that the benefits of the drug outweigh the risk(s) of misuse, abuse and accidental overdose. The REMS, should it be approved, will create enforceable obligations. We will continue discussion of your proposed REMS after your complete response to this action letter has been submitted.

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 retabulated frequencies described in the bullet above.

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

3. Present a retabulation 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, ut 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 one 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 this 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 take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the FDA Guidance for Industry, “Formal Meetings Between FDA and Sponsors or Applicants,” May 2009 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM153222.pdf.

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

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If you have any questions, call Spiros Nicols, Regulatory Project Manager, at (240) 402-5988. Sincerely, {See appended electronic signature page}

Rigoberto Roca, MD Deputy Director Division of Anesthesia, Analgesia, and Addiction Products Office of Drug Evaluation II 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.

RIGOBERTO A ROCA 09/30/2016

Reference ID: 3993094 Reference ID: 4320607