InnoPharma Licensing LLCAcetaminophen Injection, 10 mg/mL

NDA 206968 COMPLETE RESPONSE InnoPharma Licensing LLC

10 Knightsbridge Road Piscataway NJ 08854

Attention: Christy Meng Associate Director, Regulatory Affairs

Dear Ms. Meng:

Please refer to your New Drug Application (NDA) dated and received May 13, 2014, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Acetaminophen Injection, 10 mg/mL

We acknowledge receipt of your amendment dated May 17, 2016, which constituted a complete response to our February 27, 2015, action letter.

We also acknowledge receipt of your amendment dated November 3, 2016, which was not reviewed for this action. You may incorporate applicable sections of the amendment by specific reference as part of your response to the deficiencies cited in this letter.

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 reasons for this action below and, where possible, our recommendations to address these issues.

NONCLINICAL

1. You have not provided adequate nonclinical safety justification for the drug product formulation. Specifically, the submitted 28-day intravenous rat repeat-dose toxicology study did not establish a NOAEL with respect to local toxicity and the lacked a saline control arm.

To address this deficiency, conduct a 14-day repeat-dose intravenous rat local tolerance study with the drug product formulation that mimics the proposed clinical dosing regimen, including an additional saline treatment arm and an active comparator arm (the referenced drug product) to support your conclusion that the high incidence rate of thrombosis and inflammation at the local tissue site is a secondary effect of the catheter rather than the drug product solution. Include histological evaluation of the lungs, kidney, liver, and local tissue for all animals in all treatment groups.

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PRESCRIBING INFORMATION

2. 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.

f 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 ittp://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

FACILITY INSPECTIONS

3. During a recent inspection of the (Gy manufacturing facility for this application, our field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required efore this application may be approved.

REGULATORY

4. Under 21 CFR 314.54(a)(1)(vi), a 505(b)(2) application must contain a patent certification or statement with respect to any relevant patents that claim the listed drug or that claim any other drugs on which the investigations relied on for approval of the application were conducted, or that claim a use for the listed or other drug. Your 505(b)(2) application relies upon the Agency’s finding of safety and effectiveness for NDA 022450 for Ofirmev, but does not contain a patent certification or statement with respect to each patent listed in FDA’s “Approved Drug Products with Therapeutic Equivalence Evaluations” (the Orange Book) for the listed drug upon which you rely. After you submitted your 505(b)(2) application, the NDA holder for Ofirmev, timely filed information on U.S. Patent No. 9,399,012 (‘012’ patent) for listing in the Orange Book. In accordance with section 505(b)(2) of the FDCA and 21 CFR 314.50(i), you must submit an appropriate patent certification or statement with respect to the ‘012’ patent.

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.

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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:

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.

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.

ADDITIONAL COMMENTS

We have the following comment that is not an approvability issue: We remind you of your commitment in your August 8, 2016, submission to conduct long- term stability studies on the first three batches produced © and submit those to your NDA.

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

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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, available 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.

If you have any questions, call Kimberly Compton, RPh, Senior Regulatory Project Manager, Regulatory Project Manager, at (301) 796-1191.

Sincerely, {See appended electronic signature page}

Ellen Fields, MD, MPH

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.

ELLEN W FIELDS 11/15/2016

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