nnoPharma Licensing LLCAcetaminophen njection, 10 mg/mL

NDA 206968 COMPLETE RESPONSE

nnoPharma Licensing LLC 0 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, submitted

pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Acetaminophen njection, 10 mg/mL.

We acknowledge receipt of your amendments dated June 27, August 14, October 7 and 31, November 4 and 14, and December 19, 2014, and January 9, and February 5 and 9, 2015.

We also acknowledge receipt of your amendment dated February 13, 2015, 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, you did not conduct a 28-day repeat-dose toxicology study in an appropriate species to characterize the potential for systemic and local tissue toxicity nor did you conduct an adequate blood compatibility assessment.

To address this deficiency, conduct a 28-day repeat-dose intravenous toxicology study in a single species with the drug product formulation that includes all standard toxicological endpoints and an assessment of the local tissue toxicity of the drug product. Ideally, the study would mimic the clinical dosing regimen as closely as possible, define a NOAEL, and define the toxicological profile of the drug product formulation. In addition, conduct an in vitro blood compatibility assessment of the drug product to demonstrate that the drug product formulation does not result in red blood cell hemolysis, flocculation of proteins, or aggregation of platelets.

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2. You have not provided an adequate characterization of the potential leachables from the container closure system over the course of your stability studies to support your proposed expiration date. In addition, you have not provided an adequate toxicological risk assessment for unidentified leachables, described as multiple “non-volatile organic compounds” that exceed [f}mcg/day or for the levels Coy

To address these deficiencies provide the following information:

a. Based on the results of adequate leachable assessment over the course of your stability studies, identify all non-volatile organic compounds and provide a toxicological risk assessment for all of these compounds that exceed the toxicological threshold of concern of: {amcg/day following administration of the maximum daily dose of acetaminophen via this drug product formulation.

b. Provide a toxicological risk assessment to justify the safety of the resulting levels {} following administration of the maximum daily dose with the drug product at the end of expiry.

PRODUCT QUALITY

3. During the formal stability study, data , and for all of the unidentified organic leachables noted for Deficiency 2, were not collected.

(bp) (4)

To address the deficiencies in the stability studies:

Provide stability data for all unidentified organic leachables and Lae

collected over time as part of the formal stability study.

PRESCRIBING INFORMATION

Your proposed prescribing information (PI) must conform to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57. We encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information website including:

e The Final Rule (Physician Labeling Rule) on the content and format of the PI for human drug and biological products

e Regulations and related guidance documents

e A sample tool illustrating the format for Highlights and Contents, and

e The Selected Requirements for Prescribing Information (SRPI) — a checklist of 42 important format items from labeling regulations and guidances.

Submit draft labeling that addresses our proposed revisions in the attached labeling.

Prior to resubmitting the labeling, use the SRPI checklist to correct any formatting errors to ensure conformance with the format items in regulations and guidances. In addition, submit

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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.

To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy should include annotations that support any proposed changes.

FACILITY INSPECTIONS

During recent inspections of the Hikma Farmacéutica (Portugal), Lod manufacturing facilities for this application, our field

investigators conveyed deficiencies to the representatives of the respective facilities.

Satisfactory inspection reports for all facilities must be received before this application may be

approved.

ADDITIONAL COMMENTS

1. The listed drug upon which your application relies is subject to a period of patent protection and therefore final approval of your application under Section 505(c)(3) of the Act [21 U.S.C. 355(c)(3)] may not be made effective until the period has expired.

2. Given the limited leachable assessment of a single batch over the course of up to 18 months stability, since multiple batches are required to be on stability, we recommend that at least three batches be evaluated for leachables through to expiry. We remind you that as more data are generated, a toxicological risk assessment must be provided for any leachable that exceeds 5 mceg/day following administration of the maximum daily dose of acetaminophen via this drug product formulation.

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 the original NDA submission.

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

e Include tables that compare frequencies of adverse events in the original NDA 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 NDA 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. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

Under 21 CFR 314.102(d), you may request a meeting or telephone conference 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 the 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 Swati Patwardhan, Regulatory Project Manager, at (301) 796- 4085.

Sincerely, {See appended electronic signature page}

Sharon Hertz, MD Acting Director Division of Anesthesia, Analgesia, and Addiction Products Office of Drug Evaluation II Center for Drug Evaluation and Research

ENCLOSURE(S): Labeling

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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.

SHARON H HERTZ 02/27/2015

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