Mylan Laboratories LimitedAcetaminophen for Injection, 1 g/vial

NDA 206610 COMPLETE RESPONSE Mylan Laboratories Limited c/o Mylan Pharmaceuticals Inc. 81 Chestnut Ridge Road Morgantown, WV 26505

Attention: Anil Sachdeva Senior Director - Regulatory Affairs

Dear Mr. Sachdeva:

Please refer to your New Drug Application (NDA) dated May 3, 2014, received May 5, 2014, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Acetaminophen ©® for Injection, 1 g/vial.

We acknowledge receipt of your amendment dated August 4, 2016, which constituted a complete response to our March 10, 2016, action 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

You have not provided an adequate assessment of the presence of possible extractables from the

© in the final drug product formulation. We are unable to complete our review of the data submitted to date without responses to the following information request:

1. Your limit of detection (LOD) and limit of quantitation (LOQ) from your extractable study report and leachable study report are not consistent. Specifically, you appear to be able to detect lower levels of compounds in your extraction study than you were able to detect in the leachable study.

2. Based on the data provided, there is not an adequate extractables/leachables correlation. Specifically, based on your assessment bo

however, your extraction study results only predic “*’mcg/day. This suggests that either the extraction conditions were not adequate or o

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3. There are still two unknowns listed in your extraction study and four unknowns in the leachable study that exceed the qualification threshold of {jmcg/day.

Information needed to address these deficiencies:

1. Explain the apparent discrepancy in the LOD and LOQ in your extraction studies and leachable studies and provide the basis for these limits in both the extractable study and the leachable study in light of the Analytic Evaluation Threshold (AET). For a) mL total daily dose, we calculate an AET of, | gm will be necessary to be able to detect a compound that would result in exposure of “mecg/day or greater. If you believe that this AET is not feasible, justify your analytical capability. If your assay cannot meet our calculated AET, the toxicological risk assessment will be based on the limit of quantitation (LOQ). Revise your toxicological risk assessment accordingly.

2. Provide an analysis of the extractables/leachables correlation and justify the conditions of your assays. In the absence of an adequate justification for your extractable leachable study conditions, it is not clear if the extractable/leachable data accurate reflect the levels of potential © contaminants in the final drug product.

3. In order to complete a toxicological risk assessment, identify all unknowns greater than’ a mceg/day from both the extractable and leachable studies and update the toxicological ri assessment accordingly.

Alternatively, analyze the final lyophilized drug product to determine if the compounds identified in the extraction study of the O are present in the final product using an analytical method able to detect) {%} cg/day.

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 (SRPD — 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

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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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.

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, 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 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. 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.

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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 draft FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,” March 2015 at http://www. fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm 43743 L.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 Christopher Hilfiger, Regulatory Project Manager, at (301) 796- 4131.

Sincerely,

{See appended electronic signature page}

Ellen Fields, MD

Deputy Division 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 02/01/2017

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