Mylan Pharmaceuticals, Inc.acetaminophen ® for injection, 1 g/vial

NDA 206610 COMPLETE RESPONSE Mylan Pharmaceuticals, Inc. 781 Chestnut Ridge Road Morgantown, WV 26505

Attention: Anil Sachdeva Senior Director of Regulatory Affairs

Dear Mr. Sachdeva:

Please refer to your New Drug Application (NDA) dated May 2, 2014, received May 5, 2014, 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 amendments dated July 18 and 25, August 7, November 12, and December 9, 2014, and January 8, 16, 20, and 21, and February 20, 2015.

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. The drug substance impurity mi. reported to be clastogenic and therefore your

proposed drug substance specification of NMT| 9% is unacceptable. To address this deficiency, update the drug substance specification for oo

We recommend that you contact your DMF holder to determine an appropriate specification.

2. The drug substance impurity ® is predicted to be mutagenic via QSAR analysis and therefore, the proposed specification of NMT | is unacceptable. To address this deficiency, either update your drug substance specification for aa to NMT meg/day (NMT MA)04) or conduct an adequate Ames assay to demonstrate that the compound is not mutagenic. 3. You have not provided an adequate characterization of potential leachables from the [J Based on your extraction study, as much as approximately meg/day) of unknown material could be presen aa

14) (014) ( This exceeds the threshold of toxicological concern of cg/day and, therefore, requires

Reference ID: 3708847

NDA 206610 Page 2

adequate safety justification based on a toxicological risk assessment for the identified

materials.

To address this deficiency, identify the extractables from the © study and

determine if they are present in the drug product formulation. Quantitate and characterize

any unidentified foreign material from the OM that is present in the drug product. Submit

an adequate toxicological risk assessment for any leachable that is above the Toxicological (b)

Threshold of Concern of @ncg/day.

PRESCRIBING INFORMATION

4. 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 website including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) — a checklist of 42 important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the PI 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.

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 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.

Reference ID: 3708847

NDA 206610 Page 3

FACILITY INSPECTIONS

During a recent inspection of the Agila Specialties Private Limited (FEL 3007648351) manufacturing facility and Agila Specialties Private Limited Control Testing Laboratory (FEI: 3003813519) for this application, our field investigator conveyed deficiencies to the representative of the facility. Satisfactory inspection reports for all facilities must be received before this application may be approved

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.

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, but less serious, adverse events between the new data and the original NDA data.

Reference ID: 3708847

NDA 206610 Page 4

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 COMMENT

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.

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.

Reference ID: 3708847

NDA 206610 Page 5

If you have any questions, call Christopher Hilfiger, Regulatory Project Manager, at (301) 796- 4131.

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: Labeling

20 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

Reference ID: 3708847

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

Reference ID: 3708847