Shilpa Medicare LimitedPemetrexed Injection

NDA 215179 COMPLETE RESPONSE

Shilpa Medicare Limited

Attention: Krishna Chaithanya Konagalla Director, Regulatory Affairs

1980 S. Easton Road, Ste. 220 Doylestown, PA 18901

Dear Mr. Konagalla:

Please refer to your new drug application (NDA) dated and received August 27, 2020, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Pemetrexed Injection.

We acknowledge receipt of your amendment dated October 14, 2021, which constituted a complete response to our June 24, 2021, action letter.

We also acknowledge receipt of your amendments dated April 4, 2022, and

April 8, 2022, which were 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 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. We did not complete our review of your amendments dated April 4, 2022, and April 8, 2022, for this action as they did not sufficiently address the issues resulting in this

Complete Response.

PRODUCT QUALITY

1) Per ICH Q1A(R2), provide at least 12 months of long-term stability data on the NDA exhibit batches manufactured at the Cadila Healthcare Limited/Zydus Lifesciences Limited site (FEI#3007621329, DUNS#650348852).

2) Provide an acceptable leachables study performed on 12-month samples taken from the long-term stability study for the NDA exhibit batches manufactured at the Cadila Healthcare Limited/Zydus Lifesciences Limited site.

3) The product quality deficiencies listed above need to be resolved before the adequacy of the scientific bridge between the proposed drug product and the

Reference ID: 4968407

NDA 215179 Page 2

relied upon Listed Drug product can be established, i.e., in accordance with 21 CFR 320.24(b)(6).

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 Prescription Drug Labeling Resources! 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.

CARTON AND CONTAINER LABELING

We reserve comment on the proposed labeling until the application is otherwise adequate.

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.

1 https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources 2 https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs- final-rule

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

Reference ID: 4968407

NDA 215179 Page 3

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 subject 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 314.65. 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 draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

Reference ID: 4968407

NDA 215179 Page 4

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 Idara Ojofeitimi, Chief, Project Management Staff, at 301-796-3074.

Sincerely, {See appended electronic signature page}

Martha Donoghue, M.D.

Deputy Director

Division of Oncology 2

Office of Oncologic Diseases

Center for Drug Evaluation and Research

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

Reference ID: 4968407

Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

MARTHA B DONOGHUE 04/14/2022 11:40:40 AM

Reference ID: 4968407