Approval Letter Other 208419 (Jan 1, 2021)

Provide updated drug product release and stability specifications for all three presentations of Pemetrexed Injection, to reflect the change in the formulation and the addition of a new presentation. We recommend that you add an assay test for the specified component in the drug product specifications.

Recommended response: Revise and submit updated release and stability specifications for all presentations, including an assay test for the specified component.

Provide updated stability data for three batches for each presentation of Pemetrexed Injection from both Sindan and Actavis Italy sites. Provide a minimum of 12-months long-term and 6-months accelerated stability data on at least three primary batches for each presentation at the time of the NDA submission for one facility. For an alternate facility, three-months data under accelerated storage conditions for three batches of each presentation may be provided if the drug products are of comparable quality.

Recommended response: Generate and submit comprehensive long-term and accelerated stability data for all presentations from both manufacturing sites, adhering to specified batch and duration requirements.

The suitability of the kinetic-chromogenic method for the new drug product formulation proposed in the unsolicited amendment dated October 4, 2017, has not been provided.

Recommended response: Conduct and submit a study demonstrating the suitability of the kinetic-chromogenic method for the new drug product formulation.

Provide a summary of the study performed to demonstrate the suitability of the bacterial endotoxins test method performed at the S.C. Sindan-Pharma S.R.L. facility for the new formulation. The summary should include: a description of the preparation of samples; a description of the sample dilutions tested; and the actual results. Also indicate the dilution of the drug product that is proposed for routine bacterial endotoxins testing at the S.C. Sindan-Pharma S.R.L. facility.

Recommended response: Submit a detailed summary of the bacterial endotoxins test method suitability study for the new formulation, including sample preparation, dilutions, results, and proposed routine testing dilution.

Demonstration of the suitability of the sterility tests performed at Actavis Italy S.p.A. and S.C. Sindan-Pharma S.R.L. facilities for the new drug product formulation proposed in the unsolicited amendment dated October 4, 2017, has not been provided. Provide a description of the sterility test method suitability studies performed at the Actavis Italy S.P.A. and S.C. Sindan-Pharma S.R.L facilities and provide the actual results of the studies.

Recommended response: Provide a description and actual results of sterility test method suitability studies for the new formulation performed at both Actavis Italy S.p.A. and S.C. Sindan-Pharma S.R.L. facilities.

Comment on the risk for growth of adventitious microbial contamination under the specified storage conditions (not more than 14 days in the refrigerated conditions 2°C - 8°C [36° to 46°F] and not more than hours at the room temperature) after dilution with the specified diluents (5% Dextrose Injection, USP) given the reformulation of the drug product. In the absence of a scientific rationale for the safety of the specified storage conditions with the reformulated drug product, a new microbiological study will be requested.

Recommended response: Provide a scientific rationale or conduct a new microbiological study to assess the risk of microbial contamination for the reformulated drug product under specified storage conditions after dilution.

We reserve comment on the proposed labeling until the application is otherwise adequate. 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 in structured product labeling (SPL) format.

Recommended response: Revise and submit updated content of labeling in SPL format, ensuring compliance with PLR requirements, Pregnancy and Lactation Labeling Final Rule, and SRPI checklist, once other deficiencies are addressed.

Cited: 21 CFR 314.50(l)(1)(i)

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. Describe in detail any significant changes or findings in the safety profile.

Recommended response: Provide a comprehensive safety update, including all nonclinical and clinical data, detailing any significant changes in the safety profile as per 21 CFR 314.50(d)(5)(vi)(b).

Cited: 21 CFR 314.50(d)(5)(vi)(b)

Incorporate new safety data when assembling sections describing discontinuations due to adverse events, serious adverse events, and common adverse events. Present new safety data from studies/clinical trials for the proposed indication using the same format as in the original submission, tabulations of new safety data combined with original application data, and tables comparing frequencies of adverse events. For other indications, provide separate tables for adverse event frequencies.

Recommended response: Present new safety data from clinical trials in the specified format, including combined tabulations with original data and comparative tables of adverse event frequencies.

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.

Recommended response: Retabulate reasons for premature trial discontinuations, incorporating new trial data, and identify any new trends or patterns.

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.

Recommended response: Submit case report forms and narrative summaries for all patient deaths, discontinuations due to adverse events, and serious adverse events.

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.

Recommended response: Analyze and describe any substantial changes in the incidence of common adverse events between new and original application data.