International Medication Systems, LimitedEpinephrine Injection USP

NDA 211363 COMPLETE RESPONSE

International Medication Systems, Limited Attention: Gisela Sharp

Senior Manager, Regulatory Affairs

11570 6th Street

Rancho Cucamonga, CA 91730

Dear Ms. Sharp:

Please refer to your New Drug Application (NDA) dated and received on February 14, 2018, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food. Drug. and Cosmetic Ast, (Fi DCA), for Epinephrine Injection USP,

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.

PRODUCT QUALITY

A. Drug Product:

(b) (4)

(o) (4) (b) (4)

©) Your proposal @ which suggests a suboptimal formulation )@is unacceptable as per ICH Guidance for Industry - Q8 (R2) Pharmaceutical Development (2009).

To address the above-listed deficiency, we recommend you provide, using batches manufactured by the proposed commercial process © a) batch analysis data and b) long-term and accelerated stability data.

B. Quality Labeling:

Given that the term "single-use" is a retired term, replace the term "single-use" with the term "single-dose" throughout the label and labeling. See also PRESCRIBING INFORMATION below.

505(b)(2) APPLICATION Under 21 CFR 314.54(a)(1)(vi), a 505(b)(2) application must contain a patent certification or statement

with respect to any relevant patents that claim the listed drug or that claim any other drugs on which the investigations relied on for approval of the application were conducted, or that claim a use for the listed or

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other drug. Your 505(b)(2) application relies upon the Agency’s finding of safety and effectiveness for NDA 205029 for Epinephrine, but does not contain a patent certification or statement with respect to each patent listed in FDA’s “Approved Drug Products with Therapeutic Equivalence Evaluations” (the Orange Book) for the listed drug upon which you rely. Specifically, your application does not contain a patent certification or statement with respect to patents 10,004,700 and 10,039,728 that is listed in the Orange Book. Please submit an appropriate patent certification or statement with respect to the 10,004,700 and 10,039,728 patents.

Please note that if you elect to provide a paragraph IV certification (21 CFR 314.50(i)(1)(i)(A)(4)) with respect to these patents, the certification is to be accompanied by a statement that you will comply with the requirements under 314.52(a) with respect to providing a notice to each owner of the patent or their representatives and to the holder of the approved application for the drug product which is claimed by the patent or a use of which is claimed by the patent and with the requirements under 314.52(c) with respect to the content of the notice.

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 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 (SRPI) — 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/product 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.

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.

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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 314.65. 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 FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,” December 2017 at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM590547.

If you have any questions, please contact:

Quynh Nguyen, Pharm.D., RAC Regulatory Project Manager (301) 796-0510

Sincerely,

{See appended electronic signature page} Norman Stockbridge, M.D., Ph.D.

Director

Division of Cardiovascular and Renal Products

Office of Drug Evaluation I Center for Drug Evaluation and Research

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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.

NORMAN L STOCKBRIDGE 12/12/2018

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