InnoPharma Licensing LLCAcetaminophen Injection, 10 mg/mL

NDA 206968 COMPLETE RESPONSE InnoPharma Licensing LLC 100 Route 206 North PPK3/0PL/32 Peapack, NJ 07977

Attention: Lakshmi Vemuri Regulatory Affairs Associate

Dear Ms. Vemuri:

Please refer to your New Drug Application (NDA) dated and received May 13, 2014, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Acetaminophen Injection, 10 mg/mL.

We acknowledge receipt of your amendment dated May 10, 2018, which constituted a complete response to our November 15, 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

1. You have not provided adequate nonclinical data to support the safety of elemental impurities in your drug formulation.

In accordance with ICH guidance, Q3D Elemental Impurities, and FDA guidance for industry, Elemental Impurities in Drug Products, submit a risk assessment that includes the elemental impurities, their sources, and the controls and acceptance criteria to address the safety of elemental impurities in your drug product.

The above guidance documents are available at https://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM371025.pdf and https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM509432.pdf.

FACILITY INSPECTIONS

2. During a recent inspection of the ea

manufacturing facility for this application, our field investigator

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conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this application may be approved.

REGULATORY

Your submission indicates your intention to rely upon the Agency’s finding of safety and

effectivenes:

or NDA 022450 OFIRMEYV (acetaminophen) injection to support approval of your

505(b)(2) application. However, your 505(b)(2) application does not contain the following:

3.

4.

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Patent certification 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 other drug. Your 505(b)(2) application relies upon the Agency’s finding of safety and effectiveness for OFIRMEV 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 patent 9,987,238 (‘238 patent) that is listed in the Orange Book. Submit an appropriate patent certification or statement with respect to the ’238 patent.

Note that if you elect to provide a paragraph IV certification (21 CFR 314.50(i)(1)()(A)(4)) with respect to this patent, the certification is to be accompanied by a statement that you will comply with the requirements under 21 CFR 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 21 CFR 314.52(c) with respect to the content of the notice.

Written statement from patent owner consenting to approval

If a 505(b)(2) application is submitted for a drug or method of using a drug claimed by a patent and the applicant has a licensing agreement with the patent owner, the applicant must submit a paragraph IV certification as to that patent and a statement that the applicant has been granted a patent license. If the patent owner consents to approval of the 505(b)(2) application (if otherwise eligible for approval) as of a specific date, the 505(b)(2) application must contain a written statement from the patent owner that it has a licensing agreement with the applicant and that it consents to approval of the 505(b)(2) application as of a specific date. See 21 C.F.R. 314.50(i)(3).

Notwithstanding the licensing agreement to patents listed in the Orange Book for NDA 022450 referenced in your May 2018 patent certification, you are required to comply with the statutory requirements for sending notice of paragraph IV certification to the NDA holder and each patent owner.

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You are required to provide a statement in your 505(b)(2) application certifying that notice of paragraph IV certification for the patent has been provided to the NDA holder and each patent owner identified under 21 CFR 314.52(a) and that the notice met the content requirement under 21 CFR 314.52(c). The name and address of each patent owner (or its representative) can be obtained from the United States Patent and Trademark Office. In addition, you must amend your application to document receipt of notice of paragraph IV certification as described under 21 CFR 314.52(e) by each person required to receive notice.

Exclusivity waiver from NDA holder

Your exclusivity statement certifies: “InnoPharma has received a waiver, effective as of the License Entry Date, for any exclusivity from Mallinckrodt IP, the NDA holder for Ofirmev should any exclusivities exist now or in the future that would prevent final approval of InnoPharma’s Acetaminophen Injection 1000mg/10mL product.”

The holder of the NDA waiving its exclusivity with respect to your 505(b)(2) application should submit a statement regarding such waiver. Note that it is possible that, before your application is resubmitted and ready for full approval, another NDA for a single- ingredient acetaminophen drug product may qualify for exclusivity that could affect the approval of your 505(b)(2) application; in such cases, you may submit a statement explaining why such exclusivity does not affect the approval of your application.

PRESCRIBING INFORMATION

6.

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/Structured

ProductLabeling/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.

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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.

¢ 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.

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.

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.

Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

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.

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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, available at, https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM590547.

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 Kimberly Compton, RPh, RAC, Senior Regulatory Project Manager, at (301) 796-1191.

Sincerely,

{See appended electronic signature page}

Joshua Lloyd, MD

Deputy Director

Division of Anesthesia, Analgesia, and Addiction Products

Office of Drug Evaluation II

Center for Drug Evaluation and Research

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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.

JOSHUA M LLOYD 11/09/2018

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