B. Braun Medical, Inc.Acetaminophen Injection in the PAB Container, 500 mg/50 mL and 1000 mg/100 mL

NDA 204957 COMPLETE RESPONSE

B. Braun Medical, Inc. 901 Marcon Blvd. Allentown, PA 18109

Attention: Cindy Katsempris Director, Regulatory Affairs

Dear Ms. Katsempris:

Please refer to your New Drug Application, dated and received December 13, 2016, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Acetaminophen Injection in the PAB Container, 500 mg/50 mL and 1000 mg/100 mL.

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.

FACILITY INSPECTIONS

During a recent inspection of the B. Braun Medical, Inc. manufacturing facility (FEI 2021236), our field investigator observed product specific and GMP compliance issues at the facility and conveyed that information to the representative of the facility at the close of the inspection.

Information needed to resolve deficiency: Satisfactory resolution of the observations is required before this NDA may be approved.

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

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CARTON AND CONTAINER LABELING

Submit draft carton and container labeling revised as follows:

Container Labels 1. Revise the stating numbers greater than or equal to 1,000 with a comma to prevent the reader from misinterpreting thousands “1000” as hundreds “100” or ten-thousands “10000.”

2. Relocate the statement, “CAUTION: DO NOT ADD SUPPLEMENTARY MEDICATION?” to under the statement “For Intravenous Use Only” to increase its prominence and minimize the risk of healthcare professionals overlooking this important information.

3. Relocate the package type statement to below the statement “CAUTION: DO NOT ADD SUPPLEMENTARY MEDICATION” to increase its prominence.

Carton Labeling 4. See Item 1, above.

5. Relocate the statement, “CAUTION: DO NOT ADD SUPPLEMENTARY MEDICATION?” from the side panel to a prominent location on the principal display panel to minimize the risk of healthcare professionals overlooking this important information.

6. Relocate the NDC number to the top third of the principal display panel in accordance with 21 CFR 207.35(b)(3)(i).

7. Add the lot number in accordance with 21 CFR 201.10()(1). Ensure that there are no other numbers located in close proximity to the lot number where they can be mistaken as the lot number. |

8. Add the expiration date in accordance with 21 CFR 201.17. Ensure that there are no other numbers located in close proximity to the expiration date where they can be mistaken as the expiration date.

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.

! Institute for Safe Medication Practices. Safety briefs: The lot number is where? ISMP Med Saf Alert Acute Care. 2009; 14(15):1-3.

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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.

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.

ADDITIONAL COMMENTS

We have the following comments and recommendations that are not approvability issues that should be addressed prior to a subsequent NDA resubmission:

1. Tighten the drug product specification for 4-aminophenol and 4-nitrophenol based on long-term stability data to as low as technically feasible.

2. In your leachables study, 3 unknown compounds (RT ©) under normal conditions as well as 5 unknown compounds (RT ©®) under accelerated conditions were present in your leachable samples. As we cannot conduct a

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toxicological risk assessment on unknowns, either provide identification for these unknown compounds along with an adequate toxicological risk assessment or confirm that these compounds are present in other FDA-approved products that use the same container closure system at comparable total daily intake levels.

3. The safety of ™ has not been adequately addressed by the submitted 28-day and 14-day toxicology studies. Either provide data that demonstrates |{f} © and related compounds are present at comparable total daily intake levels in other FDA-approved products that use the same container closure system or conduct an adequately designed 14-day toxicology study that identifies a NOAEL that establishes adequate safety margins.

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. 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,” March 2015 at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm 43743 L.pdf.

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

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If you have any questions, contact Ogochukwu Ogoegbunam, PharmD, Regulatory Project Manager, at (240) 402-8807.

Sincerely,

{See appended electronic signature page}

Ellen Fields, MD, MPH Deputy Director Division of Anesthesia, Analgesia, and Addiction Products Office of Drug Evaluation II Center for Drug Evaluation and Research

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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

ELLEN W FIELDS 09/28/2017

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