Heron Therapeutics, Inc.Zynrelef (bupivacaine and meloxicam) Solution 60mg

NDA 211988 COMPLETE RESPONSE

Heron Therapeutics, Inc. 4242 Campus Point Court, Suite 200 San Diego, CA 92121

Attention: Kimberly J. Manhard Executive Vice President, Drug Development

Dear Ms. Manhard:

Please refer to your new drug application (NDA) dated and received October 30, 2018, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Zynrelef (bupivacaine and meloxicam) Solution 60mg / 1.8mg, 200mg / 6mg, 300mg / 9mg, 400mg / 12mg.

We acknowledge receipt of your amendment dated September 26, 2019, which constituted a complete response to our April 30, 2019, action letter.

We acknowledge receipt of your major amendments dated December 23 and 31, 2019, which extended the goal date by three months.

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 data to support your request for a waiver of reproductive and developmental studies for triacetin. Although you have concluded that the primary metabolites of triacetin do not represent a risk for reproductive and developmental effects, you have provided no data to support the conclusion that triacetin instilled into a wound at the maximum daily dose will not result in systemic exposure to the triacetin molecule.

Information needed to resolve deficiency:

Provide data to support the conclusion that triacetin levels are not present in the systemic circulation via your drug product or conduct reproductive and developmental toxicology studies with triacetin via a route that mimics the clinical exposure to this excipient. If you elect to continue to rely upon the cited oral rat reproductive and developmental study, provide justification that the animals in that study were exposed to triacetin at levels comparable to those that will occur

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NDA 211988 Page 2

following clinical use of your drug product at the maximum recommended human dose.

You have not provided an adequate scientific bridge to the referenced oral reproductive and developmental studies submitted to qualify the safety of DMSO exposure via your drug product. Instillation of the drug product may result in higher Cynax and AUC compared to oral studies and therefore it is not clear if the referenced studies adequately address the safety of your product.

Information needed to resolve deficiency:

Provide data to support your conclusion that these referenced oral studies resulted in exposures to DMSO that exceed the exposure to DMSO via your drug product or conduct studies using an appropriate route of administration.

You have not provided adequate data to support the proposed drug product specification ©® at NMT®®%. The nonclinical and clinical lots tested to date in your development program did not contain this high of a percentage of | ® and therefore does not qualify this specification. Further, you did not provide data to support your conclusion that |

would not contribute to the local tissue effects of the drug product.

Information needed to resolve deficiency: Either conduct a local tissue toxicity study that tests drug product that contains at ®

least the maximum specified level reduce the specification 2 to that which was tested in the nonclinical toxicology studies, or provide data to support your hypothesis that the ©® in the product does not contribute

to local tissue effects of the drug product.

Your embryofetal development study in rabbits tested maleic acid via an oral route of administration rather than the proposed route of administration of your drug product and you did not provide an adequate scientific bridge to support your conclusion that the study provides adequate characterization of the developmental effects of maleic acid exposures via installation into a wound.

Information needed to resolve deficiency:

Submit justification that the oral toxicology study resulted in exposures (Cmax and AUC) that provide adequate coverage for the exposure via your drug product when the product is instilled into a wound. In addition, submit the final study report for the oral maleic acid embryofetal development study in the rabbit to the NDA.

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

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NDA 211988 Page 3

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(I)(1)(i)] in structured product labeling (SPL) format as described at FDA.gov.?

PROPRIETARY NAME

Please refer to correspondence dated, December 6, 2019, which addresses the proposed proprietary name, Zynrelef. This name was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

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 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.

’ http:/Awww.fda.gov/Drugs/GuidanceComplianceRequlatoryInformation/LawsActsandRules/ucm08415 9.htm

2 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330 Zhtm

3 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

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

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NDA 211988 Page 4

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 product. Include an updated estimate of use for product marketed in other countries.

(8) Provide English translations of current approved foreign labeling not previously submitted.

ADDITIONAL COMMENTS

We have the following comments/recommendations that are not approvability issues:

Although not listed as a deficiency in the first cycle, your proposed specification for DMSO of! "% has an upper limit that has never been tested in your clinical or nonclinical development program. As DMSO may contribute to local tissue toxicity, either revise the specification to reflect the testing completed by your development program, conduct a new study to characterize the local effects of your to-be-marketed drug product containing DMSO at the upper limit of your proposed specification, or justify why DMSO at! {}% will not contribute to the local tissue effects of the drug product.

Once approved, the following PREA PMRs will be required:

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

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1. Conduct a juvenile animal study in the rodent model to characterize the impact of DMSO on the developing brain to support clinical studies in pediatric patients under three years of age.

2. Conduct a juvenile animal study in an appropriate model to characterize the impact of meloxicam on the developing kidney, liver, lung, and testes to support clinical studies in pediatric patients under three years of age.

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

his 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 ‘ake 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.

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

If you have any questions, call Allison Meyer, Regulatory Project Manager, at 301-796- 1258.

Sincerely, {See appended electronic signature page}

Rigoberto Roca, MD

Acting Director

Division of Anesthesiology, Addiction Medicine and Pain Medicine

Office of Neuroscience

Center for Drug Evaluation and Research

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

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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.

RIGOBERTO A ROCA 06/26/2020 03:11:19 PM

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