Adamis Pharmaceuticals CorporationNaloxone hydrochloride injection, 5 mg/0

NDA 212854 COMPLETE RESPONSE

Adamis Pharmaceuticals Corporation c/o Target Health Inc.

261 Madison Avenue, 24th floor New York, NY 10016

Attention: | Adam Harris, MM, RAC Associate Director, Regulatory Affairs

Dear Mr. Harris:

Please refer to your new drug application (NDA) dated and received December 31, 2018, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Naloxone hydrochloride injection, 5 mg/0.5 mL.

We also acknowledge receipt of your amendments dated September 27 and October 25, 2019, which were not reviewed for this action. You may incorporate applicable sections of the amendment by specific reference as part of your response to the deficiencies cited in this 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.

PRODUCT QUALITY

1. There is no correlation established between the extractable and leachable studies. The extractables studies failed to detect any extractables and specifically failed to detect the leachables observed in the leachable study.

To address this deficiency:

Perform a more vigorous extractables studies that can establish a good correlation with the leachable assessments. Use USP <1663> and <1664> as guides in conducting these studies.

2. We note inconsistency in the leachable data during stability testing. Additional data are required to justify these results:

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3. The photo-degradants at RRT

To address this deficiency:

a. Provide the lapsed time between the sample’s withdrawal and date of reanalysis of the 6-month time point.

b. Justify the use of ©® for the 6-month sample time point, analyzed at ®® and not for the original data presented at other time points.

c. Explain why the © related leachants have not been observed in the and have not been removed after

d. Provide the background peaks from the |

to confirm that the extra peaks are from the aa

e. Unambiguously establish the structures of the leachables at RRT! and

© by comparison with reference standards if available, or spectroscopic techniques such as Mass spectra, UV, IR and NMR.

f. Repeat the leachable study at each time point of the stability study, using validated analytical methods. Run blanks to establish background. Provide all data in your resubmission.

®® have not been identified.

To address this deficiency: Unequivocally establish the structures of the photo-degradants at RRT

by comparison with reference standards if available, or spectroscopic techniques such as Mass spectra, UV, IR and NMR.

(0) (4)

Particulate matter is a critical attribute for injectables. We note an inconsistency in the data provided at the 6-month time point for particulate matter testing under the long-term condition for Batch 1838-022. These out of trend results may mean variation in the analytical methods used for determination of particulate matter.

To address this deficiency: Re-evaluate the analytical method and revalidate if required.

As the naloxone product may be widely available in the community, it could be stored in other than controlled conditions (such as a vehicle in the summer or winter). Sufficient data to support these storage conditions were not provided.

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

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To address this deficiency:

Provide additional accelerated stability data to demonstrate lack of degradation, color change, or particulate formations. Similarly test the product when frozen and thawed. Report any particulate formation, color change, degradation and time required to thaw.

DEVICES

6. We previously requested reliability testing and analysis to demonstrate that the

reliability for drug delivery using a single device is 99.99% or greater. The provided results demonstrate that the reliability of a single device is 99.96%. Your analysis uses the availability of two devices to achieve 99.99%; however, this does not adequately mitigate the risk of a patient failing to receive the complete dose because they may need both doses. The expectation is that the reliability of an individual product dose delivery is not less than 99.99%.

To address this deficiency:

Implement appropriate modifications to the device control strategy and provide additional data demonstrating that the product has a reliability of at least 99.99% for a single device.

NONCLINICAL

7. You have not provided appropriate extractable/ leachables data to permit a

substantive nonclinical toxicological risk assessment for the proposed container closure system.

To address this deficiency:

Submit a revised toxicological risk assessment based on adequate extractable leachable data. To inform the risk assessment, conduct adequate extractable leachable studies to support the safety of your proposed container closure system, taking into consideration the following:

a. Results of the extraction studies should establish an acceptable extractable leachables correlation that will assure adequate monitoring of the drug product stability samples for all potential leachables from the container closure system.

b. Provide a justification for the compounds targeted in the leachable study based on the extraction data. In general, all extractables exceeding 5 mcg/day should be targeted in the leachable study.

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

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c. Based on the results of the leachable studies, identify all compounds in the drug product present at levels equal to or greater than 5 mcg/day taking into consideration the maximum daily dose of your drug product and submit a toxicological risk assessment for every leachable present in the drug product at or above the 5 mcg/day qualification threshold. The risk assessment must be based on the highest level of the leachable over the course of the proposed shelf-life.

d. Toxicology data from published literature or from the public domain that are used to support leachable qualifications must meet regulatory standards with adequate details to permit substantive independent review. Referencing databases, such as ECHA, with limited details regarding toxicity information is not acceptable. QSAR analysis and identification of a NOAEL (no observed adverse effect level) for structurally similar compounds to qualify leachables that have limited toxicity information is not acceptable unless it is accompanied with adequate justification via scientific data or literature that allows for such a bridge or extrapolation. These databases can be used to identify the pivotal studies used to support your toxicological risk assessment; however, the pivotal studies should be submitted with the NDA to permit independent review. Revise your toxicological risk assessment to employ permission daily exposure levels accordingly as per ICH Q3C(R5) principles. Submit copies of toxicology risk assessment reports and cited literature.

CLINICAL PHARMACOLOGY

8. Although you submitted relative bioavailability Study APC 6000-03, this

information was submitted too late in the review cycle to allow for a substantive review. Therefore, we have not determined whether you have established an acceptable scientific bridge between your proposed drug product and the referenced Narcan product to demonstrate that such reliance is scientifically justified. We are withholding any comments on the relative bioavailability study until after you submit a response to this Complete Response letter.

PRESCRIBING INFORMATION

9. During our review of your submitted labeling, we identified the following labeling

issue that should be addressed in your resubmission:

Your annotated labeling submitted December 31, 2018, included the following (b) (4)

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

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() 4)

The acceptability of the labeling will be a review issue.

We reserve remaining comments on the proposed labeling until the application is otherwise adequate.

Prior to resubmitting the labeling, use the SRPI checklist to correct any formatting errors to ensure conformance with the 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.'

To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Microsoft Word version. The marked- up copy should include annotations that support any proposed changes.

CARTON AND CONTAINER LABELING

10.We acknowledge receipt of the revised draft carton and container labeling on September 30, 2019. We reserve our comments on the acceptability of the packaging labels for the next review cycle.

PROPRITERAY NAME

11.Please refer to correspondence dated, March 28, 2019, which addresses the proposed proprietary name, Zimhi. This name was found acceptable pending approval of the application in the current review cycle. 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 drug under consideration regardless of indication, dosage form, or dose level.

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

1 http:/www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm

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

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(2) When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

a. Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

b. Present tabulations of the new safety data combined with the original application data.

c. Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

d. 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.

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.

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

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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. Note that resubmission goals will not apply to any resubmission of this application.

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 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 that this application is approved.

If you have any questions, call Swati Patwardhan, Regulatory Project Manager, at 301- 796-4085.

Sincerely, {See appended electronic signature page}

Sharon Hertz, MD

Director

Division of Anesthesia, Addiction, 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.

SHARON H HERTZ 11/22/2019 03:34:41 PM

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