Orexo ABNaloxone hydrochloride nasal powder, °®

NDA 217433 COMPLETE RESPONSE

Orexo AB

c/o DJA Global Pharmaceuticals, Inc. 325 Sentry Parkway

Building 5 West, Suite 200

Blue Bell, PA 19422

Attention: Damaris DeGraft-Johnson, RPh, MSc. Med.Chem Authorized US Agent

Dear Damaris DeGraft-Johnson:

Please refer to your new drug application (NDA) oe

for Naloxone hydrochloride nasal powder, °® . We also acknowledge receipt of your amendments dated oe , Which

were not reviewed for this action. You may incorporate applicable sections of these amendments 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 on how to address these issues.

DEVICE (1) In your response to our Information Requests (IR) sent on oe , you indicate that the final finished version of your device is not considered in your verification, reliability, stability and shipping verification tests. The following two differences between the tested versions of your device and the intended commercial version of your device were noted:

0) (4)

Reference ID: 5413659

NDA 217433 Page 2

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

Reference ID: 5413659

NDA 217433 Page 3

PRODUCT QUALITY

HUMAN FACTORS

(3) Based on the evaluation of the human factors (HF) validation study results, the user interface does not support the safe and effective use of the proposed product. The results of the HF validation study demonstrated several use errors, close calls, and use difficulties with the critical task of depressing the plunger to administer the dose. Specifically, results of your HF validation study demonstrated that several participants failed to depress the plunger, some of whom thought they had successfully administered a dose. These use errors led to administration of no doses which would likely negatively impact patient care and could increase the risk for mortality in this patient population.

As conveyed in the a: Discipline Review letter, we note that many of the participants who failed to depress the plunger provided subjective feedback indicating that early clicking sounds and plunger counterpressure after being approximately halfway depressed led the participants to believing they had successfully administered a dose when they had not.

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

Reference ID: 5413659

NDA 217433 Page 4

Information needed to resolve the deficiency:

Implement user interface revisions and design modifications to promote the safe and effective use of the proposed product, and provide data demonstrating that, with these mitigations, the product user interface can be used safely and effectively to deliver the intended dose of drug substance.

Prior to conducting an assessment to evaluate the impact of any mitigation strategies, we recommend submitting your HF validation study protocol, along with the redesigned user interface, for our review and feedback.

It is critically important for a product to be safe, effective, and easy-to-use in the proposed indication and population. As described above, you should provide data demonstrating the revised proposed product can be used safely and effectively to deliver the intended dose.

PRESCRIBING INFORMATION

(4) We reserve comment on the proposed labeling until the application is otherwise

adequate. We encourage you to review the labeling review resources on the Prescription Drug Labeling Resources® 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.

CARTON AND CONTAINER LABELING

(5) We reserve comment on the proposed labeling until the application is otherwise

adequate.

SAFETY UPDATE

(6) 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.

3 https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources

4 https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs-

final-rule

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

Reference ID: 5413659

NDA 217433

Page 5

. When assembling the sections describing discontinuations due to adverse

events, serious adverse events, and common adverse events, incorporate new safety data as follows:

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.

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

For indications other than the proposed indication, provide separate tables for he 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 subject 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. nclude an updated estimate of use for drug marketed in other countries.

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

ADDITIONAL COMMENTS

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

PRODUCT QUALITY

(b) (4)

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

Reference ID: 5413659

NDA 217433 Page 6

NONCLINICAL

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

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

Reference ID: 5413659

NDA 217433 Page 7

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 guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

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

If you have any questions, call oe

Sincerely,

{See appended electronic signature page} (b) (4)

Center for Drug Evaluation and Research

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

Reference ID: 5413659

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.

(b) (4)

07/15/2024 01:02:44 PM

Reference ID: 5413659