Complete Response Letter NDA 505b1 219045 (Oct 21, 2024)

Summary

The FDA has reviewed a New Drug Application (NDA 219045) for a naloxone HCl, 4 mg, nasal spray. While the product's efficacy is considered comparable to Narcan, significant safety concerns exist due to its higher systemic exposure, which is greater than Narcan. This higher exposure poses an increased risk of precipitated opioid withdrawal, especially in opioid-dependent individuals and in a nonprescription setting without healthcare guidance. The submitted safety data is deemed inadequate, and communicating this risk effectively on a Drug Facts Label (DFL) is challenging. The FDA recommends either product reformulation to achieve lower systemic exposure or conducting further studies to establish the safety of the current higher-exposure formulation for nonprescription use, along with potential labeling modifications. A comprehensive safety update is also required.

Key points

• Applicant may consider product reformulation to obtain a lower systemic naloxone exposure consistent with that of approved nonprescription naloxone products.
• To support nonprescription marketing approval of the currently proposed formulation, applicant must establish safety of the proposed product's higher systemic exposure for consumers in the nonprescription setting (i.e., by demonstrating that the safety profile is comparable to that of an approved nonprescription naloxone product).
• To support nonprescription marketing approval of the currently proposed formulation, applicant must potentially modify labeling and ensure adequate comprehension of the proposed product label.
• Applicant should submit protocols for review and feedback prior to the conduct of any studies.
• When responding to deficiencies, applicant must include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b).
• The safety update must describe in detail any significant changes or findings in the safety profile.
• The safety update must present a retabulation of the reasons for premature trial discontinuation by incorporating drop-outs from newly completed trials and describe any new trends or patterns identified.
• The safety update must 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, and for serious adverse events.

Cited reasons

• Inadequate Safety Data for Higher Systemic Exposure of Naloxone in Nonprescription Setting
• Challenges in Communicating Safety Risks of Higher Systemic Exposure in Nonprescription Labeling
• The FDA issued a Complete Response Letter due to inadequate safety data for the proposed product's higher systemic naloxone exposure in a nonprescription setting. Concerns include increased risk of precipitated opioid withdrawal and challenges in communicating these risks via labeling. The agency recommends reformulation or additional clinical safety studies.

Recommended actions

• Applicant may consider product reformulation to obtain a lower systemic naloxone exposure consistent with that of approved nonprescription naloxone products.
• To support nonprescription marketing approval of the currently proposed formulation, applicant must establish safety of the proposed product's higher systemic exposure for consumers in the nonprescription setting (i.e., by demonstrating that the safety profile is comparable to that of an approved nonprescription naloxone product).
• To support nonprescription marketing approval of the currently proposed formulation, applicant must potentially modify labeling and ensure adequate comprehension of the proposed product label.
• Applicant should submit protocols for review and feedback prior to the conduct of any studies.
• When responding to deficiencies, applicant must include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b).
• The safety update must describe in detail any significant changes or findings in the safety profile.
• The safety update must present a retabulation of the reasons for premature trial discontinuation by incorporating drop-outs from newly completed trials and describe any new trends or patterns identified.
• The safety update must 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, and for serious adverse events.

Deficiency summary

The FDA issued a Complete Response Letter due to inadequate safety data for the proposed product's higher systemic naloxone exposure in a nonprescription setting. Concerns include increased risk of precipitated opioid withdrawal and challenges in communicating these risks via labeling. The agency recommends reformulation or additional clinical safety studies.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

NDA

Impact

Impact score

0.95

Estimated delay

730 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary theme is the critical safety concern regarding the higher systemic exposure of the proposed nonprescription naloxone product, specifically its potential to increase the risk of precipitated opioid withdrawal, and the associated challenges in consumer labeling.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%