Hikma Pharmaceuticals USA Inc.: phenobarbital sodium

The submitted data do not support the proposed nonprescription use of your proposed product, naloxone HCI nasal spray, 4 mg.

To support and establish the efficacy and safety of your proposed product, you are relying upon the Agency's findings of efficacy and safety for NDAs 16636 (Narcan [naloxone HCl, 0.4 mg/mL] injection) and 208411 (Narcan [naloxone HCl, 4 mg] nasal spray), as well as cross-referencing your NDA 212045 (Kloxxado [naloxone HCI, 8 mg] nasal spray).

Compared to Kloxxado (naloxone HCl, 8 mg) nasal spray, the proposed product demonstrated lower Cmax and AUC values.

Regarding efficacy, your comparative bioavailability study demonstrated that the proposed product has comparable or higher systemic exposure and comparable or quicker onset of action than Narcan (naloxone HCI, 4 mg) nasal spray.

Therefore, you may rely on the Agency's finding of efficacy for Narcan (naloxone HCI, 4 mg) nasal spray.

However, without labeling changes, the proposed product would appear comparable to other 4 mg naloxone nasal spray products in the nonprescription space with regard to nominal dose, directions, and warnings.

'o the DFL and evaluated in a simulated-use human factors validation study designed to evaluate whether the user interface can be used safely and effectively by intended users for the intended use under the expected environment of use.

However, our safety concerns related to the higher naloxone exposure precluded labeling discussions.

If you determine that an additional human factors validation study is not required, we strongly recommend you submit your justification along with a side-by-side comparison of the user interface tested in the human factors study and the intend-to-market user interface for our feedback prior to resubmitting your NDA. The acceptability of your justification will be a matter of review.

Please refer to your new drug application (NDA) dated and received March 23, 2023, and your amendments, submitted under section 505(b)/pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for phenobarbital sodium injection.

Therefore, no conclusions may be drawn regarding effectiveness and safety of phenobarbital sodium injection for the treatment of neonatal seizures.

You should discuss with us the contents and formats of the efficacy and safety information derived from the NEOLEV2 study before any resubmission of an application reliant on these data.

Letter of Authorization from the holder of that IND.

We recommend that you conduct a comprehensive abuse potential assessment for our review in your response to this Complete Response letter.

Please refer to your new drug application (NDA) dated and received April 30, 2019, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for naloxone nasal spray, 8 mg.

Specifically, in the w) 2011 report, an MDD of 8 mg/day was used to calculate the AET for volatile, semi-volatile and non-volatile, while in ow report TTP-IOX-M0083, 32 mg/day (i.e., 4 doses per day) was used for the calculation of AETs for polar compounds and elemental impurities.

Alternatively provide sufficient batch data to show it is absent in the drug product with validated methods.

12.Leachable and extractable studies are critical to assure no elements or chemical substances are extracted from the manufacturing components under stress conditions to compromise quality of the drug product.

Update the extractable leachable assessment to address the Chemistry, Manufacturing, and Controls deficiencies in the resubmission.

Containing Salt Drug Substances' and USP salt policy, add equivalency statement in section 11 of the PI indicating the strength in terms of the active moiety, i.e. naloxone hydrochloride 8 mg (equivalent to 7.2 mg naloxone) in 0.1 mL. The equivalency statement should also appear on the carton labeling text and if space permits, on container label as well.

'ake before the application may be approved.