FDA CRL - Hikma Pharmaceuticals USA Inc.

The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to Hikma Pharmaceuticals USA Inc. for its New Drug Application (NDA 219045) concerning naloxone hydrochloride nasal spray, 4 mg, for nonprescription use. The FDA determined the application could not be approved in its current form due to significant safety concerns related to the product's systemic exposure.

The primary issue stems from clinical data indicating the proposed product's maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were substantially higher than the approved nonprescription Narcan (4 mg) nasal spray, despite having the same nominal dose. This higher systemic exposure, which aligned more closely with the prescription-only Kloxxado (8 mg) nasal spray, raised concerns about increased risks of precipitated opioid withdrawal, including potentially serious adverse cardiovascular events and pulmonary edema, especially for opioid-dependent individuals using the product without medical supervision. The FDA found the submitted safety data inadequate to address these elevated risks and noted the difficulty of clearly communicating these differences in systemic exposure and associated risks on a Drug Facts label to consumers.

To address these deficiencies, Hikma is advised to consider reformulating the product to achieve lower systemic naloxone exposure consistent with approved nonprescription products. Alternatively, if the current formulation is pursued, the company must establish the safety of its higher systemic exposure for nonprescription use through comprehensive clinical safety studies in relevant populations or compelling published literature, followed by potential modifications to labeling to ensure adequate consumer comprehension. The FDA also requires the submission of study protocols for review and a comprehensive safety update, as outlined in 21 CFR 314.50(d)(5)(vi)(b).