Galephar Pharmaceutical Research Inc.: Legubeti

Please refer to your new drug application (NDA) dated and received July 7, 2022, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Legubeti (acetylcysteine) for oral solution.

1. You have not provided data to demonstrate the tolerability of Legubeti, the lysine salt of acetylcysteine, for the full range of loading and maintenance doses for patients with all body weights proposed in labeling.

Both lysine and acetylcysteine have an unpleasant taste, and acetylcysteine has an unpleasant odor that may affect the tolerability of oral ingestion.

The data to address the effect of the lysine on the palatability of Legubeti is inadequate.

The completed relative bioavailability study with Legubeti and the acetylcysteine oral solution (a reference standard as a substitute for the relied-upon listed drug) conducted with 1 gm of acetylcysteine is not adequate to address palatability because most patients will receive higher doses (up to 15 gm) based on the proposed weight-based dosage.

You have not provided adequate information to support the safety of L-lysine administration to pediatric patients weighing down to 1 kg. This information is needed to inform the benefit-risk assessment of this product in the pediatric population.

The maximum daily amount of L-lysine expected to be administered with Legubeti at the proposed dosage ranges from 502.6 mg/kg/day including the loading dose on the first day to 313 mg/kg/day after completion of the maintenance doses on the last day of treatment.

To resolve this deficiency you may (1) cite and provide original publications corroborating the proposed labeling language that are not based on FDA's finding of a listed drug (including the labeling of a listed drug); or (2) cite reliance on Cetylev and comply with the legal/regulatory requirements for such reliance.

We recommend you provide a comprehensive summary of clinical pharmacology information for N-acetylcysteine and L-Lysine available in the published literature along with the original articles.