Carglumic Acid Approved To Treat Genetic Hyperammonemia

Cheryl A. Thompson

BETHESDA, MD 19 March 2010—FDA on Thursday announced the approval of carglumic acid, or Carbaglu, to treat a rare, genetic enzyme deficiency that results in elevated levels of ammonia in the blood and can be fatal.

N-acetylglutamate synthase deficiency is the rarest disorder of the urea cycle, according to Paris-based Orphan Europe, manufacturer of the new treatment. Without that enzyme, N-acetylglutamate does not form and activate the first enzyme of the urea cycle. The consequence is a buildup of ammonia, which can eventually cross the blood–brain barrier and cause neurologic problems, cerebral edema, coma, and death.

Carglumic acid, the company said, resembles N-acetylglutamate sufficiently to activate the first enzyme of the urea cycle and quickly reduce plasma ammonia levels to normal in patients deficient in N-acetylglutamate synthase.

The FDA-approved labeling (PDF) for carglumic acid describes the drug as efficacious in helping to treat acute hyperammonemia due to N-acetylglutamate synthase deficiency and in treating chronic hyperammonemia due to the disorder.

Children and adults with acute hyperammonemia, the labeling states, should initially receive 100–250 mg/kg/day of carglumic acid. The dosage should be adjusted on the basis of the patient's plasma ammonia concentration and clinical symptoms.

For the treatment of chronic hyperammonemia, patients should receive a maintenance dosage that targets the normal plasma ammonia concentration for their age. A company-conducted long-term follow-up of 22 patients treated with carglumic acid found that most received a maintenance dosage of less than 100 mg/kg/day.

The total daily dose for the treatment of acute or chronic hyperammonemia is to be divided into two, three, or four portions for administration immediately before meals or feedings.

Patients should not swallow whole or crushed carglumic acid tablets. The labeling states that all doses are to be prepared as a liquid. Instructions for preparing and administering the liquid are provided in the labeling.

The most common adverse events revealed in the long-term follow-up of patients were vomiting, abdominal pain, pyrexia, and tonsillitis. Each of these adverse events occurred in at least 17% of the patients.

Orphan Europe will market Carbaglu in bottles containing 5 or 60 200-mg tablets. Until opened, the bottles must be stored in a refrigerator at 2–8 °C. Once opened, bottles are to be stored at room temperatures not exceeding 30 °C and the contents discarded in one month.

Information on how to obtain the new product was not immediately available from the company.