General Information

Carbaglu contains the active substance carglumic acid, a synthetic structural analogue of N-acetylglutamate (NAG), which is an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1) in liver mitochondria. CPS 1 is the first enzyme of the urea cycle, which converts ammonia into urea. NAG is the product of N-acetylglutamate synthase (NAGS), a mitochondrial enzyme. Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS 1.

Carbaglu is specifically indicated as an adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS) and for maintenance therapy in pediatric and adult patients for chronic hyperammonemia due to the deficiency of the hepatic enzyme NAGS.

Carbaglu is supplied as a tablet for oral administration. Carbaglu tablets should not be swallowed whole or crushed. The tablets should be dispersed in water immediately before use. The recommended dosage is as follows:
Adults
100 mg/kg/day to 250 mg/kg/day. Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms. The recommended maintenance dose should be titrated to target normal plasma ammonia level for age. In clinical studies, the maintenance doses were usually less than 100 mg/kg/day. The total daily dose should be divided into 2 to 4 doses and rounded to the nearest 100 mg.
Pediatrics
100 mg/kg/day to 250 mg/kg/day. Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms. The recommended maintenance dose should be titrated to target normal plasma ammonia level for age. In clinical studies, maintenance doses were usually less than 100 mg/kg/day. The total daily dose should be divided into 2 to 4 doses.

Clinical Results

FDA Approval
The efficacy of Carbaglu in the treatment of hyperammonemia due to NAGS deficiency was evaluated in a retrospective review of the clinical course of 23 NAGS deficiency patients who received Carbaglu treatment for a median of 7.9 years (range 0.6 to 20.8 years). Short-term efficacy was evaluated using mean and median change in plasma ammonia levels from baseline to days 1 to 3. Persistence of efficacy was evaluated using long-term mean and median change in plasma ammonia level. All 13 patients had abnormal ammonia levels at baseline. The overall mean baseline plasma ammonia level was 271 µmol/L. By day 3, normal plasma ammonia levels were attained in patients for whom data were available. Long-term efficacy was measured using the last reported plasma ammonia level for each of the 13 patients analyzed (median length of treatment was 6 years; range 1 to 16 years). The mean and median ammonia levels were 23 µmol/L and 24 µmol/L, respectively, after a mean treatment duration of 8 years.

Side Effects

Adverse events associated with the use of Carbaglu may include, but are not limited to, the following:

• infections
• vomiting
• abdominal pain
• pyrexia
• tonsilitis
• anemia
• ear infection
• diarrhea
• nasopharyngitis
• headache

Mechanism of Action

Carbaglu contains the active substance carglumic acid, a synthetic structural analogue of N-acetylglutamate (NAG), which is an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1) in liver mitochondria. CPS 1 is the first enzyme of the urea cycle, which converts ammonia into urea. NAG is the product of N-acetylglutamate synthase (NAGS), a mitochondrial enzyme. Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS 1.