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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. Carbaglu acts as a replacement for NAG in NAGS deficiency, PA, and MMA patients by activating CPS 1, improves or restores the function of the urea cycle, and facilitates ammonia detoxification and urea production.
Carbaglu is specifically indicated:
- for adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency
- for maintenance therapy for the treatment of chronic hyperammonemia due to NAGS deficiency
- for acute hyperammonemia due to propionic acidemia or methylmalonic acidemia
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:
NAGS Deficiency
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.
Propionic acidemia (PA) or methylmalonic acidemia (MMA)
The recommended daily dosage of Carbaglu in pediatric and adult patients with acute hyperammonemia due to PA or MMA is:
- 150 mg/kg/day for patients less than or equal to 15 kg
- 3.3 g/m2 /day for patients greater than 15 kg
Divide the daily dosage into 2 equal doses and round up to the next multiple of 50 mg tablet. Administer doses 12 hours apart. Continue Carbaglu treatment until the patient’s ammonia level is less than 50 micromol/L and for a maximum duration of 7 days. During acute hyperammonemic episodes, administer Carbaglu with other ammonia lowering therapies, such as intravenous glucose, insulin, L-carnitine, protein restriction, and dialysis.
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.
Side Effects
Adverse events associated with the use of Carbaglu may include, but are not limited to, the following:
NAGS deficiency
- vomiting
- abdominal pain
- pyrexia
- tonsillitis
- anemia
- diarrhea
- ear infection
- infections
- nasopharyngitis
- hemoglobin decreased
- headache
PA and MMA
- neutropenia
- anemia
- vomiting
- electrolyte imbalance
- decreased appetite
- hypoglycemia
- lethargy/stupor
- encephalopathy
- pancreatitis/lipase increased
Clinical Trial Results
NAGS deficiency
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.
Propionic acidemia (PA) or methylmalonic acidemia (MMA)
A randomized, double-blind, placebo-controlled, multicenter clinical trial compared the effectiveness of Carbaglu to placebo in the treatment of hyperammonemic episodes in patients with PA or MMA. The efficacy evaluation, based on 90 hyperammonemic episodes occurring in 24 patients, showed that patients receiving Crabaglu demonstrated a quicker reduction of ammonia compared to patients receiving placebo. The primary endpoint was the time from the first dose to the earlier of blood ammonia level below 50 micromol/L or hospital discharge. Throughout the first three days of treatment, a higher proportion of Carbaglu-treated episodes reached the primary endpoint compared to placebo-treated episodes.
Approval Date: 2010-03-01
Company Name: Recordati Rare Diseases