Carglumic acid

1. INDICATIONS AND USAGE CARBAGLU is a carbamoyl phosphate synthetase 1 (CPS 1) activator indicated in pediatric and adult patients as: Adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency. Maintenance therapy for the treatment of chronic hyperammonemia due to NAGS deficiency. Adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA).

Carglumic acid is a synthetic structural analogue of N-acetylglutamate (NAG) which is produced from glutamate and acetyl-CoA in a reaction catalyzed by N‑acetylglutamate synthase (NAGS), a mitochondrial liver enzyme. NAG acts as the essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1), a mitochondrial liver enzyme which catalyzes the first reaction of the urea cycle. The urea cycle, whose role is the disposition of ammonia, includes a series of biochemical reactions in the liver resulting in the conversion of ammonia into urea, which is then excreted through the urine. Carglumic acid acts as a CPS1 activator, improves or restores the function of the urea cycle, and facilitates ammonia detoxification and urea production.

2. DOSAGE AND ADMINISTRATION Acute Hyperammonemia due to NAGS deficiency. The recommended dosage in adult and pediatric patients is 100 mg/kg to 250 mg/kg orally daily. Divide the daily dosage into 2 to 4 doses. Chronic Hyperammonemia due to NAGS deficiency. The recommended dosage in adult and pediatric patients is 10 mg/kg to 100 mg/kg orally daily. Therapeutic Monitoring for NAGS Deficiency. Closely monitor plasma ammonia and titrate dosage to maintain the ammonia level within normal range for the patient's age, taking into consideration their clinical condition. Acute Hyperammonemia due to PA or MMA. The recommended dosage in adult and pediatric patients is: 150 mg/kg orally daily for patients less than or equal to 15 kg 3.3 g/m 2 orally daily for patients greater than 15 kg Divide the daily dosage into 2 doses.

4. CONTRAINDICATIONS None None.

6. ADVERSE REACTIONS NAGS deficiency: Most common adverse reactions (≥13%) are vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache. PA and MMA: Most common adverse reactions (≥5%) are neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased.

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original unopened bottle. Do not refrigerate. After first opening of the bottle: Store at room temperature between 15°C and 30°C (59°F and 86°F). Keep the bottle tightly closed between openings in order to protect from moisture.