Introduction
Carbaglu® (carglumic acid) is a synthetic structural analogue of N-acetylglutamate (NAG) used for the treatment of hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency. This rare autosomal recessive urea cycle disorder results in impaired ammonia detoxification, leading to potentially life-threatening hyperammonemia. Carbaglu received FDA approval in 2010 and represents a targeted therapy for this specific metabolic disorder.
Mechanism of Action
Carbaglu functions as a carbamoyl phosphate synthetase 1 (CPS1) activator. In the urea cycle, N-acetylglutamate serves as an essential allosteric activator of CPS1, the first and rate-limiting enzyme in the urea cycle. In NAGS deficiency, the absence of endogenous NAG results in CPS1 inactivation and subsequent impairment of ammonia incorporation into the urea cycle. Carbaglu, being a structural analogue of NAG, substitutes for the missing endogenous activator, thereby restoring CPS1 activity and enabling normal urea cycle function and ammonia detoxification.
Indications
Carbaglu is indicated for:
- Treatment of acute hyperammonemia in patients with N-acetylglutamate synthase (NAGS) deficiency
- Maintenance therapy for chronic management of hyperammonemia in NAGS deficiency
- Adjunctive treatment of hyperammonemia in organic acidemias (off-label use in some cases)
Dosage and Administration
Initial dose for acute hyperammonemia: 100-250 mg/kg/day administered in 2-4 divided doses Maintenance therapy: 10-100 mg/kg/day in 2-4 divided doses, titrated to individual patient needs Administration:- Tablets must be dispersed in water immediately before administration
- Administer at least one hour before meals
- Dosage should be individualized based on ammonia levels, clinical response, and protein tolerance
- Renal impairment: No specific dosage adjustment recommended
- Hepatic impairment: Use with caution and monitor closely
- Pediatric patients: Safety and effectiveness established in pediatric patients
Pharmacokinetics
Absorption: Rapidly absorbed following oral administration. Peak plasma concentrations reached within 1-4 hours. Distribution: Not extensively characterized due to the specific nature of its action at the hepatic mitochondrial level. Metabolism: Undergoes minimal hepatic metabolism. Elimination: Primarily excreted unchanged in urine with a half-life of approximately 5-6 hours. Protein binding: Minimal protein binding observed.Contraindications
- Hypersensitivity to carglumic acid or any component of the formulation
- No other absolute contraindications exist beyond hypersensitivity
Warnings and Precautions
- Hyperammonemic crises: May still occur despite therapy; patients should maintain emergency protocol
- Dietary protein restriction: Required in conjunction with drug therapy
- Pregnancy: Category C - use only if potential benefit justifies potential risk to fetus
- Lactation: Exercise caution when administering to nursing women
- Monitoring: Requires continuous monitoring of plasma ammonia levels
- Non-compliance: May lead to rapid development of hyperammonemia
Drug Interactions
- No formal drug interaction studies conducted
- Theoretical interactions with drugs that affect urea cycle function
- Potential interaction with valproic acid, which may cause hyperammonemia
- corticosteroids may increase protein catabolism and ammonia levels
Adverse Effects
Common adverse effects (≥1%):- Vomiting (14%)
- Abdominal pain (11%)
- Fever (10%)
- Tonsillitis (9%)
- Anemia (8%)
- Diarrhea (7%)
- Headache (7%)
- Infection (6%)
- Hyperammonemia (may indicate treatment failure)
- Reye-like syndrome (rare)
- Neurological complications related to hyperammonemia
Monitoring Parameters
- Plasma ammonia levels: Frequently during initiation, then regularly (goal: maintain <100 μmol/L)
- Blood amino acid levels: Quantitative plasma amino acids
- Nutritional status: Regular assessment of protein intake and overall nutrition
- Growth parameters: In pediatric patients
- Neurological status: Regular developmental assessment
- Renal function: Periodic assessment
- Liver function tests: Regular monitoring
- Complete blood count: Periodic assessment
Patient Education
- Importance of strict adherence to prescribed dosing regimen
- Recognize signs and symptoms of hyperammonemia: vomiting, lethargy, seizures, behavioral changes
- Maintain emergency protocol for hyperammonemic crises
- Adhere to dietary protein restrictions as prescribed
- Never discontinue medication without medical supervision
- Keep regular follow-up appointments with metabolic specialist
- Inform all healthcare providers about NAGS deficiency and Carbaglu therapy
- Proper administration technique: disperse tablets in water immediately before ingestion
References
1. FDA prescribing information: Carbaglu (carglumic acid) tablets 2. Haberle J, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32 3. Summar ML, et al. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008;97(10):1420-1425 4. Tuchman M, et al. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008;94(4):397-402 5. Ah Mew N, et al. Urea cycle disorders overview. GeneReviews® [Internet]. University of Washington, Seattle; 1993-2023 6. Clinical experience from the Urea Cycle Disorders Consortium longitudinal study protocol 7. European Medicines Agency assessment report for Carbaglu 8. Drug interaction data from Micromedex® and Lexicomp® databases
This monograph is intended for educational purposes only and should not replace clinical judgment. Always consult current prescribing information and clinical guidelines for specific patient care decisions.