Class: Ammonia Detoxicants
Chemical Name: N-carbamoyl-l-glutamic acid
Molecular Formula: C6H10N2O5
CAS Number: 1188-38-1
Ammonia detoxicant; a synthetic structural analog of N-acetylglutamate (NAG), a physiologic activator of the urea cycle.
Uses for Carglumic Acid
Adjunctive therapy for the treatment of acute hyperammonemia in patients with deficiency of N-acetylglutamate synthase (NAGS), a hepatic enzyme required for activation of the first enzyme in the urea cycle; designated an orphan drug by FDA for treatment of NAGS deficiency.
Treat any episode of acute symptomatic hyperammonemia as a life-threatening emergency; prompt use of all necessary therapies (e.g., dialysis [preferably hemodialysis], caloric supplementation, protein restriction, sodium phenylacetate and sodium benzoate, IV arginine) to reduce ammonia concentrations is essential.
Maintenance therapy for chronic hyperammonemia in patients with NAGS deficiency. During maintenance therapy, protein restriction and other concomitant therapies used to reduce ammonia concentrations may be reduced or discontinued.
Carglumic Acid Dosage and Administration
Initiate therapy as soon as the diagnosis of hyperammonemia due to NAGS deficiency is suspected.
During acute hyperammonemic episodes, concomitant use of other therapies to lower plasma ammonia concentrations is recommended. (See Hyperammonemia under Uses.)
Must be obtained from Accredo Health Group; not available in US from other distributors or at community pharmacies.
Distributed to hospital pharmacies via Accredo wholesale distribution services.
Contact Accredo at 888-454-8860 or [Web] for additional information or to enroll patients.
Administer orally in 2–4 divided doses daily immediately before meals or feedings.
Administer as aqueous dispersion; tablets should not be swallowed whole or crushed. Do not disperse tablets in food or mix with liquids other than water.
Dispersion for Adult Use
Place each 200-mg tablet in a cup containing ≥2.5 mL of water. Stir or shake gently until tablet is dispersed (tablet will not completely dissolve).
Administer immediately; to ensure full dose is administered, resuspend any residue in the cup with additional volumes of water and swallow immediately.
Dispersion for Pediatric Use
Place each 200-mg tablet in a cup containing 2.5 mL of water to prepare a suspension containing 80 mg/mL. Stir or shake gently until tablet is dispersed (tablet will not completely dissolve).
Using oral syringe, withdraw appropriate dose and administer immediately; to ensure full dose is administered, refill the oral syringe with 1–2 mL of water and administer immediately. Discard any unused portion of dispersion.
May administer aqueous dispersion through NG tube.
100–250 mg/kg daily given in 2–4 divided doses. Adjust dosage based on symptoms and plasma ammonia concentrations.
Based on limited data, maintenance dosage usually <100 mg/kg daily; give in 2–4 divided doses. Adjust dosage to maintain a target normal (age-adjusted) plasma ammonia concentration.
100–250 mg/kg daily. Round total daily dosage to nearest 100 mg (i.e., half-tablet dosage strength) and administer in 2–4 divided doses. Adjust dosage based on symptoms and plasma ammonia concentrations.
Based on limited data, maintenance dosage usually <100 mg/kg daily. Round total daily dosage to nearest 100 mg (i.e., half-tablet dosage strength) and administer in 2–4 divided doses. Adjust dosage to maintain a target normal plasma ammonia concentration.
No special population dosage recommendations at this time.
Cautions for Carglumic Acid
Manufacturer states none known.
Emergency Treatment of Hyperammonemia
Risk of rapid brain damage or death if acute symptomatic hyperammonemia is left uncontrolled; treat as a life-threatening emergency. Prompt use of all necessary therapies to reduce serum ammonia concentrations (e.g., dialysis [preferably hemodialysis]) is essential. Caloric supplementation recommended to reverse catabolism and reduce protein turnover; complete restriction of dietary protein recommended for 24–48 hours. (See Hyperammonemia under Uses.)
Manage hyperammonemia due to inborn errors of metabolism in coordination with medical personnel familiar with such conditions; usually requires health-care facilities able to provide multidisciplinary treatment (e.g., hemodialysis, nutritional management, medical support).
Closely monitor plasma ammonia concentrations, neurologic status, laboratory tests, and clinical response during treatment.
Protein restriction and hypercaloric intake recommended to block ammonia-generating catabolic pathways during acute hyperammonemic episodes. Dietary protein intake may be increased when plasma ammonia concentrations normalize, with goal of unrestricted protein intake.
Distributed into milk in rats; not known whether distributed into human milk. Use not recommended because of potential risk to nursing infants.
Efficacy evaluated in neonates, infants, and children. No substantial differences in response relative to adults; however, data limited.
Safety and efficacy not established.
Common Adverse Effects
Infections (e.g., tonsilitis, ear infection, nasopharyngitis), vomiting, abdominal pain, diarrhea, fever, anemia, headache.
Interactions for Carglumic Acid
No formal drug interaction studies to date.
Carglumic Acid Pharmacokinetics
Peak plasma concentration usually attained within 2–4 hours. Absolute bioavailability not determined.
Ammonia concentrations decrease within 24 hours.
Distributed into milk in rats; not known whether distributed into human milk.
Part of administered dose may be metabolized by intestinal bacteria to form carbon dioxide.
Excreted in feces (≤60%) and in urine (9%) as unchanged drug and through the lungs as carbon dioxide.
Median terminal half-life: 5.6 hours.
Unopened container: 2–8°C.
Opened container: Store tightly closed at ≤30°C; do not refrigerate. Discard 1 month after first opening container.
Structurally similar to NAG, an activator of carbamoyl phosphate synthetase 1 (CPS 1), the first enzyme in the urea cycle. Replaces NAG in the urea cycle.
Restores activity of the urea cycle, normalizes plasma ammonia concentrations, and increases urea production in patients with deficiency of NAGS (a mitochondrial enzyme that produces NAG).
Normal neurologic development may be possible if therapy is started early (before irreversible brain damage).
Advice to Patients
Importance of instructing patients and/or their caregivers regarding proper dosage, preparation, and administration. Importance of not crushing tablets or swallowing tablets whole. Importance of dispersing each tablet in ≥2.5 mL of water and immediately swallowing or administering mixture.
Importance of informing patients and/or their caregivers that treatment is continuous and lifelong for patients with NAGS deficiency.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of informing patients and/or their caregivers of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of carglumic acid is restricted. (See Restricted Distribution under Dosage and Administration.)
Tablets, dispersible, scored
AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 1, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.