Carglumic Acid

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.

• 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.

• 4. CONTRAINDICATIONS None None.contraindicated

2. DOSAGE AND ADMINISTRATION Acute Hyperammonemia due to NAGS deficiency ( 2.2 ) 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 ( 2.2 ) The recommended dosage in adult and pediatric patients is 10 mg/kg to 100 mg/kg orally daily. Divide the daily dosage into 2 to 4 doses. Therapeutic Monitoring for NAGS Deficiency ( 2.2 ) 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 ( 2.3 ) 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. Continue treatment until ammonia level is less than 50 micromol/L and for a maximum duration of 7 days. Patients with Renal Impairment ( 2.4 ) See Full Prescribing Information for Instructions on Dosage Adjustment. Preparation and Administration ( 2.5 ) Disperse CARBAGLU tablets in water. Do not swallow whole or crushed. Take immediately before meals or feedings. For additional instructions on preparation and administration orally or through a nasogastric tube or gastrostomy tube, see Full Prescribing Information. 2.1 Important Administration Instructions Disperse CARBAGLU tablets in water. Do not swallow whole or crush [see Dosage and Administration (2.5) ] .

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. ( 6.1 ) PA and MMA : Most common adverse reactions (≥5%) are neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Acute and Chronic Hyperammonemia due to NAGS Deficiency In a retrospective case series of 23 NAGS deficiency patients treated with CARBAGLU, 17 of the 23 patients reported an adverse reaction. The most common adverse reactions (occurring in ≥ 13% of patients) were vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with CARBAGLU.

8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women with NAGS deficiency exposed to CARBAGLU. If CARBAGLU is administered during pregnancy, health care providers should report CARBAGLU exposure by calling 1-888-575-8344. Risk Summary Although rare case reports of CARBAGLU use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, untreated NAGS deficiency, PA and MMA can result in irreversible neurologic damage and death in pregnant women (see Clinical Considerations ). In an animal reproduction study, decreased survival and growth occurred in offspring born to rats that received carglumic acid at a dose approximately 38 times the maximum reported human maintenance dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Metabolism

The pharmacokinetics of carglumic acid in healthy subjects following an intravenous (IV) infusion over 2 hours at 8 mg/kg or an oral administration at 100 mg/kg are summarized in Table 3 . Table 3: Mean (SD) Pharmacokinetic Parameter Values of Carglumic Acid in Healthy Subjects # Median (range); N/A, not applicable PK parameter IV infusion 8 mg/kg (N=10) Oral 100 mg/kg (N=12) C max (ng/mL) 8613 (558) 3284 (321) T max (hr) # 2 (1-2) 3 (2-4) AUC (ng*hr/mL) 24501 (1613) 31426 (2150) T ½ (hr) 31 (3) 25 (2) CL (L/hr/kg) 0.34 (0.02) N/A Vd (L/kg) 15 (1) N/A Abso r p ti o n Following an oral administ…

10. OVERDOSAGE One patient treated with 650 mg/kg/day of CARBAGLU developed symptoms resembling monosodium glutamate intoxication-like syndrome and characterized by tachycardia, profuse sweating, increased bronchial secretions, increased body temperature, and restlessness. These symptoms resolved upon reduction of the dose.

• Mar 18, 2010NDANDA022562Recordati Rare
• Oct 13, 2021ANDAANDA213729Novitium Pharma
• Jun 22, 2022ANDAANDA213395Navinta Llc

1. 1Off Label Use15121%
2. 2Vomiting14420%
3. 3Ammonia Increased9213%
4. 4Hyperammonaemia547.4%
5. 5Hospitalisation506.8%
6. 6Death486.5%
7. 7Diarrhoea466.3%
8. 8Pyrexia304.1%
9. 9Metabolic Disorder273.7%
10. 10Condition Aggravated243.3%
11. 11Drug Ineffective243.3%
12. 12Seizure212.9%
13. 13Constipation202.7%
14. 14Fatigue182.5%
15. 15Nasopharyngitis182.5%

The 9 most recently updated of 9 ClinicalTrials.gov registrations naming Carglumic Acid as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• An Observational Study of Carbaglu® for the Treatment of MMA and PA in Adults and Pediatrics
  Recruiting · Observational · 20 enrolled · RECORDATI GROUP
  NCT05040178updated 2025-04-15
• Long-term Efficacy of Carglumic Acid in Organic Acidemia.
  Completed · Interventional · 3 enrolled · National Taiwan University Hospital
  NCT04284917updated 2025-03-20
• Orphan Europe Carbaglu® Surveillance Protocol
  Recruiting · Observational · 30 enrolled · Nicholas Ah Mew
  NCT03409003updated 2024-02-07
• Understanding the Long-Term Management of Organic Acidemia Patients With CARBAGLU®: A Mixed Methods Approach
  Recruiting · Observational · 95 enrolled · RECORDATI GROUP
  NCT04176523updated 2024-02-05
• Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
  Completed · Phase 2 · Interventional · 35 enrolled · Mendel Tuchman
  NCT01599286updated 2021-02-15
• N-Carbamylglutamate (Carbaglu) In The Treatment Of Hyperammonemia
  Unknown · Phase 2 · Phase 3 · Interventional · 52 enrolled · Mendel Tuchman
  NCT00843921updated 2020-02-17
• Carglumic Acid in Methylmalonic Acidemia and Propionic Acidemia
  Completed · Phase 3 · Interventional · 33 enrolled · King Abdullah International Medical Research Center
  NCT02426775updated 2019-04-25
• Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia
  Terminated · Phase 2 · Interventional · 1 enrolled · Mendel Tuchman
  NCT01597440updated 2017-04-26
• Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate
  Withdrawn · Phase 2 · Interventional · 0 enrolled · Children's Hospital of Philadelphia
  NCT01341379updated 2014-05-29

CPIC-curated drug–gene pairs for Carglumic Acid. Levels describe the strength of curated evidence and guideline status — never a recommendation to test or to adjust therapy.

• NAGSCPIC B (provisional)

Frequently asked questions

How does Carglumic Acid work?

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.

What is Carglumic Acid used for?

According to FDA labeling, Carglumic Acid carries indications including: 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.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Carglumic Acid?

Carglumic Acid is classified as Amino acids and derivatives, Carbamoyl Phosphate Synthetase 1 Activator, Carbamoyl Phosphate Synthetase 1 Activators.

What are the brand names for Carglumic Acid?

Carglumic Acid is marketed under brand names including Carbaglu.

What are the contraindications for Carglumic Acid?

Carglumic Acid labeling lists contraindications including: 4. CONTRAINDICATIONS None None.. Always consult the full prescribing information and a clinician.