Treating hyperammonemia due to NAGS deficiency with CARBAGLU

CARBAGLU® (carglumic acid) is a synthetic structural analogue of
N-acetylglutamate (NAG), which is an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS1) in liver mitochondria.

  • CPS1 is the first enzyme of the urea cycle, which converts ammonia into urea.
  • NAG is the product (cofactor) of N-acetylglutamate synthase (NAGS), a mitochondrial enzyme.
  • Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS1.1
  • CARBAGLU thus acts as a key to start the urea cycle, enabling it to function as it should to maintain normal blood ammonia levels.2

Indications and Usage

Carbaglu® (carglumic acid) is a Carbamoyl Phosphate Synthetase 1 (CPS 1) activator indicated in pediatric and adult patients as:

  • Adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS).
  • Maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS).

Important Safety Information

  • Hyperammonemia: Monitor plasma ammonia level during treatment. Prolonged exposure to elevated plasma ammonia level can result in brain injury or death. Prompt use of all therapies necessary to reduce plasma ammonia level is essential.
  • Most common adverse reactions (>9%) are: vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache.
  • To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1‑800-FDA-1088 or
  • If CARBAGLU is administered during pregnancy, health care providers should report CARBAGLU exposure to the pregnancy pharmacovigilance program by calling 1-888-575-8344.

You and your patients can learn more about the urea cycle, NAGS deficiency, and how CARBAGLU (carglumic acid) activates the CPS1 enzyme, the first step of the urea cycle.

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Because hyperammonemic crises can result in serious neurological complications, including severe cerebral edema, brain stem herniation, and death, clinicians must act quickly to diagnose and treat.3

CARBAGLU clinical data: Results of a retrospective study

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). Treatment with CARBAGLU was divided in two regimens. For acute treatment, patients received a total daily dose of 100 to 250 mg/kg per day primarily administered in 2 to 4 divided doses for the first few days of treatment. For maintenance treatment, the dosage was reduced over time based upon biochemical and clinical responses. 1

Study objectives


The primary objective was to review the clinical and biological response of NAGS deficiency patients to carglumic acid within the first 7 days of treatment (short-term) and at the last report (long-term).

  • For the short-term analysis, ammonemia was the primary biomarker supported by glutaminemia and citrullinemia results.
  • For the long-term analysis, all three biomarkers (ammonemia, glutaminemia and citrullinemia) were considered equally.4


The secondary objectives were:4

  • Evaluation of patient clinical development, that is, neurological and psychomotor status, and anthropometric development (growth) parameters.
  • Analysis of the implementation of restrictive/free protein diet and concomitant treatment.
  • Analysis of the carglumic acid doses prescribed as an indirect efficacy parameter and as a definition of the dose response determination.

Efficacy results

Plasma ammonia levels at baseline and after treatment with CARBAGLU 1

  • All 13 patients had abnormal ammonia levels at baseline. The overall mean baseline plasma ammonia level was 271 micromol/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 micromol/L and 24 micromol/L, respectively, after a mean treatment duration of 8 years. 1
  • The mean plasma ammonia level at baseline and the decline that is observed after treatment with CARBAGLU in 13 evaluable patients with NAGS deficiency is illustrated below.

Ammonia response for 13 evaluable NAGS deficiency patients at baseline and after treatment with CARBAGLU1

Safety results

Adverse Reactions Reported in ≥ 2 Patients in the Retrospective Case Series 1

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.

This table summarizes adverse reactions occurring in 2 or more patients treated with CARBAGLU in the retrospective case series (≥ 9%). The most common adverse reactions in this study, regardless of causality, were:1

  • Vomiting
  • Abdominal Pain
  • Pyrexia
  • Tonsillitis
  • Anemia
  • Diarrhea
  • Ear infection
  • Infections
  • Nasopharyngitis
  • Hemoglobin decreased
  • Headache


  1. CARBAGLU [Package Insert]. Lebanon, NJ: Recordati Rare Diseases; 2017.
  2. Tuchman M, Caldovic L, Daikhin Y, Horyn O, Nissim Il, Nissam It, Korson M, Burton B, Yudkoff M. N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers. Pediatr Res. 2008;64:213–217.
  3. Cartagena A, Prasad AN, Rupar CA, Strong M, Tuchman M, Ah Mew N, Prasad C. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can J Neurol Sci. 2013;40:3-9.
  4. Orphan Europe, data on file, 2009.