Arginine carglumate

Arginine Carglumate (N-Carbamylglutamate / Carglumic Acid)

1. Identity: Chemical Names, Structure, and Physical Properties

Arginine carglumate is a term that encompasses compounds combining arginine with the metabolically active moiety carglumate — most prominently used to refer to N-carbamylglutamate (also written N-carbamoylglutamate or N-carbamyl-L-glutamate), the free acid form of which is known as carglumic acid. The chemical name of carglumic acid is N-carbamoyl-L-glutamic acid or (2S)-2-(carbamoylamino)pentanedioic acid. It is also referred to by the synonyms N-Carbamoyl-L-Glutamic Acid, N-Carbamyl-L-glutamate, and (S)-2-ureidopentanedioic acid.

The empirical formula is C₆H₁₀N₂O₅ and the molecular weight is 190.16. The active ingredient is a chiral amino acid (L-isomer) with pKa values of 2.50, 3.55, and 8.60, and a molecular weight of 190.06. The active substance has one chiral carbon atom and has an optical isomer, N-carbamoyl-D-glutamic acid. Carglumic acid is a white crystalline powder, soluble in boiling water and slightly soluble in cold water. Carglumic acid is stable in an alkaline medium (pH 10) but undergoes rapid degradation in very acidic medium (pH 1), and is slowly degraded when exposed to light or an oxidizing medium such as hydrogen peroxide.

Carglumic acid is a synthetic structural analogue of N-acetylglutamate (NAG), which is an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1) in liver mitochondria. The relationship to arginine arises because the primary downstream effect of carglumic acid is to stimulate the urea cycle and thereby enhance the biosynthesis of arginine: the N-carbamoyl glutamate additive stimulates the endogenous production of the arginine essential amino acid, neutralizes ammonia formed in metabolic processes, and optimizes the amount of metabolic energy spent on binding ammonia in the urea cycle.

Common Names and Brand Forms

• IUPAC/chemical name: N-carbamoyl-L-glutamic acid; (2S)-2-(carbamoylamino)pentanedioic acid
• Common synonyms: N-Carbamoyl-L-Glutamic Acid; N-Carbamyl-L-glutamate; N-Carbamylglutamate; carglumic acid
• Brand name (pharmaceutical): Carbaglu is a medicine that contains the active substance carglumic acid; it is available as dispersible tablets.
• Agricultural designation: NCG (N-carbamoylglutamate), used as a feed additive

Physical Form and Pharmaceutical Preparations

Tablets for oral suspension contain 200 mg of carglumic acid per tablet; the tablets are white, elongated, and functionally scored with 3 lines (for splitting into 4 equal portions), printed "C" on one side. This medicine is for oral use only (ingestion or via a nasogastric tube using a syringe, if necessary). Based on pharmacokinetic data and clinical experience, it is recommended to divide the total daily dose into two to four doses to be given before meals or feedings. The tablets must be dispersed in water and must not be swallowed whole or crushed.

2. Natural Sources and Relationship to Endogenous Biochemistry

Unlike many dietary supplements derived from plant or animal extracts, carglumic acid (N-carbamylglutamate) is a synthetic molecule. There is no known dietary plant or herbal source from which it is traditionally obtained in concentrated form. Its significance as a "natural ingredient" arises from its close structural relationship to an endogenous mammalian metabolite:

Carglumic acid is a small molecule that resembles N-acetylglutamate, a normally occurring metabolite that activates the enzyme carbamoyl phosphate synthetase I (CPS-1), the first step in the urea cycle which is responsible for removal and detoxification of ammonia. NAG is the product of N-acetylglutamate synthase (NAGS), a mitochondrial enzyme. The key distinction between carglumic acid and the endogenous NAG is resistance to deacylation: N-carbamyl-L-glutamate is a deacylase-resistant NAG analogue that is taken up enterally and replaces NAG in the activation of CPS1.

In agricultural nutrition science, N-carbamylglutamate is investigated as a functional feed additive. A low concentration of mitochondrial N-acetylglutamate (an activator of both pyrroline-5-carboxylate synthase and carbamoyl phosphate synthase-I) is responsible for the striking decline in the intestinal synthesis of citrulline and arginine during the suckling period in pigs.

3. Historical and Traditional Use

N-carbamylglutamate has no traditional medicinal use in the classical ethnopharmacological sense (no history of use in Ayurveda, Traditional Chinese Medicine, European herbal medicine, or other traditional healing systems). It is entirely a product of modern biochemistry and inborn-errors-of-metabolism research.

N-carbamylglutamate was first used to relieve acute hyperammonemia and to restore neurological development by replacing absent or deficient N-acetylglutamate caused by N-acetylglutamate synthetase deficiency and activating the enzyme carbamyl phosphate synthetase I. The earliest documented clinical use in humans dates to the early 1990s in case reports of neonatal NAGS deficiency. A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate was reported by Guffon et al. in the Journal of Inherited Metabolic Disease in 1995.

Its agricultural application is more recent still. Research establishing its utility as a functional feed additive in swine and ruminant production began to accumulate in the 2000s and 2010s, driven by the recognition that endogenous arginine synthesis in neonatal animals is limited by NAG availability.

4. Key Active Compounds and Mechanisms of Action

The Urea Cycle and the Role of CPS1

In mammals, the urea cycle converts ammonia to urea in a five-step process. The failure to activate this enzyme causes an accumulation of nitrogenous waste, mostly in the form of ammonia, causing hepatic encephalopathy. Carglumic acid, the active ingredient in Carbaglu, is a synthetic structural analogue of N-acetylglutamate (NAG), which is the essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS1) in liver mitochondria. The enzyme CPS1 is the first enzyme of the urea cycle, which converts ammonia into urea.

Mechanism of CPS1 Activation

Patients who have NAGS deficiency are unable to adequately activate CPS1. Carglumic acid acts as replacement for NAG in NAGS deficiency patients and activates CPS1, thereby activating the urea cycle which converts ammonia to urea. Carglumic acid mimics the action of NAG and activates CPS, which permits production of carbamoyl phosphate, thereby restoring the function of the urea cycle.

Because carglumic acid carries a carbamyl (–CONH₂) group rather than an acetyl (–COCH₃) group at the amino nitrogen of glutamate, it is resistant to the intramitochondrial deacylase enzyme that normally degrades NAG. N-carbamyl-L-glutamate is a deacylase-resistant NAG analogue that is taken up enterally and replaces NAG in the activation of CPS1, thus being the definitive therapy for NAGSD. This resistance confers a longer duration of pharmacological action compared to exogenously administered NAG itself.

Downstream Effect: Endogenous Arginine Biosynthesis

By restoring urea cycle function via CPS1 activation, carglumic acid ultimately augments the production of urea cycle intermediates including citrulline and arginine. Arginine is also a positive regulator of acetylglutamate synthesis. Studies in animals show that treatment results in a decrease in the content of ammonia and urea in blood plasma, an increase in the concentration of arginine. The N-carbamoyl glutamate additive stimulates the endogenous production of the arginine essential amino acid, neutralizes ammonia formed in metabolic processes, and optimizes the amount of metabolic energy spent on binding ammonia in the urea cycle.

In agricultural research, the mechanism is described as follows: N-carbamylglutamate (NCG) can increase endogenous arginine synthesis through the activation of carbamyl phosphate synthetase-1. N-carbamylglutamate is structurally similar to N-acetylglutamate, a necessary co-factor for carbamyl phosphate synthetase I, the enzyme that catalyzes the first step of the urea cycle.

Pharmacokinetics

A pharmacokinetic study was conducted in 12 healthy male adults after a single oral administration of 100 mg/kg in order to determine plasma concentrations and urine excretion of carglumic acid. The median time to maximum concentration (Tmax) was 3 hours (range: 2–4). The daily dose of carglumic acid ranges from 100 to 250 mg/kg, and doses are normally adjusted to maintain normal plasma levels of ammonia. Median values for the terminal half-life were 5.6 hours (range 4.3–9.5). Oral bioavailability is approximately 30%.

The likely end product of carglumic acid metabolism is carbon dioxide, eliminated through respiration. Based on in vitro studies, Carbaglu is not an inducer of CYP1A1/2, CYP2B6, CYP2C, and CYP3A4/5 enzymes, and not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1. Plasma concentrations of carglumic acid increased in patients with renal impairment; the Carbaglu dosage should be reduced in patients with moderate or severe renal impairment.

5. Regulatory Status

Carbaglu (carglumic acid) tablets for oral suspension was approved by the U.S. Food and Drug Administration on March 18, 2010. Carbaglu is indicated generally for the treatment of hyperammonemia in pediatric and adult patients having NAGS deficiency. It is licensed in Europe by the European Medicines Agency (EMA). The drug carries orphan drug designation on both sides of the Atlantic.

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, and maintenance therapy for the treatment of chronic hyperammonemia due to NAGS deficiency. It is also indicated as adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA).

6. Scientific Evidence by Area of Use

6.1 N-Acetylglutamate Synthase (NAGS) Deficiency

NAGS deficiency is the primary and best-established indication for carglumic acid. N-acetylglutamate synthase deficiency (estimated incidence, less than 1:2,000,000) is inherited as an autosomal recessive trait and leads to a lack of N-acetylglutamate, which serves as a cofactor and allosteric activator of carbamoyl phosphate synthase (CPS1), the first enzymatic step in the urea cycle. Carglumic acid is used to treat the severe hyperammonemia that occurs in the urea cycle disorder caused by deficiency of hepatic NAGS, which normally produces N-acetylglutamate.

Clinical evidence: The pivotal evidence base consists of retrospective case series rather than prospective randomized controlled trials, owing to the extreme rarity of the disease. 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 years). All 13 evaluable patients had abnormal ammonia levels at baseline. The overall mean baseline plasma ammonia level was 271 µmol/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 analyzed patients (median length of treatment 6 years; range 1 to 16 years). The mean and median ammonia levels were 23 µmol/L and 24 µmol/L, respectively, after a mean treatment duration of 8 years.

Authors studied patients with NAGS deficiency prior to and after 3 days of Carbaglu treatment (2.2 g/m²/day). NAGS deficiency patients treated with Carbaglu show a quick, significant and steady decrease in the key biological response markers, ammonemia and glutaminemia, in response to specific treatment. Early treatment has been demonstrated to be critical for neurological outcomes: in neonates with congenital hyperammonemia, NCG should always be started together with the standard management of hyperammonemia until all laboratory investigations are complete or indicate another disease.

Evidence strength: The clinical evidence for NAGS deficiency is based on retrospective, uncontrolled case series. No randomized controlled trial has been conducted in NAGS deficiency, largely because the condition is too rare. Carglumic acid can also be used as an emergency medication and a tool for diagnosis of NAGS deficiency in neonatal hyperammonemia; despite the lack of controlled studies, its use should be considered in severe hyperammonemic decompensations. Both the EMA and the FDA have granted full approval based on this uncontrolled evidence, given the life-threatening nature of untreated NAGS deficiency and the lack of therapeutic alternatives. The CHMP concluded that Carbaglu was effective in reducing blood ammonia to normal levels and decided that Carbaglu's benefits are greater than its risks.

6.2 Organic Acidurias: Propionic Acidemia (PA), Methylmalonic Acidemia (MMA), and Isovaleric Aciduria (IVA)

A secondary but well-characterized application is the management of hyperammonemia in classical organic acidurias. Isovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonemia arising partly from secondary deficiency of N-acetylglutamate (NAG) synthase. Hyperammonemia is related to a secondary deficiency of N-acetylglutamate (NAG), the activator of carbamoyl phosphate synthetase 1, which is an irreversible rate-limiting enzyme in the urea cycle.

Since the 1970s, hyperammonemia in organic acidemias has been known to be due to an accumulation of propionyl-CoA, which decreases the synthesis of N-acetylglutamate, the natural activator of carbamyl phosphate synthetase 1. A treatment approach with carglumic acid, the structural analogue of N-acetylglutamate, has been proposed to decrease high ammonia levels encountered in MMA and PA crises.

Retrospective phase IIIb study (acute hyperammonemia): A retrospective, multicentre, open-label, uncontrolled, phase IIIb study evaluated the efficacy and safety of carglumic acid for treating hyperammonemia during OA decompensation. Eligible patients had confirmed OA and hyperammonemia (plasma NH₃ > 60 µmol/L) in ≥1 decompensation episode treated with carglumic acid (dose discretionary, mean first dose 96.3 [73.8] mg/kg). The efficacy population comprised 41 patients (MMA: 21, PA: 16, IVA: 4) with 48 decompensation episodes. Mean baseline plasma ammonia concentration was 468.3 (±365.3) µmol/L in neonates and 171.3 (±75.7) µmol/L in non-neonates. At endpoint, the mean plasma NH₃ concentration was 60.7 (±36.5) µmol/L in neonates and 55.2 (±21.8) µmol/L in non-neonates. Median time to normalize ammonemia was 38.4 hours in neonates versus 28.3 hours in non-neonates and was similar between OA subgroups (MMA: 37.5 hours, PA: 36.0 hours, IVA: 40.5 hours). Carglumic acid, when used with or without ammonia scavengers, is an effective treatment for restoration of normal plasma ammonia concentrations in hyperammonemic episodes in OA patients.

Randomized controlled trial (long-term, PA and MMA): A prospective, multicenter, randomized, parallel-group, open-label, controlled clinical trial enrolled patients aged ≤15 years with confirmed PA and MMA. Patients were followed for two years. Thirty-eight patients were included. On the primary efficacy endpoint, a mean of 6.31 emergency room admissions was observed for the carglumic acid arm, compared with 12.76 for standard treatment, with a significant difference between the groups (p = 0.0095). Of the secondary outcomes, the only significant differences were in glycine and free carnitine levels. Using carglumic acid in addition to standard treatment over the long term significantly reduces the number of ER admissions due to hyperammonemia in patients with PA and MMA.

Italian qualitative survey (long-term): Participating centers in Italy reported a reduction between 69% and 81% in the annual number of metabolic decompensations with the chronic use of carglumic acid and an improvement in protein intake. Most centers reported no difficulty using carglumic acid as a long-term therapy, along with a great compliance. Additional studies aimed at better defining a proper dosage for the chronic administration of carglumic acid and the clinical and biochemical characteristics of patients treated chronically are needed.

Evidence strength: For acute hyperammonemia in organic acidurias, the evidence base is primarily retrospective and uncontrolled, but consistent across multiple studies. The one prospective randomized trial in PA/MMA for long-term management provides moderate-quality evidence. Carglumic acid is well tolerated and its use in normalizing ammonia levels during acute hyperammonemic episodes in patients with PA and MMA is well established. However, there are limited data available on the long-term safety and effectiveness of carglumic acid.

6.3 Carbamoyl Phosphate Synthetase 1 (CPS1) Deficiency

Case reports have also described therapeutic benefit in CPS1 deficiency. In at least one case, at 26 months of age, a patient led a stable life while receiving carglumic acid and regular rehabilitation. Carglumic acid treatment in combination with carnitine supplementation and protein restriction prevented metabolic decompensation, which would have otherwise required hospitalization, and resulted in improved quality of life and developmental outcomes. Evidence here is limited to individual case reports; no controlled studies exist.

6.4 Agricultural and Animal Science Applications (Non-Human Evidence)

A substantial body of preclinical and animal research investigates NCG as a livestock feed additive to enhance endogenous arginine synthesis and improve productive performance. This evidence is relevant to the compound's biological plausibility but does not directly translate to human dietary supplement claims.

In swine: Oral administration of N-carbamoylglutamate (a metabolically stable analogue of N-acetylglutamate; 2 × 50 mg/[kg body weight per day]) enhances plasma arginine level (68%) and weight gain (61%) of 4- to 14-day-old sow-reared pigs. Thus, the metabolic activation of intestinal citrulline and arginine synthesis provides a novel, effective means to increase endogenous arginine provision and therefore piglet growth.

In ruminants: NCG is a functional micronutrient that stimulates endogenous synthesis of arginine, which can improve survival, growth, lactation, reproductive performance, and feed efficiency in mammals. As a precursor of arginine, N-carbamylglutamate is a more viable and cost-effective functional feed additive by increasing the synthesis and metabolism of endogenous arginine to improve swine production.

A key advantage in agricultural use is stability: arginine is useful, but not very practical due to its shorter half-life, higher degradation by arginase, higher cost, more susceptibility to impairing the absorption of dietary basic and/or structurally related amino acids such as tryptophan, histidine, or lysine, and higher microbial degradation rate as compared to N-carbamylglutamate.

7. Body Systems and Health Areas Associated with Carglumic Acid

Hepatic and Metabolic System (Primary)

The primary target organ is the liver, specifically hepatic mitochondria where CPS1 resides. Carglumic acid acts as a replacement of NAG in patients that have a deficiency of the mitochondrial enzyme NAGS. It activates carbamoyl phosphate synthetase 1 (CPS1) in liver mitochondria and hence restores the urea cycle, since the enzyme CPS1 is the first enzyme of the urea cycle that converts ammonia into urea.

Neurological System (Secondary, via Ammonia Control)

NAGS deficiency results in reduced levels of NAG, limited activation of CPS, and limited elimination of ammonia, which results in elevated levels of ammonia. NAGS deficiency leads to various neurological and gastrointestinal (including hepatic) symptoms, and the severity depends on the degree of enzymatic deficiency. By normalizing blood ammonia levels, carglumic acid prevents the neurotoxic effects of hyperammonemia. Ammonia is very toxic when it circulates in blood and tissues and can cause permanent brain damage, coma, or death.

Urea Cycle / Amino Acid Metabolism

Arginine supplies adequate urea cycle intermediates to encourage the incorporation of more nitrogen moieties into urea cycle intermediates, each of which is readily excretable. By stimulating the urea cycle at its rate-limiting first step, carglumic acid promotes the net conversion of toxic ammonia to excretable urea, and simultaneously increases the production of the conditionally essential amino acid arginine.

Gastrointestinal System

In neonatal animals, NCG has been studied for its effects on intestinal development and health. N-carbamylglutamate improves intestinal health and development of young pigs. The mechanistic basis relates to increased arginine availability, which is important for intestinal mucosal integrity and protein synthesis in neonates.

Reproductive System (Animal Data Only)

In swine production research, N-carbamylglutamate boosts the reproductive performance of sows. A growing number of studies indicate that NCG treatment can increase the growth rate, muscle protein synthesis, reproductive efficiency, and fetal development in mammals. These findings derive from animal studies and have not been evaluated in human reproductive medicine.

8. Dosage Forms and Dosages Reported in Studies

Pharmaceutical Dosage Form

Tablets for oral suspension: 200 mg, functionally scored. Carglumic acid tablets must be taken immediately before meals or feedings.

Dosages Reported in Clinical Studies and Regulatory Labels

• Starting dose (acute hyperammonemia): The initial daily dose of Carbaglu should be 100 mg per kilogram body weight, but up to 250 mg/kg can be used if necessary.
• Proposed starting dose (FDA pharmacology review): The proposed starting dose is 100 to 250 mg/kg/day by mouth in divided doses. No specific maintenance dose has been proposed; however, in practice the maintenance doses are dictated by plasma ammonia levels and clinical response.
• EMA dosing schedule: Based on pharmacokinetic data and clinical experience, it is recommended to divide the total daily dose into two to four doses to be given before meals or feedings.
• Long-term NAGS deficiency treatment: Carglumic acid (Carbaglu, Orphan Europe) 100–300 mg/kg per day is the commercially available pharmacological formulation.
• Pharmacokinetic study dose: A pharmacokinetic study was conducted in 12 healthy male adults after a single oral administration of 100 mg/kg.
• NAGS deficiency tracer study: Patients with NAGS deficiency were studied prior to and after 3 days of Carbaglu treatment at 2.2 g/m²/day.
• Organic aciduria retrospective study: Mean first dose in the OA decompensation study was 96.3 (73.8) mg/kg (discretionary dosing).
• Dose-response relationship: No dose-response relationship has been established for Carbaglu. Data from six patients in which dosing was available (range 122 to 396 mg/kg/day) and for whom sufficient pre-dose and 24-hour post-dose ammonia levels are documented does not show a clear relationship.
• Neonatal swine (animal study): N-carbamoylglutamate at 2 × 50 mg/kg body weight per day was administered to 4- to 14-day-old sow-reared pigs in one reported animal study.

9. Safety Considerations and Notable Interactions

General Tolerability

Carglumic acid is an orphan drug and a derivative of N-acetylglutamate that activates the first enzyme in the urea cycle responsible for removal and detoxification of ammonia. Clinical experience with carglumic acid is limited, but it has not been linked to significant serum enzyme elevations during therapy or to instances of clinically apparent acute liver injury. Carglumic acid was well-tolerated with no major adverse events reported in the clinical pharmacology studies.

Reported Adverse Reactions — NAGS Deficiency

In a retrospective case series of 23 NAGS deficiency patients treated with carglumic acid, 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. It should be noted that, given the retrospective nature of the data collection, it is not always possible to reliably estimate the frequency of these events or establish a causal relationship to drug exposure.

Reported Adverse Reactions — PA and MMA

For PA and MMA, the most common adverse reactions (≥5%) are neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased. Many of these events reflect the underlying metabolic disease state rather than direct drug toxicity.

High-Dose Toxicity Signal

One patient treated with 650 mg/kg/day of carglumic acid developed symptoms characterized as a monosodium glutamate intoxication-like syndrome: tachycardia, profuse sweating, increased bronchial secretion, increased body temperature and restlessness. These symptoms resolved upon reduction of dose.

Renal Impairment

Plasma concentrations of carglumic acid increased in patients with renal impairment; dosage reduction is required in patients with moderate or severe renal impairment. The pharmacokinetics of carglumic acid have not been evaluated in patients with end-stage renal disease.

Pregnancy

There are no adequate and well-controlled studies or available human data with Carbaglu in pregnant women. Decreased survival and growth occurred in offspring born to animals that received carglumic acid at a dose approximately 38 times the maximum reported human maintenance dose. Pregnant females with urea cycle disorders may experience an increase in catabolic stress which can trigger a hyperammonemic crisis both intrapartum and in the postpartum (3–14 days post-partum) period. Maternal complications related to a hyperammonemic crisis can include neurological impairment, coma, and in some cases death.

Lactation

Carbaglu must not be used in women who are breastfeeding. Carglumic acid is present in rat milk, and an increase in mortality and impairment of body weight gain occurred in neonatal rats nursed by mothers receiving carglumic acid.

Cytochrome P450 Interactions

Based on in vitro studies, Carbaglu is not an inducer of CYP1A1/2, CYP2B6, CYP2C, and CYP3A4/5 enzymes, and not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1. No formal drug-drug interaction studies have been conducted in humans.

Hepatotoxicity

Since approval, there have been no published reports of hepatotoxicity attributed to carglumic acid, and the product label does not mention liver injury as an adverse event. The LiverTox likelihood score is E (unlikely cause of clinically apparent liver injury, but experience with its use is limited).

Postmarketing (Skin) Reactions

Postmarketing reports have included pruritus, and rash including rash erythematous, rash maculopapular, and rash pustular.

Hypersensitivity

Carbaglu should not be used in people who may be hypersensitive (allergic) to carglumic acid or any of the other ingredients.

Limitations of Evidence Base

The overall evidence base for carglumic acid is constrained by the extreme rarity of the target conditions. The prognosis of NAGS deficiency has not been firmly established because of its very low prevalence; however, as in any other urea cycle disorder, the aim of long-term therapy has been to maintain metabolic control with normal plasma ammonia and glutamine concentrations. The clinically relevant outcome is to prevent cumulative morbidity and mortality. There are insufficient data to determine if there is a difference in clinical or biochemical responses between adult and pediatric patients treated with Carbaglu. Clinical studies of Carbaglu did not include patients 65 years of age and older. The relationship between exposure and long-term safety has not been established.

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