CARGLUMIC ACID (Generic for CARBAGLU)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Use actual body weight to calculate dosing.
-Administer immediately before meals or feedings.
-Do not administer tablets whole or crushed. Carglumic acid tablets are scored with 3 lines for splitting into 4 equal portions. Disperse each 200 mg tablet or partial tablet (one-half or one-fourth) in a minimum of 2.5 mL of water immediately before administration. The tablets do not dissolve completely in water, and undissolved tablet particles may remain in the mixing container. Rinse the mixing container with additional water and administer to the patient; repeat as needed until no pieces of the tablet are left to ensure complete delivery of the dose. Dispersion in other liquids or in food has not been clinically studied and is not recommended.
-Administration via oral syringe: Mix each 200 mg tablet or partial tablet (one-half or one-fourth) in a minimum of 2.5 mL of water. Carefully stir the tablet and water mixture and draw into an oral syringe. Administer immediately. Refill the oral syringe with a minimum volume of water (1 to 2 mL) and administer immediately; repeat as needed until no pieces of the tablet are left to ensure complete delivery of the dose.
-Administration via nasogastric or gastrostomy tube: Mix each 200 mg tablet or partial tablet (one-half or one-fourth) in a minimum of 2.5 mL of water. Carefully stir the tablet and water mixture and draw into a catheter-tip syringe. Administer the dose immediately through the nasogastric or gastrostomy tube. Flush with 1 to 2 mL of additional water to clear the tube; repeat as needed until no pieces of the tablet are left to ensure complete delivery of the dose.

Vomiting (26%), abdominal pain (17%), diarrhea (13%), weight loss (9%), anorexia (9%), and dysgeusia (9%) have been reported retrospectively for 23 patients (age 0.6 to 20.8 years) with N-acetylglutamate synthase (NAGS) deficiency receiving carglumic acid. In patients (age 4 days to 29 years) with propionic acidemia (PA) or methylmalonic acidemia (MMA) taking carglumic acid, vomiting (7% vs. 2% placebo) and anorexia/decreased appetite (5% vs. 2% placebo) were reported during a clinical trial.

Fever (17%), tonsillitis (17%), infection (13%), ear infections (13%), influenza (9%), pneumonia (9%), and naso-pharyngitis (13%) have been reported retrospectively for 23 patients (age 0.6 to 20.8 years) with N-acetylglutamate synthase (NAGS) deficiency receiving carglumic acid.

Hyperhidrosis (9%) and rash (9%) have been reported retrospectively for 23 patients (age 0.6 to 20.8 years) with N-acetylglutamate synthase (NAGS) deficiency receiving carglumic acid. Infusion site extravastion was reported in 2% of patients receiving carglumic acid. Pruritus and rash, including erythematous rash, maculopapular rash, and pustular rash, were reported during postmarketing experience.

Anemia (13%) and decreased hemoglobin (13%) were reported retrospectively for 23 patients (age 0.6 to 20.8 years) with N-acetylglutamate synthase (NAGS) deficiency receiving carglumic acid. Anemia was reported in 12% (vs. 8% placebo) of patients (age 4 days to 29 years) with propionic acidemia (PA) or methylmalonic acidemia (MMA) receiving carglumic acid in a clinical trial.

Headache (13%), somnolence or drowsiness (9%), and asthenia (9%) have been reported retrospectively for 23 patients (age 0.6 to 20.8 years) with N-acetylglutamate synthase (NAGS) deficiency receiving carglumic acid.

Psychiatric and nervous system adverse reactions have been reported during a carglumic acid clinical trial. Lethargy or stupor (5% vs. 2% placebo), encephalopathy (5% vs. 0% placebo), behavior disorder (2% vs. 0% placebo), and sleep disorder (2% vs. 0% placebo) were reported during a clinical trial in patients (age 4 days to 29 years) with propionic acidemia (PA) or methylmalonic acidemia (MMA) taking carglumic acid. Mania was reported during postmarketing experience.

In patients 4 days to 29 years of age with propionic acidemia (PA) or methylmalonic acidemia (MMA) taking carglumic acid, neutropenia (14% vs. 8% placebo), electrolyte imbalance (7% vs. 4% placebo), hypoglycemia (5% vs. 2% placebo), and increased white blood cell count (2% vs. 0% placebo) were reported during a clinical trial.

Pancreatitis or increased lipase (5% vs. 0% placebo) and elevated hepatic enzymes (increased alanine aminotransferase and aspartate aminotransferase, 2% vs. 0% placebo) were reported during a clinical trial in patients (age 4 days to 29 years) with propionic acidemia (PA) or methylmalonic acidemia (MMA) taking carglumic acid.

Cardiomyopathy was reported in 2% (vs. 0% placebo) of patients (age 4 days to 29 years) with propionic acidemia (PA) or methylmalonic acidemia (MMA) taking carglumic acid in a clinical trial.

In patients 4 days to 29 years of age with propionic acidemia (PA) or methylmalonic acidemia (MMA) taking carglumic acid, apnea (2% vs. 0% placebo) and hyperventilation (2% vs. 0% placebo) were reported during a clinical trial.

Do not use carglumic acid as monotherapy for the treatment of acute symptomatic hyperammonemia; this clinical condition should be treated as a life-threatening emergency. Uncontrolled hyperammonemia can rapidly result in brain injury/damage or death, and prompt use of all therapies necessary to reduce plasma ammonia concentrations is essential. Dialysis, preferably hemodialysis, may be needed to remove a large burden of ammonia. Other ammonia lowering therapies such as alternate pathway medications should be considered.

During episodes of acute hyperammonemia, in addition to carglumic acid therapy, dietary protein restriction and hypercaloric intake is recommended to block ammonia generating catabolic pathways. During maintenance therapy, protein restriction may be reduced or discontinued based on plasma ammonia concentrations.

Use carglumic acid cautiously in patients with renal impairment (renal disease or renal failure). Carglumic acid plasma concentrations are increased in patients with renal impairment. Patients with moderate to severe renal impairment require dosage reduction.

Description: Carglumic acid is the structural analogue of N-acetyl-glutamate and is an oral treatment for acute and chronic hyperammonemia due to N-acetylglutamate synthase deficiency and acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA). In organic aciduria, propionyl-CoA accumulates and in return decreases the synthesis of N-acetyl-glutamate, resulting in hyperammonemia. Plasma ammonia concentrations may be reduced the first day of treatment and may remain reduced. Among 13 patients, carglumic acid was used daily for a mean of 8 years (range, 1 to 16 years); the median plasma ammonia concentration was 157 micromol/L (range, 72 to 1,428 micromol/L) at baseline, 65 micromol/L (range, 25 to 1,190 micromol/L) on day 1, 25 micromol/L (range, 12 to 42 micromol/L) on day 3, and 24 micromol/L (range, 9 to 34 micromol/L) on the last value obtained on treatment. Carglumic acid tablets must be dissolved in water immediately before administration; do not administer whole or crushed tablets. Carglumic acid is FDA-approved in pediatric patients as young as neonates.

General dosing information:
-During acute hyperammonemic episodes, concomitant administration of carglumic acid with other ammonia lowering therapies such as alternate pathway medications, hemodialysis, and dietary protein restriction/hypercaloric intake to block ammonia generating catabolic pathways is recommended.
-During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be reduced or discontinued based on plasma ammonia concentrations. Maintain plasma ammonia concentrations within normal range for age via individual dose adjustment.

For the treatment of hyperammonemia due to N-acetylglutamate synthase deficiency both as an adjunctive therapy for the treatment of acute hyperammonemia and as maintenance therapy for chronic hyperammonemia:
NOTE: Carglumic acid is designated as an orphan drug for this indication.
NOTE: Use actual body weight for dosing.
Oral dosage:
Neonates: Initially, 100 to 250 mg/kg/day PO divided into 2 to 4 doses (round to the nearest 100 mg; one-half of a carglumic acid tablet) given immediately before meals or feedings and in combination with other ammonia-lowering therapies. Titrate the dose based on individual patient plasma ammonia concentrations and clinical symptoms. Recommended maintenance dose is 10 to 100 mg/kg/day. Titrate the maintenance dose to target a normal plasma ammonia concentration for age.
Infants, Children, and Adolescents: Initially, 100 to 250 mg/kg/day PO divided into 2 to 4 doses (round to the nearest 100 mg; one-half of a carglumic acid tablet) given immediately before meals or feedings and in combination with other ammonia-lowering therapies. Titrate the dose based on individual patient plasma ammonia concentrations and clinical symptoms. Recommended maintenance dose is 10 to 100 mg/kg/day. Titrate the maintenance dose to target a normal plasma ammonia concentration for age.

For the treatment of acute hyperammonemia due to propionic acidemia (PA) or hyperammonemia due to methylmalonic acidemia (MMA) as an adjunctive therapy:
NOTE: Use actual body weight for dosing.
Oral dosage:
Neonates: 150 mg/kg/day PO divided into 2 equal doses (round up to the next multiple of 50 mg; one-quarter of a carglumic acid tablet) given every 12 hours immediately before meals or feedings and in combination with other ammonia-lowering therapies. Continue until ammonia concentration is less than 50 micromol/L and for a maximum of 7 days.
Infants and Children weighing 15 kg or less: 150 mg/kg/day PO divided into 2 equal doses (round up to the next multiple of 50 mg; one-quarter of a carglumic acid tablet) given every 12 hours immediately before meals or feedings and in combination with other ammonia-lowering therapies. Continue until ammonia concentration is less than 50 micromol/L and for a maximum of 7 days.
Children and Adolescents weighing more than 15 kg: 3.3 g/m2/day PO divided into 2 equal doses (round up to the next multiple of 50 mg; one-quarter of a carglumic acid tablet) given every 12 hours immediately before meals or feedings and in combination with other ammonia-lowering therapies. Continue until ammonia concentration is less than 50 micromol/L and for a maximum of 7 days.

Maximum Dosage Limits:
-Neonates
Specific maximum dosage information is not available. Individualize dosage based on careful monitoring of plasma ammonia concentrations and clinical response.
-Infants
Specific maximum dosage information is not available. Individualize dosage based on careful monitoring of plasma ammonia concentrations and clinical response.
-Children
Specific maximum dosage information is not available. Individualize dosage based on careful monitoring of plasma ammonia concentrations and clinical response.
-Adolescents
Specific maximum dosage information is not available. Individualize dosage based on careful monitoring of plasma ammonia concentrations and clinical response.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Acute hyperammonemia due to NAGS deficiency
eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment needed.
eGFR 30 to 59 mL/minute/1.73 m2: 50 to 125 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet).
eGFR 15 to 29 mL/minute/1.73 m2: 15 to 60 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet).
eGFR less than 15 mL/minute/1.73 m2: Safety and efficacy have not been established.

Chronic Hyperammonemia due to NAGS deficiency
eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment needed.
eGFR 30 to 59 mL/minute/1.73 m2: 5 to 50 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet).
eGFR 15 to 29 mL/minute/1.73 m2: 2 to 25 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet).
eGFR less than 15 mL/minute/1.73 m2: Safety and efficacy have not been established.

Acute hyperammonemia due to PA or MMA
eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment needed.
eGFR 30 to 59 mL/minute/1.73 m2 (for patients weighing 15 kg or less): 75 mg/kg/day divided into 2 equal doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet); administer each dose 12 hours apart.
eGFR 30 to 59 mL/minute/1.73 m2 (for patients weighing more than 15 kg): 1.7 g/m2/day divided into 2 equal doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet); administer each dose 12 hours apart.
eGFR 15 to 29 mL/minute/1.73 m2 (for patients weighing 15 kg or less): 25 mg/kg/day divided into 2 equal doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet); administer each dose 12 hours apart.
eGFR 15 to 29 mL/minute/1.73 m2 (for patients weighing more than 15 kg): 0.55 g/m2/day divided into 2 equal doses and rounded to the nearest 50 mg (i.e., one-quarter of a carglumic acid tablet); administer each dose 12 hours apart.
eGFR less than 15 mL/minute/1.73 m2: Safety and efficacy have not been established.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: The mitochondrial enzyme N-acetylglutamate synthase (NAGS) produces N-acetylglutamate (NAG), which is an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1) in liver mitochondria. CPS 1 is the first enzyme of the urea cycle, and the enzyme converts ammonia to urea. Patients with NAGS deficiency do not produce enough NAG resulting in hyperammonemia. Carglumic acid is a synthetic structural analogue of NAG that works to activate CPS 1 and thus, convert ammonia to urea.

Pharmacokinetics: Carglumic acid is administered orally. Carglumic acid is not bound to plasma proteins. The most likely end product of carglumic acid metabolism is carbon dioxide, which is then eliminated via the lungs. Some carglumic acid may be metabolized by intestinal bacterial flora, but a significant portion of each dose is excreted unchanged in the feces. After a single oral dose of 100 mg/kg, 9% of the dose was excreted unchanged in the urine and up to 60% was excreted unchanged in the feces. The median half-life in healthy volunteers was 25 hours (+/- 2 hours).

Among 23 patients with N-acetylglutamate synthase deficiency, plasma ammonia concentrations fell within 24 hours after carglumic acid with and without concomitant ammonia lowering therapies. No dose response relationship has been identified.

Affected cytochrome P450 enzymes and drug transporters: OAT1 transporter
Based on in-vitro studies, carglumic acid is a substrate of the OAT1 transporter. It is not an inducer of CYP1A1/2, CYP2B6, CYP2C, or CYP3A4/5 enzymes and not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 enzymes. It is not a substrate of MDR1, BCRP, MATE1, MATE2-K, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2. It is not an inhibitor of BSEP, BCRP, MDR1, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2 transporters.


-Route-Specific Pharmacokinetics
Oral Route
After oral administration of carglumic acid to healthy volunteers, the absolute bioavailability was approximately 10%. The Cmax was 3,284 ng/mL (+/- 321 ng/mL), median Tmax was 3 hours (2 to 4 hours), and AUC was 31,426 ng x hour/mL (+/- 2,150 ng x hour/mL).


-Special Populations
Renal Impairment
The pharmacokinetics of carglumic acid have not been evaluated in patients with end stage renal disease. Plasma concentrations of carglumic acid are increased in patients with renal impairment. The mean plasma exposure (AUC) of carglumic acid doubled in patients who received a single dose of 80 mg/kg with mild renal impairment (39,545 ng x hour/mL, eGFR 60 to 89 mL/minute/1.73 m2) and tripled in patients with moderate renal impairment (79,766 ng x hour/mL, eGFR 30 to 59 mL/minute/1.73 m2) compared to patients with normal renal function (28,313 ng x hour/mL, eGFR 90 mL/minute/1.73 m2 and more). The mean AUC in patients with severe renal impairment (143,075 ng x hour/mL, eGFR 15 to 29 mL/minute/1.73 m2) who received a single dose of 40 mg/kg was 7 times that of patients with normal renal function (20,212 ng x hour/mL). The Cmax of carglumic acid in patients who received a single dose of 80 mg/kg was 2,983 ng/mL in patients with normal renal function, 4,310 ng/mL in patients with mild renal impairment, and 6,129 ng/mL in patients with moderate renal impairment. The Cmax of carglumic acid in patients who received a single dose of 40 mg/kg was 1,890 ng/mL in patients with normal renal function and 8,377 ng/mL in patients with severe renal impairment.