carglumic acid

Therapeutic Classification: hyperammonemia treatments (due to an enzyme deficiency)

Pharmacologic Classification: enzyme activators

REMS

Treatment of acute and chronic hyperammonemia due to deficiency of hepatic enzyme N-acetylglutamate synthase (NAGS).
Treatment of acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA).

Serves as an analogue of N-acetyl glutamate (NAG), the natural activator of cabamoyl phosphate synthetase 1 (CPS 1) in the liver. CPS 1 helps to convert ammonia into urea. Carglumic acid replaces NAG in NAGS deficiency patients by activating CPS 1.

Therapeutic effects:

↓ammonia levels in NAGS deficiency.
Reduced time to ↓ ammonia levels or hospital discharge in PA or MMA.

Absorption: 10% absorbed following oral administration.

Distribution: Extensively distributed into extravascular space.

Metabolism/Excretion: Some metabolism by intestinal bacteria; 9% excreted unchanged in urine, 60% excreted unchanged in feces. Metabolic end product (CO₂) eliminated via lungs.

Half-Life: 5.6 hr.

(↓ ammonia levels)

ROUTE	ONSET	PEAK	DURATION
PO	within 24 hr	3 days	unknown

Contraindicated in:

None.

Use Cautiously in:

Moderate or severe renal impairment (dose adjustment required);
OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk;
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant.

Derm: rash

EENT: nasopharyngitis

GI: abdominal pain, diarrhea, vomiting, abnormal taste

Hemat: anemia

Metab: ↓weight

Neuro: headache, drowsiness, weakness

Misc: fever, infection

Drug-drug:

None reported.

Acute Hyperammonemia due to NAGS Deficiency

PO (Adults and Children ): 100–250 mg/kg/day initially, given in 2–4 divided doses immediately before meals/feedings, adjusted to maintain normal plasma ammonia levels based on age. Dose should be rounded to the nearest 100 mg. Should be used with other ammonia lowering treatments including alternate pathway medications, hemodialysis, and protein restriction.

Renal Impairment

PO (Adults and Children ): eGFR 30–59 mL/min/m²: 50–125 mg/kg/day initially, given in 2–4 divided doses immediately before meals/feedings, adjusted to maintain normal plasma ammonia levels based on age. Dose should be rounded to the nearest 50 mg. Should be used with other ammonia lowering treatments including alternate pathway medications, hemodialysis, and protein restriction. eGFR ≤29 mL/min/m²: 15–60 mg/kg/day initially, given in 2–4 divided doses immediately before meals/feedings, adjusted to maintain normal plasma ammonia levels based on age. Dose should be rounded to the nearest 50 mg. Should be used with other ammonia lowering treatments including alternate pathway medications, hemodialysis, and protein restriction.

Chronic Hyperammonemia due to NAGS Deficiency

PO (Adults and Children ): 10–100 mg/kg/day, given in 2–4 divided doses immediately before meals/feedings, adjusted to maintain normal plasma ammonia levels based on age. Dose should be rounded to the nearest 100 mg. May be used with other ammonia lowering treatments and protein restriction, based on plasma ammonia levels.

Renal Impairment

PO (Adults and Children ): eGFR 30–59 mL/min/m²: 5–50 mg/kg/day, given in 2–4 divided doses immediately before meals/feedings, adjusted to maintain normal plasma ammonia levels based on age. Dose should be rounded to the nearest 50 mg. May be used with other ammonia lowering treatments and protein restriction, based on plasma ammonia levels. eGFR ≤29 mL/min/m²: 2–25 mg/kg/day, given in 2–4 divided doses immediately before meals/feedings, adjusted to maintain normal plasma ammonia levels based on age. Dose should be rounded to the nearest 50 mg. May be used with other ammonia lowering treatments and protein restriction, based on plasma ammonia levels.

Acute Hyperammonemia due to PA or MMA

PO (Adults and Children >15 kg): 3.3 g/m²/day given in 2 divided doses (12 hr apart) immediately before meals/feedings (dose should be rounded to the nearest 50 mg). Continue therapy until ammonia level <50 micromol/L and for a maximum duration of 7 days. Should be used with other ammonia lowering treatments, including IV glucose, insulin, L-carnitine, protein restriction, and dialysis.
PO (Adults and Children ≤15 kg): 150 mg/kg/day given in 2 divided doses (12 hr apart) immediately before meals/feedings (dose should be rounded to the nearest 50 mg). Continue therapy until ammonia level <50 micromol/L and for a maximum duration of 7 days. Should be used with other ammonia lowering treatments, including IV glucose, insulin, L-carnitine, protein restriction, and dialysis.

Renal Impairment

PO (Adults and Children >15 kg): eGFR 30–59 mL/min/m²: 1.7 g/m²/day given in 2 divided doses (12 hr apart) immediately before meals/feedings (dose should be rounded to the nearest 50 mg). Continue therapy until ammonia level <50 micromol/L and for a maximum duration of 7 days. Should be used with other ammonia lowering treatments, including IV glucose, insulin, L-carnitine, protein restriction, and dialysis. eGFR ≤29 mL/min/m²: 75 mg/kg/day given in 2 divided doses (12 hr apart) immediately before meals/feedings (dose should be rounded to the nearest 50 mg). Continue therapy until ammonia level <50 micromol/L and for a maximum duration of 7 days. Should be used with other ammonia lowering treatments, including IV glucose, insulin, L-carnitine, protein restriction, and dialysis.

Renal Impairment

PO (Adults and Children ≤15 kg): eGFR 30–59 mL/min/m²: 0.55 g/m²/day given in 2 divided doses (12 hr apart) immediately before meals/feedings (dose should be rounded to the nearest 50 mg). Continue therapy until ammonia level <50 micromol/L and for a maximum duration of 7 days. Should be used with other ammonia lowering treatments, including IV glucose, insulin, L-carnitine, protein restriction, and dialysis. eGFR ≤29 mL/min/m²: 25 mg/kg/day given in 2 divided doses (12 hr apart) immediately before meals/feedings (dose should be rounded to the nearest 50 mg). Continue therapy until ammonia level <50 micromol/L and for a maximum duration of 7 days. Should be used with other ammonia lowering treatments, including IV glucose, insulin, L-carnitine, protein restriction, and dialysis.

(Generic available)

Tablets: 200 mg

Assess for hyperammonemia (neurological status, plasma ammonia levels) during therapy.

Lab Test Considerations:

Monitor plasma ammonia levels periodically during therapy. Maintain within normal range for age via individual dose adjustment.
- May cause ↓ hemoglobin.

Concomitant administration of other ammonia-lowering therapies is recommended.
PO: Administer immediately before meals or feedings. DNC: Disperse each tablet in at least 2.5 mL of water immediately before use and take immediately; do not crush or swallow whole. Stir carefully. Tablets may not dissolve completely in water; undissolved particles may remain in mixing container. Rinse mixing container with additional volumes of water to ensure complete delivery of dose; swallow immediately. Administer via oral syringe or nasogastric tube before meals or feedings. May have a slightly acidic taste.
- For administration via nasogastric (NG) tube: After mixing tablet and water mixture, draw up mixture in a catheter-tip syringe and administer immediately through NG tube. If pieces of tablet remain in the catheter-tip syringe or NG tube, flush immediately with 1–2 mL of water to clear NG tube. Flush tube again until no pieces of tablet are left in syringe or NG tube.
- For administration via oral syringe: After mixing tablet and water mixture, draw up mixture in an oral syringe and administer immediately. If pieces of tablet remain in the oral syringe, flush immediately with 1–2 mL of water to clear. Flush tube again until no pieces of tablet are left in oral syringe.
- Refrigerate before opening. After first opening of container, do not refrigerate; store at room temperature. Keep container tightly closed to protect from moisture. Write date of opening on tablet container; discard 1 mo after first opening. Do not use after expiration date stated on container.

Instruct patient to take carglumic acid as directed. Advise patient to read Instructions for Use before starting therapy and with each Rx refill in case of changes.
Advise patient that during acute hyperammonemic episodes, protein restriction and hypercaloric intake is recommended to block ammonia generating catabolic pathways. When plasma ammonia levels have normalized, protein intake can usually be ↑ with goal of unrestricted protein intake.
Rep: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Untreated NAGS deficiency can result in irreversible neurologic damage and death in pregnant women. If carglumic acid is administered during pregnancy, report exposure to pregnancy exposure registry by calling 1-888-575-8344.

Normalization of plasma ammonia levels.

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Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆