Dosing & Uses
Dosage Forms & Strengths
dispersible tablet
- 200mg
Hyperammonemia Due to NAGS Deficiency
Initiate treatment as soon as N-acetylglutamate synthase (NAGS) deficiency is suspected, which may be at birth
Acute hyperammonemia
- Indicated as adjunctive therapy to standard of care for acute hyperammonemia due to NAGS deficiency
- 100-250 mg/kg/day PO divided into 2-4 doses; round to the nearest 100 mg (ie, half of a tablet)
- During acute episodes, administer with other ammonia lowering therapies, such as alternate pathway medications, hemodialysis, and protein restriction
Chronic hyperammonemia
- Indicated as maintenance therapy for chronic hyperammonemia due to NAGS deficiency
- 10-100 mg/kg/day PO/NG divided in 2-4 doses; round to the nearest 100 mg
- During maintenance, concomitant use of other ammonia lowering therapies and protein restriction may be needed based on plasma ammonia levels
Hyperammonemia Due to PA or MMA
Indicated as adjunctive therapy to standard of care for acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA)
Initiate treatment of acute hyperammonemia in patients with a suspected or confirmed diagnosis of PA or MMA
3.3 g/m2/day PO divided into 2 equal doses (administered 12 hr apart) and round up to next multiple of 50 mg (ie, 1/4 of a tablet)
Continue treatment until ammonia level <50 micromol/L and for a maximum duration of 7 days
Use concomitantly with other ammonia lowering therapies, such as IV glucose, insulin, L-carnitine, protein restriction, and dialysis
Renal Impairment
No dosage adjustment warranted in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2)
Hyperammonemia due to NAGS Deficiency
- Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2): 50 mg/kg/day to 125 mg/kg/day divided into 2 to 4 doses and rounded to nearest 50 mg (ie, one-quarter of a tablet)
- Severe renal impairment (eGFR ≤29 mL/min/1.73 m2): 15 mg/kg/day to 60 mg/kg/day divided into 2 to 4 doses and rounded to nearest 50 mg (ie, one-quarter of a tablet)
Chronic Hyperammonemia due to NAGS Deficiency
- Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2): 5 mg/kg/day to 50 mg/kg/day divided into 2 to 4 doses and rounded to nearest 50 mg (ie, one-quarter of a tablet)
- Severe renal impairment (eGFR ≤29 mL/min/1.73 m2): 2 mg/kg/day to 25 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 50 mg (ie, one-quarter of a tablet)
Acute hyperammonemia due to PA or MMA
- Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2): 1.7 g/m2/day; divide daily dosage into 2 equal doses and round up to nearest 50 mg (ie, one-quarter of a CARBAGLU tablet); administer each dose 12 hours apart
- Severe renal impairment (eGFR ≤29 mL/min/1.73 m2): 0.55 g/m2/day; divide daily dosage into 2 equal doses and round up to nearest 50 mg (ie, one-quarter of a tablet); administer each dose 12 hours apart
Dosing Considerations
Monitoring parameters
- Closely monitor plasma ammonia levels
- Titrate dosage to maintain the plasma ammonia level within normal range for age, taking into consideration the patient’s clinical condition (eg, nutritional requirements, protein intake, growth parameters
Dosage Forms & Strengths
dispersible tablet
- 200mg
Hyperammonemia Due to NAGS Deficiency
Initiate treatment as soon as N-acetylglutamate synthase (NAGS) deficiency is suspected, which may be at birth
Acute hyperammonemia
- Indicated as adjunctive therapy to standard of care for acute hyperammonemia due to NAGS deficiency
- 100-250 mg/kg/day PO divided into 2-4 doses; round to the nearest 100 mg (ie, half of a tablet)
- During acute episodes, administer with other ammonia lowering therapies, such as alternate pathway medications, hemodialysis, and protein restriction
Chronic hyperammonemia
- Indicated as maintenance therapy for chronic hyperammonemia due to NAGS deficiency
- 10-100 mg/kg/day PO/NG divided in 2-4 doses; round to the nearest 100 mg
- During maintenance, concomitant use of other ammonia lowering therapies and protein restriction may be needed based on plasma ammonia levels
Hyperammonemia Due to PA or MMA
Indicated as adjunctive therapy to standard of care for acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA) in adults and children
Initiate treatment of acute hyperammonemia in patients with a suspected or confirmed diagnosis of PA or MMA
≤15 kg: 150 mg/kg/day PO
>15 kg: 3.3 g/m2/day PO
Divided into 2 equal doses (administered 12 hr apart) and round up to next multiple of 50 mg (ie, 1/4 of a tablet)
Continue treatment until ammonia level <50 micromol/L and for a maximum duration of 7 days
Use concomitantly with other ammonia lowering therapies, such as IV glucose, insulin, L-carnitine, protein restriction, and dialysis
Renal Impairment
No dosage adjustment warranted in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2)
Hyperammonemia due to NAGS Deficiency
- Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2): 50 mg/kg/day to 125 mg/kg/day divided into 2 to 4 doses and rounded to nearest 50 mg (ie, one-quarter of a tablet)
- Severe renal impairment (eGFR ≤29 mL/min/1.73 m2): 15 mg/kg/day to 60 mg/kg/day divided into 2 to 4 doses and rounded to nearest 50 mg (ie, one-quarter of a tablet)
Chronic Hyperammonemia due to NAGS Deficiency
- Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2): 5 mg/kg/day to 50 mg/kg/day divided into 2 to 4 doses and rounded to nearest 50 mg (ie, one-quarter of a tablet)
- Severe renal impairment (eGFR ≤29 mL/min/1.73 m2): 2 mg/kg/day to 25 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 50 mg (ie, one-quarter of a tablet)
Acute Hyperammonemia due to PA or MMA
-
Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2):
- ≤15 kg: 75 mg/kg/day f
- >15 kg: 1.7 g/m2/day; divide daily dosage into 2 equal doses and round up to nearest 50 mg (ie, one-quarter of a CARBAGLU tablet); administer each dose 12 hours apart
-
Severe renal impairment (eGFR ≤29 mL/min/1.73 m2):
- ≤15 kg: 25 mg/kg/day
- > 15 kg: 0.55 g/m2/day; divide daily dosage into 2 equal doses and round up to nearest 50 mg (ie, one-quarter of a tablet); administer each dose 12 hours apart
Dosing Considerations
Monitoring parameters
- Closely monitor plasma ammonia levels
- Titrate dosage to maintain the plasma ammonia level within normal range for age, taking into consideration the patient’s clinical condition (eg, nutritional requirements, protein intake, growth parameters)
Adverse Effects
>10%
Acute and chronic hyperammonemia due to NAGS deficiency
- Vomiting (26%)
- Abdominal pain (17%)
- Pyrexia (17%)
- Tonsillitis (17%)
- Anemia (13%)
- Diarrhea (13%)
- Ear infection (13%)
- Infections (13%)
- Nasopharyngitis (13%)
- Hemoglobin decreased (13%)
- Headache (13%)
Acute hyperammonemia due to PA and MMA
- Neutropenia (14%)
- Anemia (12%)
1-10%
Acute and chronic hyperammonemia due to NAGS deficiency
- Dysgeusia (9%)
- Asthenia (9%)
- Hyperhidrosis (9%)
- Influenza (9%)
- Pneumonia (9%)
- Weight decreased (9%)
- Anorexia (9%)
- Somnolence (9%)
- Rash (9%)
Acute hyperammonemia due to PA and MMA
- Vomiting (7%)
- Electrolyte imbalance (7%)
- Decreased appetite (5%)
- Hypoglycemia (5%)
- Lethargy/stupor (5%)
- Encephalopathy (5%)
- Pancreatitis/lipase increased (5%)
- Cardiomyopathy (2%)
- Alanine aminotransferase increased (2%)
- Aspartate aminotransferase increased (2%)
- Infusion site extravasation (2%)
- White blood cell count increased (2%)
- Behavior disorder (2%)
- Sleep disorder (2%)
- Apnea (2%)
- Hyperventilation (2%)
Postmarketing Reports
Psychiatric disorders: Mania
Skin and subcutaneous tissue disorders: Pruritus, rash including rash erythematous, rash maculopapular, rash pustular
Warnings
Contraindications
None
Cautions
Plasma concentrations of carglumic acid increased in patients with renal impairment; reduce the dosage in patients with moderate or severe renal impairment; the pharmacokinetics of carglumic acid have not been evaluated in patients with end stage renal disease
Hyperammonemia
- Monitor serum ammonia levels and adjust dose to maintain within normal range for age
- Treat acute hyperammonemia episode as life-threatening emergency
- Treatment of severe hyperammonemia may require dialysis, preferably hemodialysis and/or hemofiltration, to reduce plasma ammonia concentration
- Untreated hyperammonemia can result in brain damage and death, and prompt use of all therapies necessary to reduce plasma ammonia level is essential
- Protein restriction during an acute hyperammonemic episode is recommended for no longer than 12-36 hr while maximizing caloric supplementation to reverse catabolism; protein should be reintroduced as early as possible, following improvement of metabolic and clinical abnormalities in this setting; during long-term management, dietary protein restriction should be instituted to maintain blood ammonia level within an acceptable range for age
- Ongoing monitoring of plasma ammonia level, neurological status, growth parameters, protein intake/nutritional status (both during acute hyperammonemic episodes and long-term), and relevant laboratory tests in patients receiving therapy should be part of evaluating clinical response to treatment
Pregnancy & Lactation
Pregnancy
Rare case reports of use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
Pregnancy pharmacovigilance program for carglumic acid exposures: 1-888-575-8344
Pregnant females with urea cycle disorders may experience an increase in catabolic stress which can trigger a hyperammonemic crisis both in intrapartum and in postpartum (3-14 days post-partum) periods
Maternal complications related to hyperammonemic crisis can include neurological impairment, coma and in some cases death
Animal data
- Decreased survival and growth occurred in offspring born to rats that received carglumic acid at a dose ~38x maximum reported human maintenance dose
Lactation
Unknown whether drug is excreted in human milk
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
Breastfeeding is not recommended during therapy; treatment is continuous and life-long for NAGS deficiency patients
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
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 an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1), a mitochondrial liver enzyme which catalyzes the first reaction of the urea cycle
Carglumic acid acts as a CPS1 activator in patients with NAGS deficiency, thereby removing the block in the urea cycle and facilitating ammonia detoxification and urea production
Absorption
Peak plasma concentration: 8,613 ng/mL (8 mg/kg IV); 3,284 ng/mL (100 mg/kg PO)
Peak plasma time: 2 hr (8 mg/kg IV); 3 hr (100 mg/kg PO)
AUC: 24,501 ng·hr/mL (8 mg/kg IV); 31,426 ng·hr/mL (100 mg/kg PO)
Absolute bioavailability: ~10% (100 mg/kg PO)
Distribution
Vd: 15 L/kg (8 mg/kg IV)
Carglumic acid is not bound to plasma proteins
Metabolism
Proportion of carglumic acid may be metabolized by intestinal bacterial flora
Likely end product of metabolism is carbon dioxide, eliminated through the lungs
Elimination
Half-time: 31 hr (8 mg/kg IV); 25 hr (100 mg/kg PO)
Clearance: 0.34 L/hr/kg (8 mg/kg IV)
Excretion: Urine (9%, unchanged); feces (up to 60%)
Administration
Oral Preparation
Add ~2.5 mL of water into a small cup for each tablet or each 1/2 or 1/4 tablet needed for prescribed dose
Tablets do not dissolve completely in water and undissolved tablet particles may remain in mixing container
Add tablet(s) to water in cup
Carefully stir tablet and water mixture and administer immediately
Oral Administration
Do not swallow tablet whole or crush
Take immediately before meals or feedings
Suspension has a slightly acidic taste
For all preparations, use in foods or liquids, other than water, has not been studied clinically and is not recommended
Orally
- Swallow mixture immediately after dispersing tablet
- Pieces of tablet may remain in cup
- Rinse cup with additional water and swallow mixture immediately; repeat until no tablet pieces are left in cup
Nasogastric
- Draw up mixture into a catheter-tip syringe
- Administer mixture immediately through nasogastric (NG)-tube or Gastrostomy (G)-tube
- Pieces of tablet may remain in catheter-tip syringe, NG-tube, or G-tube
- Flush immediately with 1-2 mL of additional water to clear NG-tube or G-tube
- Flush NG-tube or G-tube again, as needed, until no pieces of tablet are left in syringe, NG-tube, or G-tube
Oral syringe
- Draw up mixture in oral syringe and administer immediately
- Pieces of tablet may remain in oral syringe
- Refill oral syringe with a minimum volume of water (1-2 mL) and administer immediately
- Flush oral syringe again, as needed, until no pieces of tablet are left in syringe
Storage
Unopened container: Refrigerate at 2-8ºC (36-46ºF)
Opened container
- Store at room temperature between 15-30ºC (59-86ºF); do NOT refrigerate
- Keep container tightly closed between openings to protect from moisture
- Write date of opening on container; discard 1 month after first opening
- Do not use after the expiration date stated on container
- Keep out of reach of children
Images
| BRAND | FORM. | UNIT PRICE | PILL IMAGE |
|---|---|---|---|
| carglumic acid oral - | 200 mg tablet |  |
Copyright © 2010 First DataBank, Inc.
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