CARBAGLU® (carglumic acid)

CARBAGLU® (carglumic acid) tablets

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CARBAGLU® (carglumic acid)

CARBAGLU tablets for oral suspension contain 200 mg of carglumic acid. Carglumic acid, the active substance, is a carbamoyl phosphate synthetase 1 (CPS 1) activator and is soluble in boiling water, slightly soluble in cold water, and practically insoluble in organic solvents.

Chemically, carglumic acid is N-carbamoyl-L-glutamic acid or (2S)-2-(carbamoylamino) pentanedioic acid, with a molecular weight of 190.16.

Molecular Formula: C6H10N2O5

The inactive ingredients of CARBAGLU are croscarmellose sodium, hypromellose, microcrystalline cellulose, silica colloidal anhydrous, sodium lauryl sulfate, and sodium stearyl fumarate.

Indications and usage

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.
  • Maintenance therapy for the treatment of chronic hyperammonemia due to NAGS deficiency.
  • Adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA).

Mechanism of Action

Carglumic acid is a synthetic 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 the essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1), a mitochondrial liver enzyme which catalyzes the first reaction of the urea cycle. The urea cycle, whose role is the disposition of ammonia, includes a series of biochemical reactions in the liver resulting in the conversion of ammonia into urea, which is then excreted through the urine. Carglumic acid acts as a CPS1 activator, improves or restores the function of the urea cycle, and facilitates ammonia detoxification and urea production.

Dosage and administration

Initiate CARBAGLU treatment as soon as the diagnosis of NAGS deficiency is suspected, which may be as soon as at birth, and managed by a physician and medical team experienced in metabolic disorders.

Acute Hyperammonemia due to NAGS deficiency

  • The recommended pediatric and adult dosage is 100 mg/kg/day to 250 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 100 mg.
  • During acute hyperammonemic episodes, administer CARBAGLU with other ammonia lowering therapies, such as alternate pathway medications, hemodialysis, and protein restriction.

Chronic Hyperammonemia due to NAGS deficiency

  • The recommended pediatric and adult dosage is 10 mg/kg/day to 100 mg/kg/day divided into 2 to 4 doses and rounded to the nearest 100 mg.
  • During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be needed based on plasma ammonia levels.

Therapeutic Monitoring for NAGS Deficiency

  • Closely monitor plasma ammonia and titrate dosage to maintain the ammonia level within normal range for the patient’s age, taking into consideration their clinical condition.

Acute Hyperammonemia due to PA or MMA

  • The recommended pediatric and adult dosage is: 150 mg/kg/day for patients less than or equal to 15 kg
  • 3.3 g/m2/day for patients greater than 15 kg
  • Divide the daily dosage into two equal doses and round up to the nearest 50 mg; administer each dose 12 hours apart.
  • Continue treatment until ammonia level is less than 50 micromol/L and for a maximum duration of 7 days.

Preparation and Administration

Overview

  • Disperse CARBAGLU tablets in water. Do not swallow whole or crushed.
  • CARBAGLU tablets do not dissolve completely in water, and undissolved particles of the tablet may remain in the mixing container.
  • Take CARBAGLU immediately before meals or feedings.
  • The CARBAGLU suspension has a slightly acidic taste.
  • For all preparations, use in foods or liquids other than water has not been studied and is not recommended.

Oral Administration

For oral administration, administer CARBAGLU as follows:

  • Add a minimum of 2.5 mL of water into a small cup for each CARBAGLU tablet or each ½ or ¼ CARBAGLU tablet needed for the prescribed dose.
  • Add the CARBAGLU tablets to the water in the cup.
  • Carefully stir the tablet and water mixture.
  • Swallow the mixture immediately. Pieces of the tablet may remain in the cup.
  • Rinse the cup with additional water and swallow the mixture immediately. Repeat as needed until no pieces of the tablet are left in the cup.

Use of an Oral Syringe for Oral Administration

For administration via an oral syringe, administer CARBAGLU as follows:

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  • Add a minimum of 2.5 mL of water into a small cup for each CARBAGLU tablet or each ½ or ¼ CARBAGLU tablet needed for the prescribed dose.
  • Add the CARBAGLU tablets to the water in the cup.
  • Carefully stir the tablet and water mixture.
  • Draw up the mixture in an oral syringe and administer immediately. Pieces of the tablet may remain in the oral syringe.
  • Refill the oral syringe with a minimum volume of water (1 mL to 2 mL) and administer immediately.

Use of Nasogastric Tube (NG Tube) or Gastrostomy Tube (G-Tube) for Feeding Tube Administration

For patients who have a NG tube or G-tube in place, administer CARBAGLU as follows:

  • Add a minimum of 2.5 mL of water into a small cup for each CARBAGLU tablet or each ½ or ¼ CARBAGLU tablet needed for the prescribed dose.
  • Add the CARBAGLU tablets to the water in the cup.
  • Carefully stir the tablet and water mixture.
  • Draw up the mixture into a catheter-tip syringe.
  • Administer the mixture immediately through the NG tube or G-tube. Pieces of the tablet may remain in the catheter-tip syringe or the feeding tube.
  • Flush immediately with 1 to 2 mL of additional water to clear the NG tube or G-tube.
  • Flush the NG tube or G-tube again, as needed, until no pieces of the tablet are left in the syringe or the feeding tube.

Adverse reactions

NAGS deficiency: Most common adverse reactions (≥13%) are vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache.

PA and MMA: Most common adverse reactions (≥5%) are neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased.

Use in specific populations

Pregnancy: Although rare case reports of CARBAGLU use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, untreated NAGS deficiency, PA and MMA can result in irreversible neurologic damage and death in pregnant women.

Lactation: Risk Summary It is not known whether carglumic acid is present in human milk. There are no available data on the effects of carglumic acid on the breastfed infant or the effects on milk production. Carglumic acid is present in milk from treated rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CARBAGLU and any potential adverse effects on the breastfed child from CARBAGLU or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of CARBAGLU for the treatment of pediatric patients (birth to 17 years of age) with acute or chronic hyperammonemia due to NAGS deficiency and acute hyperammonemia due to PA or MMA have been established, and the information on these uses are discussed throughout the labeling. There are insufficient data to determine if there is a difference in clinical or biochemical responses between adult and pediatric patients treated with CARBAGLU.

Geriatric Use: Clinical studies of CARBAGLU did not include patients 65 years of age and older.

Overdosage

One patient treated with 650 mg/kg/day of CARBAGLU developed symptoms resembling monosodium glutamate intoxication-like syndrome and characterized by tachycardia, profuse sweating, increased bronchial secretions, increased body temperature, and restlessness. These symptoms resolved upon reduction of the dose.

Storage

Store in the original unopened container at 2°C to 8°C (36°F to 46°F).

After first opening of the container:

  • Do not refrigerate, store at room temperature between 15°C and 30°C (59°F and 86°F).
  • Keep the container tightly closed between openings in order to protect from moisture.
  • Write the date of opening on the tablet container.
  • Do not use after the expiration date stated on the tablet container.
  • Discard one month after first opening.
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