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  • CLASSES

    Hyperammonemia Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral treatment for acute and chronic hyperammonemia due to N-acetylglutamate synthase deficiency; plasma ammonia concentrations may be reduced the first day and may remain reduced with continued daily treatment.

    COMMON BRAND NAMES

    Carbaglu

    HOW SUPPLIED

    Carbaglu Nasogastric Tab: 200mg
    Carbaglu Oral Tab: 200mg

    DOSAGE & INDICATIONS

    For the treatment of hyperammonemia in patients with 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 the treatment of N-acetylglutamate synthase deficiency.
    Oral dosage
    Adults

    Initially, 100 to 250 mg/kg/day PO divided into 2 to 4 doses 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. Titrate the maintenance dose to target a normal plasma ammonia concentration for age.

    Adolescents, Children, and Infants

    Initially, 100 to 250 mg/kg/day PO divided into 2 to 4 doses 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. Maintenance doses were usually less than 100 mg/kg/day among 22 patients (mean age at carglumic acid initiation was 2 years, range 0 to 13 years) in a retrospective case series. Titrate the maintenance dose to target a normal plasma ammonia concentration for age.

    Neonates

    Initially, 100 to 250 mg/kg/day PO divided into 2 to 4 doses 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. Maintenance doses were usually less than 100 mg/kg/day among 22 patients (mean age at carglumic acid initiation was 2 years, range 0 to 13 years) in a retrospective case series. Titrate the maintenance dose to target a normal plasma ammonia concentration for age.

    MAXIMUM DOSAGE

    Adults

    Specific maximum dosage information is not available. Individualize dosage based on careful monitoring of plasma ammonia concentrations and clinical response.

    Elderly

    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.

    Children

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Do not administer whole or crushed tablets. Disperse each 200 mg tablet 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 to ensure complete delivery of the dose. Dispersion in other liquids or in food has not been clinically studied and is not recommended.
    For patients who have a nasogastric tube in place, mix each 200 mg tablet in a minimum of 2.5 mL of water, which will yield a concentration of 80 mg/mL. Shake gently to allow for quick dispersal. Administer the appropriate volume of dispersion immediately through the nasogastric tube. Flush with additional water to clear the nasogastric tube. Discard any unused portion.
    For administration via oral syringe, mix each 200 mg tablet in a minimum of 2.5 mL of water, which will yield a concentration of 80 mg/mL. Shake gently to allow for quick dispersal. Draw up the appropriate volume of dispersion in an oral syringe and administer immediately. Refill the oral syringe with a minimum volume of water (1—2 mL) and administer immediately. Discard any unused portion.

    STORAGE

    Carbaglu :
    - Discard opened bottle after 30 days
    - May be stored at room temperature not exceeding 86 degrees F for up to 1 month
    - Product stored at controlled room temperature should not be returned to a refrigerator
    - Protect from moisture
    - Store unopened containers in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Pregnancy

    Carglumic acid is classified in FDA pregnancy category C. No adequate and well controlled studies of carglumic acid in pregnant women exist. Women with N-acetylglutamate synthase deficiency must remain on treatment throughout pregnancy, as untreated deficiency results in irreversible neurologic damage and death. In animals that received carglumic acid at doses similar to the maximum recommended starting human dose during pregnancy and lactation, decreased survival and growth occurred in offspring.

    Breast-feeding

    According to the manufacturer, breast-feeding is not recommended because of the potential for serious adverse reactions in nursing infants. Carglumic acid excretion into human milk is unknown. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    The safety and efficacy of carglumic acid in geriatric patients have not been established.

    ADVERSE REACTIONS

    Moderate

    anemia / Delayed / 13.0-13.0

    Mild

    dysgeusia / Early / 1.0-10.0
    anorexia / Delayed / 1.0-10.0
    weight loss / Delayed / 1.0-10.0
    influenza / Delayed / 1.0-10.0
    infection / Delayed / 1.0-10.0
    asthenia / Delayed / 1.0-10.0
    hyperhidrosis / Delayed / 9.0-9.0
    rash / Early / 9.0-9.0
    diarrhea / Early / 10.0
    abdominal pain / Early / 10.0
    vomiting / Early / 10.0
    pharyngitis / Delayed / 10.0
    fever / Early / 10.0
    headache / Early / 10.0

    DRUG INTERACTIONS

    There are no drug interactions associated with Carglumic Acid products.

    PREGNANCY AND LACTATION

    Pregnancy

    Carglumic acid is classified in FDA pregnancy category C. No adequate and well controlled studies of carglumic acid in pregnant women exist. Women with N-acetylglutamate synthase deficiency must remain on treatment throughout pregnancy, as untreated deficiency results in irreversible neurologic damage and death. In animals that received carglumic acid at doses similar to the maximum recommended starting human dose during pregnancy and lactation, decreased survival and growth occurred in offspring.

    According to the manufacturer, breast-feeding is not recommended because of the potential for serious adverse reactions in nursing infants. Carglumic acid excretion into human milk is unknown. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    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. The most likely end product of carglumic acid metabolism is carbon dioxide, which is then eliminated via the lungs. A small portion of each dose, 4.5% (range, 3.5—7.5), is excreted in the urine within 24 hours. Some carglumic acid may be metabolized by intestinal bacterial flora, and a significant portion of each dose is excreted unchanged in the feces. The median terminal half-life in healthy male volunteers was 5.6 hours (range, 4.3—9.5 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.

    Oral Route

    After oral administration of carglumic acid to healthy male volunteers, the median Tmax was 3 hours (range, 2—4). 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.