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  • CLASSES

    Hyperammonemia Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Structural analogue of N-acetyl-glutamate; aids in conversion of ammonia to urea
    Used for acute and chronic hyperammonemia due to N-acetylglutamate synthase deficiency and acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA)
    Must dissolve tablets prior to administration

    COMMON BRAND NAMES

    Carbaglu

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    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 the treatment of N-acetylglutamate synthase deficiency.
    Oral dosage
    Adults

    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.

    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.

    For the treatment of acute hyperammonemia due to propionic acidemia (PA) or hyperammonemia due to methylmalonic acidemia (MMA) as an adjunctive therapy.
    Oral dosage
    Adults

    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.

    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.

    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.

    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.

    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

    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 29 mL/minute/1.73 m2 or less: 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).
     
    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 29 mL/minute/1.73 m2 or less: 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).
     
    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 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 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 29 mL/minute/1.73 m2 or less (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 29 mL/minute/1.73 m2 or less (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.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer immediately before meals or feedings.
    Do not administer whole or crushed tablets. 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.

    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

    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 rats that received carglumic acid at doses approximately 38 times the maximum reported human maintenance dose, decreased survival and growth occurred in offspring. If carglumic acid is administered during pregnancy, health care providers should report exposure by calling 1-888-575-8344.

    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.

    Renal disease, renal failure, renal impairment

    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.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / 5.0-5.0
    cardiomyopathy / Delayed / 2.0-2.0
    apnea / Delayed / 2.0-2.0

    Moderate

    neutropenia / Delayed / 14.0-14.0
    anemia / Delayed / 12.0-13.0
    hypoglycemia / Early / 5.0-5.0
    elevated hepatic enzymes / Delayed / 2.0-2.0
    mania / Early / Incidence not known

    Mild

    vomiting / Early / 7.0-26.0
    abdominal pain / Early / 17.0-17.0
    fever / Early / 17.0-17.0
    diarrhea / Early / 13.0-13.0
    infection / Delayed / 13.0-13.0
    pharyngitis / Delayed / 13.0-13.0
    headache / Early / 13.0-13.0
    anorexia / Delayed / 5.0-9.0
    weight loss / Delayed / 9.0-9.0
    dysgeusia / Early / 9.0-9.0
    influenza / Delayed / 9.0-9.0
    hyperhidrosis / Delayed / 9.0-9.0
    rash / Early / 9.0-9.0
    asthenia / Delayed / 9.0-9.0
    drowsiness / Early / 9.0-9.0
    lethargy / Early / 5.0-5.0
    hyperventilation / Early / 2.0-2.0
    maculopapular rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Carglumic Acid products.

    PREGNANCY AND LACTATION

    Pregnancy

    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 rats that received carglumic acid at doses approximately 38 times the maximum reported human maintenance dose, decreased survival and growth occurred in offspring. If carglumic acid is administered during pregnancy, health care providers should report exposure by calling 1-888-575-8344.

    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. 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.

    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).