Carglumic Acid Drug Information

Acute and Chronic

Hyperammonemia due to N-acetylglutamate Synthase (NAGS) Deficiency Carglumic acid tablets for oral suspension is indicated in adult and pediatric patients as: Adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to NAGS deficiency. Maintenance therapy for the treatment of chronic hyperammonemia due to NAGS deficiency.

Important Administration Instructions

Disperse carglumic acid tablets for oral suspension in water. Do not swallow whole or crush. Carglumic acid tablets for oral suspension may be administered by mouth or via a nasogastric or gastrostomy tube.

Recommended Dosage for Acute or Chronic

Hyperammonemia due to NAGS Deficiency Treatment Initiation Initiate Carglumic acid tablets for oral suspension treatment as soon as the diagnosis of NAGS deficiency is suspected, which may be as soon as at birth, and supervised by a healthcare provider experienced in the treatment of metabolic disorders. Dosage for Acute Hyperammonemia due to NAGS Deficiency The recommended dosage of Carglumic acid tablets for oral suspension in adult and pediatric patients for acute hyperammonemia due to NAGS deficiency is (based on actual body weight) 100 mg/kg to 250 mg/kg orally daily. Divide the daily dosage into 2 to 4 doses and round to the nearest 100 mg (i.e., half of a Carglumic acid tablets for oral suspension).

During acute hyperammonemic episodes, administer Carglumic acid tablets for oral suspension with other ammonia lowering therapies, such as alternate pathway medications, hemodialysis, and protein restriction. During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be needed based on plasma ammonia levels. Therapeutic Monitoring Closely monitor plasma ammonia levels.

Titrate the Carglumic acid tablets for oral suspension dosage to maintain the plasma ammonia level within the normal range for the patient's age, taking into consideration their clinical condition (e.g., nutritional requirements, protein intake, growth parameters, etc.). Adjust the recommended dosage in patients with moderate or severe renal impairment.

Dosage Adjustment in Patients with Renal Impairment

No dosage adjustment is warranted in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m 2 ).

Preparation and Administration Overview

Carglumic acid tablets for oral suspension do not dissolve completely in water, and undissolved particles of the tablet may remain in the mixing container. Take carglumic acid tablets for oral suspension immediately before meals or feedings. The carglumic acid tablets for oral 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 Carglumic acid tablets for oral suspension as follows: Add a minimum of 2.5 mL of water into a small cup for each carglumic acid tablet for oral suspension or each ½ or ¼ carglumic acid tablet for oral suspension needed for the prescribed dose. Add the carglumic acid tablets for oral suspension 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. 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. Flush the oral syringe again, as needed, until no pieces of the tablet are left in the syringe.

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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Acute and Chronic Hyperammonemia due to NAGS Deficiency In a retrospective case series of 23 NAGS deficiency patients treated with Carglumic acid tablets for oral suspension, 17 of the 23 patients reported an adverse reaction. The most common adverse reactions (occurring in ≥ 13% of patients) were vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache.

Table 1 summarizes adverse reactions occurring in 2 or more patients treated with carglumic acid tablets for oral suspension. Table 1: Adverse Reactions Reported in ≥ 2 Patients with NAGS deficiency Treated with Carglumic Acid Tablets for Oral Suspension in the Retrospective Case Series 2

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Carglumic acid tablets for oral suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Psychiatric disorders: mania Skin and subcutaneous tissue disorders: pruritus, rash including rash erythematous, rash maculopapular, rash pustular

Pregnancy Risk Summary Although rare case reports of carglumic acid tablets for oral suspension 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 can result in irreversible neurologic damage and death in pregnant women (see Clinical Considerations). In an animal reproduction study, decreased survival and growth occurred in offspring born to rats that received carglumic acid at a dose approximately 38 times the maximum reported human maintenance dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnant women with urea cycle disorders may experience an increase in catabolic stress which can trigger a hyperammonemic crisis both in the intrapartum and in the post-partum (3 - 14 days post-partum) periods.

Maternal complications related to hyperammonemic crisis can include neurological impairment, coma and in some cases death. Data Animal Data No effects on embryo-fetal development were observed in pregnant rats treated with up to 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose based on AUC ) from two weeks prior to mating through organogenesis or in pregnant rabbits treated with up to 1000 mg/kg/day (approximately 6 times the maximum reported human maintenance dose based on AUC) during organogenesis. In a pre- and post-natal developmental study, female rats received oral carglumic acid from organogenesis through lactation at doses of 500 mg/kg/day and 2000 mg/kg/day.

Decreased growth of offspring was observed at 500 mg/kg/day and higher (approximately 38 times the maximum reported human maintenance dose based on AUC), and reduction in offspring survival during lactation was observed at 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose based on AUC). No effects on physical and sexual development, learning and memory, or reproductive performance were observed through maturation of the surviving offspring at maternal doses up to 2000 mg/kg/day. The high dose (2000 mg/kg/day) produced maternal toxicity (impaired weight gain and approximately 10% mortality).

Pediatric Use The safety and effectiveness of carglumic acid tablets for oral suspension for the treatment of pediatric patients (birth to 17 years of age) with acute or chronic hyperammonemia due to NAGS deficiency 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 Carglumic acid tablets for oral suspension.

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