Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 09 August 2018

Indication(s)

1. INDICATIONS AND USAGE CARBAGLU is a Carbamoyl Phosphate Synthetase 1 (CPS 1) activator indicated as: Adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). ( 1.1) Maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). ( 1.2) 1.1 Acute Hyperammonemia in Patients with NAGS Deficiency CARBAGLU is indicated as an adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). During acute hyperammonemic episodes, concomitant administration of CARBAGLU with other ammonia lowering therapies, such as alternate pathway medications, hemodialysis, and dietary protein restriction, is recommended. 1.2 Chronic Hyperammonemia in Patients with NAGS Deficiency CARBAGLU is indicated as maintenance therapy in pediatric and adult patients for the treatment of chronic hyperammonemia due to deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be needed based on plasma ammonia levels.

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Advisory information

contraindications
4. CONTRAINDICATIONS None None. ( 4)
Adverse reactions
6. ADVERSE REACTIONS Most common adverse reactions (>9%) are: vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache ( 6.1). To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with CARBAGLU in the retrospective case series (≥ 9%). Table 1: Adverse Reactions Reported in ≥ 2 Patients in the Retrospective Case Series Treated with CARBAGLU Adverse Reaction Number of Patients (N) (%) Vomiting 6 (26) Abdominal pain 4 (17) Pyrexia 4 (17) Tonsillitis 4 (17) Anemia 3 (13) Diarrhea 3 (13) Ear infection 3 (13) Infections 3 (13) Nasopharyngitis 3 (13) Hemoglobin decreased 3 (13) Headache 2 (9) Dysguesia 2 (9) Asthenia 2 (9) Hyperhidrosis 2 (9) Influenza 2 (9) Pneumonia 2 (9) Weight decreased 2 (9) Anorexia 2 (9) Somnolence 2 (9) Rash 2 (9)

Usage information

Dosing and administration
2. DOSAGE AND ADMINISTRATION CARBAGLU treatment should be initiated by a physician experienced in metabolic disorders. Based on clinical experience, the treatment may be started as early as the first day of life. CARBAGLU tablets are uncoated and should not be swallowed whole or crushed. Disperse CARBAGLU tablets in water immediately before use. For all preparations, use in other foods and liquids has not been studied clinically and is therefore not recommended. Dosing ( 2.1): Acute Hyperammonemia: The recommended initial pediatric and adult dosage is 100 mg/kg/day to 250 mg/kg/day. Titrate based on plasma ammonia level and clinical symptoms. Maintenance for chronic hyperammonemia: The recommended pediatric and adult maintenance dosage is 10 mg/kg/day to 100 mg/kg/day. Titrate to target normal plasma ammonia level for age. Divide the total daily dose into two to four doses. Monitor plasma ammonia and adjust the dosage to maintain the level within the normal range for age. Preparation and Administration ( 2.2) Disperse CARBAGLU tablets in water. Do not swallow whole or crushed. Take immediately before meals or feedings. For instructions on administration orally or through a nasogastric tube, see the full prescribing information. 2.1 Recommended Dosage CARBAGLU should be initiated 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. Initial Dosage: The recommended initial daily dosage of CARBAGLU in pediatric and adult patients for acute hyperammonemia is 100 mg/kg to 250 mg/kg divided into 2 to 4 doses and rounded to the nearest 100 mg (i.e., half of a CARBAGLU tablet). Concomitant administration of other ammonia lowering therapies is recommended. Maintenance Dosage: The recommended daily maintenance dosage of CARBAGLU in pediatric and adult patients is 10 mg/kg to 100 mg/kg divided into 2 to 4 doses and rounded to the nearest 100 mg (i.e., half of a CARBAGLU tablet). Therapeutic Monitoring Closely monitor plasma ammonia levels. Titrate the CARBAGLU 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.). 2.2 Preparation and Administration Disperse CARBAGLU tablets in water. Do not swallow whole or crushed. Mix each 200 mg tablet in a minimum of 2.5 mL of water to yield a concentration of 80 mg/mL. 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 clinically and is not recommended. Preparation for Oral Administration in Pediatric and Adult Patients Add about 2.5 mL of water into a small cup for each CARBAGLU tablet or each ½ 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. Preparation for Nasogastric Tube Administration in Pediatric and Adult Patients For patients who have a nasogastric tube in place, CARBAGLU should be administered as follows: Add about 2.5 mL of water into a small cup for each CARBAGLU tablet or each ½ 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 nasogastric (NG) tube. Pieces of the tablet may remain in the catheter-tip syringe or NG tube. Flush immediately with 1 to 2 mL of additional water to clear the NG tube. Flush the NG tube again, as needed, until no pieces of the tablet are left in the syringe or NG tube. Preparation for Oral Administration Using an Oral Syringe in Pediatric Patients For administration via oral syringe, CARBAGLU should be administered as follows: Add about 2.5 mL of water into a small cup for each CARBAGLU tablet or each ½ 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 to 2 mL) and administer immediately. Flush the oral syringe again, as needed, until no pieces of the tablet are left in the syringe.
Use in special populations
8. USE IN SPECIFIC POPULATIONS Pregnancy: No human data; decreased survival and growth in animal offspring. ( 8.1) Nursing Mothers: Breastfeeding is not recommended while taking CARBAGLU. ( 8.3) 8.1 Pregnancy Pregnancy Category C There are no adequate and well controlled studies or available human data with CARBAGLU in pregnant women. Decreased survival and growth occurred in offspring born to animals that received carglumic acid at a dose approximately 38 times the maximum reported human maintenance dose. Because untreated N-acetylglutamate synthase (NAGS) deficiency results in irreversible neurologic damage and death, women with NAGS must remain on treatment throughout pregnancy. 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 [100 mg/kg/day] based on AUC [area under the plasma concentration-time curve]) 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 [100 mg/kg/day] based on AUC). In a peri- and post-natal developmental study, female rats received oral carglumic acid from organogenesis through lactation at doses of 500 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 [100 mg/kg/day] 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 [100 mg/kg/day] 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). 8.3 Nursing Mothers It is not known whether CARBAGLU is excreted in human milk. Carglumic acid is excreted in rat milk, and an increase in mortality and impairment of body weight gain occurred in neonatal rats nursed by mothers receiving carglumic acid. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CARBAGLU, breast-feeding is not recommended. Treatment is continuous and life-long for NAGS deficiency patients. 8.4 Pediatric Use The efficacy of CARBAGLU for the treatment of hyperammonemia in patients with NAGS deficiency from birth to adulthood was evaluated in a retrospective review of the clinical course of 23 NAGS deficiency patients who all began CARBAGLU treatment during infancy or childhood. There are no apparent differences in clinical response between adults and pediatric NAGS deficiency patients treated with CARBAGLU, however, data are limited. 8.5 Geriatric Use CARBAGLU has not been studied in the geriatric population. Therefore, the safety and effectiveness in geriatric patients have not been established.
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether CARBAGLU is excreted in human milk. Carglumic acid is excreted in rat milk, and an increase in mortality and impairment of body weight gain occurred in neonatal rats nursed by mothers receiving carglumic acid. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CARBAGLU, breast-feeding is not recommended. Treatment is continuous and life-long for NAGS deficiency patients.

More information

Category Value
Authorisation number NDA022562
Agency product number 5L0HB4V1EW
Orphan designation No
Product NDC 52276-312
Date Last Revised 14-11-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Orphan Europe, SARL