Carbaglu Drug Information

1. 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.

2. DOSAGE AND ADMINISTRATION Acute Hyperammonemia due to NAGS deficiency The recommended dosage in adult and pediatric patients is 100 mg/kg to 250 mg/kg orally daily. Divide the daily dosage into 2 to 4 doses.

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. Continue treatment until ammonia level is less than 50 micromol/L and for a maximum duration of 7 days. Patients with Renal Impairment See Full Prescribing Information for Instructions on Dosage Adjustment.

Preparation and Administration Disperse CARBAGLU tablets in water. Do not swallow whole or crushed. Take immediately before meals or feedings.

Do not swallow whole or crush. CARBAGLU may be administered by mouth or via a nasogastric or gastrostomy tube. 2.2 Recommended Dosage for Acute or Chronic Hyperammonemia due to NAGS Deficiency Treatment Initiation Initiate CARBAGLU 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. During acute hyperammonemic episodes, administer CARBAGLU with other ammonia lowering therapies, such as alternate pathway medications, hemodialysis, and protein restriction.

Dosage for Chronic Hyperammonemia due to NAGS Deficiency The recommended dosage of CARBAGLU in adult and pediatric patients for chronic hyperammonemia due to NAGS deficiency is (based on actual body weight) 10 mg/kg to 100 mg/kg orally daily. 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 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.). Adjust the recommended dosage in patients with moderate or severe renal impairment. 2.3 Recommended Dosage for Acute Hyperammonemia due to PA or MMA Treatment Initiation Initiate CARBAGLU for the treatment of acute hyperammonemia in patients with a suspected or confirmed diagnosis of PA or MMA. Dosage for Acute Hyperammonemia due to PA or MMA The recommended dosage of CARBAGLU in adult and pediatric patients with acute hyperammonemia due to PA or MMA is (based on actual body weight): 150 mg/kg orally daily for patients less than or equal to 15 kg 3.3 g/m 2 orally daily for patients greater than 15 kg Divide the daily dosage into 2 equal doses and round up to the nearest 50 mg (i.e., one-quarter of a CARBAGLU tablet).

Administer doses 12 hours apart. During acute hyperammonemic episodes, administer CARBAGLU with other ammonia lowering therapies, such as intravenous glucose, insulin, L-carnitine, protein restriction, and dialysis. Adjust the recommended dosage in patients with moderate or severe renal impairment. 2.4 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 ).

CARBAGLU tablets do not dissolve completely in water, and undissolved particles of the tablet may remain in the mixing container. 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. 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.

6. 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.

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. Acute and Chronic Hyperammonemia due to NAGS Deficiency In a retrospective case series of 23 NAGS deficiency patients treated with CARBAGLU, 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 CARBAGLU. Table 1: Adverse Reactions Reported in ≥ 2 Patients with NAGS deficiency Treated with CARBAGLU in the Retrospective Case Series 2 Acute Hyperammonemia due to PA and MMA In a randomized, double-blind, placebo-controlled clinical trial, 24 patients (15 with PA and 9 with MMA) experienced a total of 90 hyperammonemic episodes which were randomized 1:1 to be treated with either CARBAGLU or placebo, each in addition to standard-of-care therapy, with randomization based on each hyperammonemic episode. The average patient age (SD) was 9.2 years and 12 (50 %) were males.

At least 1 adverse reaction was reported during the course of hyperammonemic episodes in 42% of hyperammonemic episodes. The most common adverse reactions (≥5%) during hyperammonemic episodes were neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased. Table 2 summarizes adverse reactions (≥2%) during hyperammonemic episodes in patients with PA or MMA treated with CARBAGLU or placebo.

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 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women with NAGS deficiency exposed to CARBAGLU. If CARBAGLU is administered during pregnancy, health care providers should report CARBAGLU exposure by calling 1-888-575-8344. Risk Summary 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 (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, PA, and MMA 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 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.

4. CONTRAINDICATIONS None None.

10. 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.