Carglumic acid

1 INDICATIONS AND USAGE Carglumic acid tablets for oral suspension 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. ( 1.1 ) Maintenance therapy for the treatment of chronic hyperammonemia due to NAGS deficiency. ( 1.1 ) 1.1 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.

2 DOSAGE AND ADMINISTRATION Acute Hyperammonemia due to NAGS deficiency ( 2.2 ) 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. Chronic Hyperammonemia due to NAGS deficiency (2.2) The recommended dosage in adult and pediatric patients is 10 mg/kg to 100 mg/kg orally daily. Divide the daily dosage into 2 to 4 doses. Therapeutic Monitoring for NAGS Deficiency (2.2) 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. Patients with Renal Impairment ( 2.4 ) See Full Prescribing Information for Instructions on Dosage Adjustment. Preparation and Administration ( 2.5 ) Disperse carglumic acid tablets for oral suspension in water. Do not swallow whole or crushed. Take immediately before meals or feedings. For additional instructions on preparation and administration orally or through a nasogastric tube or gastrostomy tube, see the full prescribing information. 2.1 Important Administration Instructions Disperse carglumic acid tablets for oral suspension in water. Do not swallow whole or crush [see Dosage and Administration ( 2.5 )] . Carglumic acid tablets for oral suspension may be administered by mouth or via a nasogastric or gastrostomy tube [see Dosage and Administration ( 2.5 )]. 2.2 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. Dosage for Chronic Hyperammonemia due to NAGS Deficiency • The recommended daily dosage of Carglumic acid tablets for oral suspension 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. • 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 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 [see Dosage and Administration ( 2.4 )] . 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 ). The recommended dosage of carglumic acid tablets for oral suspension in patients with moderate or severe renal impairment is shown below. Moderate Renal Impairment (eGFR 30-59 mL/min/1.73 m 2 ) Severe Renal Impairment (eGFR 15-19 mL/min/1.73 m 2 ) Acute Hyperammonemia due to NAGS Deficiency 50 mg/kg/day 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 …

3 DOSAGE FORMS & STRENGTHS Tablets for oral suspension: 200 mg of carglumic acid, white to off-white, elongated, functionally scored with 3 lines (for splitting into 4 equal portions) and coded "120" on one side and ''N" on other side. Tablets for oral suspension: 200 mg, functionally scored. (3)

4 CONTRAINDICATIONS None None. (4)

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. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eton Pharmaceuticals, Inc. at 1-855-224-0233, 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 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 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 3 (13) Dysgeusia 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) 6.2 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

8 USE IN SPECIFIC POPULATIONS 8.1 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 2% to 4% and 15% to 20%, 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 [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) 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 [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). 8.2 Lactation Risk Summary It is not known whether carglumic acid is present in human milk. There are no available data on the effects of carglumic acid on the breastfed infant or the effects on milk production. Carglumic acid is present in milk from treated rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for carglumic acid tablets for oral suspension and any potential adverse effects on the breastfed child from carglumic acid tablets for oral suspension or from the underlying maternal condition. 8.4 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. 8.5 Geriatric Use Clinical studies of Carglumic acid tablets for oral susp …

12.1 Mechanism of Action Carglumic acid is a synthetic structural analogue of N-acetylglutamate (NAG) which is produced from glutamate and acetyl-CoA in a reaction catalyzed by N-acetylglutamate synthase (NAGS), a mitochondrial liver enzyme. NAG acts as the essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1), a mitochondrial liver enzyme which catalyzes the first reaction of the urea cycle. The urea cycle, whose role is the disposition of ammonia, includes a series of biochemical reactions in the liver resulting in the conversion of ammonia into urea, which is then excreted through the urine. Carglumic acid acts as a CPS1 activator, improves or restores the function of the urea cycle, and facilitates ammonia detoxification and urea production.

11 DESCRIPTION Carglumic acid tablets for oral suspension contain 200 mg of carglumic acid. Carglumic acid, the active substance, is a carbamoyl phosphate synthetase 1 (CPS 1) activator and is soluble in boiling water, slightly soluble in cold water, and practically insoluble in organic solvents. The chemical name of carglumic acid is N-carbamoyl-L-glutamic acid or (2S)-2-(carbamoylamino) pentanedioic acid. The empirical formula is C 6 H 10 N 2 O 5 and the molecular weight is 190.16. The structural formula is: The inactive ingredients of Carglumic acid tablets for oral suspension are croscarmellose sodium, microcrystalline cellulose, colloidal silicon dioxide, sodium lauryl sulfate, sodium stearyl fumarate, magnesium stearate, mannitol and povidone. structure

10 OVERDOSAGE 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 secretions, increased body temperature, and restlessness. These symptoms resolved upon reduction of the dose.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Carglumic acid tablets for oral suspension 200 mg are white to off-white elongated tablets, functionally scored with 3 lines for splitting into 4 equal portions, and engraved 'N's on one side. Carglumic acid tablets for oral suspension is supplied in a high-density polyethylene bottle with a child resistant polypropylene cap and desiccant unit. Each bottle contains either 5 or 60 tablets. Bottle of 5 tablets: NDC 68475-006-01 Bottle of 60 tablets: NDC 68475-006-02 Storage Store at 20° to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. After first opening of the bottle: Store at room temperature between 15°C and 30°C (59°F and 86°F). Do not refrigerate. Keep the bottle tightly closed between openings in order to protect from moisture. Write the date of opening on the bottle. Do not use carglumic acid tablets for oral suspension after the expiration date stated on the bottle. Discard bottle one month after first opening.