CARGLUMIC ACID

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 dimethyl formamide and sparingly soluble in water. 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, sodium lauryl sulfate, colloidal silicon dioxide and sodium stearyl fumarate. Image

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.

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 tablets for oral suspension) 15 mg/kg/day 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 tablets for oral suspension) Chronic Hyperammonemia due to NAGS Deficiency 5 mg/kg/day 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 tablets for oral suspension) 2 mg/kg/day 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 tablets for oral suspension) 2.5 Preparation and Administration Overview Disperse carglumic acid tablets for oral suspension in water. Do not swallow whole or crush. 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. Use of an Oral Syringe for Oral Administration For administration via an oral syringe, 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 tablets for oral suspension or each ½ or ¼ Carglumic acid tablets 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. 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. Use of Nasogastric Tube (NG Tube) or Gastrostomy Tube (G-Tube) for Feeding Tube Administration For patients who have a NG tube or G-tube in place, 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. 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. Flush the NG tube or G-tube again, as needed, until no pieces of the tablet are left in the syringe or the feeding tube.

None None.

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 Navinta LLC at 1-609-883-1135, 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