DailyMed Label: Carglumic Acid

DailyMed Label: Carglumic Acid

2024

DailyMed Prescription

Carglumic Acid

Carglumic Acid

Eton Pharmaceuticals, Inc.

NDC: 71863-114

NDC: 71863-114

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.

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)

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 Full Prescribing Information.

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.

None

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).

How Supplied Carglumic Acid Tablet for Oral Suspension is supplied as a white to off-white elongated 200 mg tablet for oral suspension, functionally scored with 3 lines for splitting into 4 equal portions, and coded "120" on one side and ''N" on other side. Carglumic Acid Tablets for Oral Suspension are supplied in a high density polyethylene bottle with a child resistant cap and desiccant unit. Each bottle contains 60 tablets. Bottles of 60 tablets: NDC 71863-114-60 Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] in the original unopened bottle. After first opening of the container: Store at room temperature between 20° to 25°C (68° to 77°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 after 90 days from first opening.

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.

The carcinogenic potential of carglumic acid was assessed in a 2-year carcinogenicity study in rats. Carglumic acid was not tumorigenic at oral doses up to 1000 mg/kg/day (approximately 34 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC). Carglumic acid was negative in the Ames test, chromosomal aberration assay in human lymphocytes, and the in vivo micronucleus assay in rats. There were no effects on fertility or reproductive performance in female rats at oral doses up to 2000 mg/kg/day (approximately 38 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC). In a separate study, mating and fertility were unaffected in male rats at oral doses up to 1000 mg/kg/day (approximately 34 times the maximum reported human maintenance dose [100 mg/kg/day] based on AUC).

The efficacy of Carglumic acid tablets for oral suspension in the treatment of acute and chronic hyperammonemia due to NAGS deficiency was evaluated in a retrospective case series of 23 NAGS deficiency patients treated with Carglumic acid tablets for oral suspension over a median duration of 7.9 years (range 0.6 to 20.8 years). For acute treatment, patients received Carglumic acid tablets for oral suspension at 100 mg/kg/day to 250 mg/kg/day orally administered in 2 to 4 divided doses. For maintenance treatment, the dosage was reduced over time based on plasma ammonia level and clinical response. The baseline characteristics of the patient population are shown in Table 5. Table 5: Baseline Characteristics of 23 NAGS Deficiency Patients Treated with Carglumic acid tablets for oral suspension  Patients N=23  Sex  Male  14 (61%)  Female  9 (39%)  Age at initiation of Carglumic acid tablets for oral suspension therapy (years)  Mean (SD)  2 (4)  Min-Max  0-13  Age groups at initiation of Carglumic acid tablets for oral suspension therapy  <30 days  9 (39%)  >30 days - 11 months  9 (39%)  ≥1 - 13 years  5 (22%)  NAGS gene mutations by DNA testing  Homozygous  14 (61%)  Heterozygous  4 (17%)  Not available  5 (22%)  Patients current treatment status  On-going  18 (78%)  Discontinued  5 (22%) The clinical and biochemical data in the 23-patient case series were retrospectively collected, unblinded, and uncontrolled and preclude formal statistical testing. Short-term efficacy was evaluated using mean and median change in plasma ammonia levels from baseline to days 1 to 3. Persistence of the effect was evaluated using long-term mean and median change in plasma ammonia level. Of the 23 NAGS deficiency patients in the case series, 13 patients had documented plasma ammonia levels prior to Carglumic acid tablets for oral suspension treatment and after long-term treatment with Carglumic acid tablets for oral suspension and were evaluable. Table 5 summarizes the plasma ammonia levels at baseline, days 1 to 3 post- Carglumic acid tablets for oral suspension treatment, and long-term Carglumic acid tablets for oral suspension treatment (mean 8 years) in the 13 evaluable patients. All 13 patients had increased plasma ammonia levels at baseline (mean 271 micromol/L; normal range: 5 to 50 micromol/L). By day 3 and with long-term treatment, normal plasma ammonia levels were attained (Table 6). Table 6: Plasma Ammonia Levels in NAGS Deficiency Patients at Baseline and After Treatment with Carglumic acid tablets for oral suspension Timepoint Patients (N = 13) Ammonia level (micromol/L) Baseline (prior to first dose of Carglumic acid tablets for oral suspension) N 13 Mean (SD) 271 (359) Median 157 Range 72-1428 Missing Data 0 Day 1 N 10 Mean (SD) 181 (358) Median 65 Range 25-1190 Missing Data 3 Day 2 N 8 Mean (SD) 69 (78) Median 44 Range 11-255 Missing Data 5 Day 3 N 5 Mean (SD) 27 (11) Median 25 Range 12-42 Missing Data 8 Long-term treatment (mean duration 8 years; median duration 6 years; range 1-16 years based on last available value while on Carglumic acid tablets for oral suspension treatment) N 13 Mean (SD) 23 (7) Median 24 Range 9-34 Missing Data 0 The mean plasma ammonia level at baseline and the decline that is observed after treatment with Carglumic acid tablets for oral suspension in 13 evaluable patients with NAGS deficiency is illustrated in Figure 1. Figure 1: Mean Plasma Ammonia in 13 Evaluable NAGS Deficiency Patients at Baseline and After Treatment with Carglumic acid tablets for oral suspension

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