Carbaglu Drug Information
Generic name: CARGLUMIC ACID
Carbamoyl Phosphate Synthetase 1 Activator [EPC]
Uses of Carbaglu
Acute and Chronic Hyperammonemia due to N‑acetylglutamate Synthase (NAGS) Deficiency
CARBAGLU 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 Propionic Acidemia (PA) or Methylmalonic Acidemia (MMA)
CARBAGLU is indicated in adult and pediatric patients as adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to PA or MMA.
Dosage & Administration of Carbaglu
| 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 CARBAGLU tablet) |
|---|---|
| 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 CARBAGLU tablet) |
| Acute Hyperammonemia due to PA or MMA |
|
Side Effects of Carbaglu
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 Adverse Reaction Number of Patients (N) (%) Vomiting 6 Abdominal pain 4 Pyrexia 4 Tonsillitis 4 Anemia 3 Diarrhea 3 Ear infection 3 Infections 3 Nasopharyngitis 3 Hemoglobin decreased 3 Headache 3 Dysgeusia 2 Asthenia 2 Hyperhidrosis 2 Influenza 2 Pneumonia 2 Weight decreased 2 Anorexia 2 Somnolence 2 Rash 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. CARBAGLU was administered at a dosage of 150 mg/kg/day for patients ≤15 kg or 3.3 g/m 2 /day for patients >15 kg, divided into 2 doses, for a median duration of 4.14 days.
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.
Table 2: Adverse Reactions (≥ 2%) During Hyperammonemic Episodes in Patients with PA or MMA Treated with CARBAGLU or Placebo Adverse Reaction Treatment Arm CARBAGLU N=42 episodes PLACEBO N=48 episodes N (%) N (%) Neutropenia 6 4 Anemia 5 4 Vomiting 3 1 Electrolyte imbalance 3 2 Decreased appetite 2 1 Hypoglycemia 2 1 Lethargy/Stupor 2 1 Encephalopathy 2 0 Pancreatitis/Lipase increased 2 0 Cardiomyopathy 1 0 Alanine aminotransferase increased 1 0 Aspartate aminotransferase increased 1 0 Infusion site extravasation 1 0 White blood cell count increased 1 0 Behavior disorder 1 0 Sleep disorder 1 0 Apnea 1 0 Hyperventilation 1 0
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of CARBAGLU. 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 Safety for Carbaglu
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 2% to 4% and 15% to 20%, 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 of Carbaglu
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.
Contraindications for Carbaglu
4. CONTRAINDICATIONS None None.
Overdosage Information for Carbaglu
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.
Clinical Studies of Carbaglu
Acute and Chronic Hyperammonemia due to
NAGS Deficiency The efficacy of CARBAGLU 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 CARBAGLU over a median duration of 7.9 years (range 0.6 to 20.8 years). For acute treatment, patients received CARBAGLU 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 CARBAGLU Patients N=23 Sex Male 14 (61%) Female 9 (39%) Age at initiation of CARBAGLU therapy (years) Mean (SD) 2 Min-Max 0-13 Age groups at initiation of CARBAGLU 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 CARBAGLU treatment and after long-term treatment with CARBAGLU and were evaluable. Table 5 summarizes the plasma ammonia levels at baseline, days 1 to 3 post-CARBAGLU treatment, and long-term CARBAGLU 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 CARBAGLU Timepoint Patients (N = 13) Ammonia level (micromol/L) Baseline (prior to first dose of CARBAGLU) N 13 Mean (SD) 271 Median 157 Range 72-1428 Missing Data 0 Day 1 N 10 Mean (SD) 181 Median 65 Range 25-1190 Missing Data 3 Day 2 N 8 Mean (SD) 69 Median 44 Range 11-255 Missing Data 5 Day 3 N 5 Mean (SD) 27 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 CARBAGLU treatment) N 13 Mean (SD) 23 Median 24 Range 9-34 Missing Data 0 The mean plasma ammonia level at baseline and the decline that is observed after treatment with CARBAGLU 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 CARBAGLU ammonia response chart
Acute Hyperammonemia due to PA and
MMA A randomized, double-blind, placebo-controlled, multicenter clinical trial evaluated the efficacy of CARBAGLU in the treatment of hyperammonemia in patients with PA and MMA (NCT01599286). Eligible hyperammonemic episodes, defined as an admission to the hospital with a plasma ammonia level ≥ 70 micromol/L, were randomized 1:1 to receive either CARBAGLU or placebo for 7 days or until hospital discharge, whichever occurred earlier. All patients received standard of care, including a combination of protein restriction, intravenous glucose, insulin, and/or L-carnitine; the use of alternative pathway medications (e.g., sodium benzoate and medications with phenylacetate as an active metabolite) was prohibited. CARBAGLU was dosed orally at 150 mg/kg/day for patients ≤ 15 kg or 3.3 g/m 2 /day for patients > 15 kg and was divided into 2 equal doses administered 12 hours apart by NG tube, G-tube, or oral syringe.
Plasma ammonia testing was performed at pre-randomization and at post-dosing intervals of every 6 -12 hours for the first 48 hours and every day thereafter if the ammonia level was ≥ 50 micromol/L. The efficacy evaluation was based on 90 hyperammonemic episodes (42 treated with CARBAGLU and 48 with placebo) in 24 patients (12 male and 12 female) with PA (n = 15) or MMA (n = 9). The median patient age was 8 years (range 4 days to 29 years). The primary endpoint was the time from the first dose of drug to the earlier of plasma ammonia level ≤ 50 micromol/L (normal range) or hospital discharge. The median time to reach the primary endpoint was 1.5 days in the CARBAGLU group compared to 2.0 days in the placebo group, a difference of 0.5 days (95% confidence interval: -1.2, 0.1), driven by an effect on plasma ammonia normalization. Throughout the first three days of treatment, a higher proportion of CARBAGLU-treated episodes reached the primary endpoint compared to placebo-treated episodes ( Figure 2 ). Figure 2: Episodes Reaching the Earlier of Plasma Ammonia Level ≤ 50 micromol/L or Hospital Discharge in Patients with PA or MMA Treated with CARBAGLU or Placebo for up to 7 days Figure 2
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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