Carbaglu

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. (
  1.1 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.
  )
• Maintenance therapy for the treatment of chronic hyperammonemia due to NAGS deficiency. (
  1.1 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.
  )
• Adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA). (
  1.2 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.
  )

Tablets for oral suspension: 200 mg of carglumic acid, white, elongated, functionally scored with 3 lines (for splitting into 4 equal portions) and printed "C" on one side.

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.

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).

• 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 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 1summarizes 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 (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)

  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 (7.7) and 12 (50 %) were males.

  CARBAGLU was administered at a dosage of 150 mg/kg/day for patients ≤15 kg or 3.3 g/m²/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 2summarizes 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 (14)	4 (8)
  Anemia	5 (12)	4 (8)
  Vomiting	3 (7)	1 (2)
  Electrolyte imbalance	3 (7)	2 (4)
  Decreased appetite	2 (5)	1 (2)
  Hypoglycemia	2 (5)	1 (2)
  Lethargy/Stupor	2 (5)	1 (2)
  Encephalopathy	2 (5)	0 (0)
  Pancreatitis/Lipase increased	2 (5)	0 (0)
  Cardiomyopathy	1 (2)	0 (0)
  Alanine aminotransferase increased	1 (2)	0 (0)
  Aspartate aminotransferase increased	1 (2)	0 (0)
  Infusion site extravasation	1 (2)	0 (0)
  White blood cell count increased	1 (2)	0 (0)
  Behavior disorder	1 (2)	0 (0)
  Sleep disorder	1 (2)	0 (0)
  Apnea	1 (2)	0 (0)
  Hyperventilation	1 (2)	0 (0)
  )
• PA and MMA
  : Most common adverse reactions (≥5%) are neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased. (
  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 1summarizes 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 (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)

  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 (7.7) and 12 (50 %) were males.

  CARBAGLU was administered at a dosage of 150 mg/kg/day for patients ≤15 kg or 3.3 g/m²/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 2summarizes 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 (14)	4 (8)
  Anemia	5 (12)	4 (8)
  Vomiting	3 (7)	1 (2)
  Electrolyte imbalance	3 (7)	2 (4)
  Decreased appetite	2 (5)	1 (2)
  Hypoglycemia	2 (5)	1 (2)
  Lethargy/Stupor	2 (5)	1 (2)
  Encephalopathy	2 (5)	0 (0)
  Pancreatitis/Lipase increased	2 (5)	0 (0)
  Cardiomyopathy	1 (2)	0 (0)
  Alanine aminotransferase increased	1 (2)	0 (0)
  Aspartate aminotransferase increased	1 (2)	0 (0)
  Infusion site extravasation	1 (2)	0 (0)
  White blood cell count increased	1 (2)	0 (0)
  Behavior disorder	1 (2)	0 (0)
  Sleep disorder	1 (2)	0 (0)
  Apnea	1 (2)	0 (0)
  Hyperventilation	1 (2)	0 (0)
  )

CARBAGLU 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 C₆H₁₀N₂O₅ and the molecular weight is 190.16.

The structural formula is:

The inactive ingredients of CARBAGLU are croscarmellose sodium, hypromellose, microcrystalline cellulose, silica colloidal anhydrous, sodium lauryl sulfate, and sodium stearyl fumarate.