Carbaglu

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

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 ) 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, 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 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 (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/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 (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) 6.2 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