® carglumic acid Making a Key Difference in NAGS Deficiency Carbaglu INDICATIONS AND USAGE CARBAGLU® (carglumic acid) is a Carbamoyl Phosphate Synthetase 1 (CPS1) activator indicated as: • Adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). During acute hyperammonemic episodes, concomitant administration of CARBAGLU with other ammonia lowering therapies, such as alternate pathway medications, hemodialysis, and dietary protein restriction, is recommended. • Maintenance therapy in pediatric and adult patients for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be needed based on plasma ammonia levels. IMPORTANT SAFETY INFORMATION • Most common adverse reactions (>9%) are: vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache. WHAT IS NAGS DEFICIENCY? N-acetylglutamate synthase (NAGS) deficiency is a rare, autosomal recessive urea cycle disorder.1,2 NAGS is an essential mitochondrial liver enzyme that triggers activation of the urea cycle. When NAGS is deficient, ammonia fails to convert to urea and accumulates in the blood, resulting in hyperammonemia.3,4 Rapid accumulation of ammonia and other precursor metabolites may result in cerebral edema with severe neurological complications.5,6 Fast and effective treatment is critical for improving the patient’s outcome.4,7 DIAGNOSING NAGS DEFICIENCY ASSESS CLINICAL SIGNS, SYMPTOMS, AND TRIGGERS NEONATAL (DAYS 1-28) ONSET 7,8,9 LATE ONSET 7,8 may present within the first few days can present at any age » » of life episodes may be triggered by infection, » symptoms traumatic injury, increased protein intake, » poor feeding or other metabolic stresses » vomiting symptoms » » somnolence, lethargy vomiting » » respiratory distress protein aversion » » sepsis-like symptoms confusion, lethargy » » acute encephalopathy psychiatric symptoms » » untreated hyperammonemia may lead to intellectual/learning disabilities » » irreversible brain damage or death CONDUCT LABORATORY EVALUATIONS Blood ammonia levels10: Normal blood ammonia levels, according to the Association of Clinical Biochemistry, are: • Premature neonates: < 150 µmol/L • Infants: < 40 µmol/L • Term neonates: < 100 µmol/L • Adults: 11-32 µmol/L Additional Lab Tests The causes of hyperammonemia are diverse; therefore, once elevated plasma ammonia is confirmed, other laboratory tests necessary for differential diagnosis should follow.9 Test results that may be helpful in diagnosing NAGS deficiency include8,9,11: Elevated plasma glutamine level Low plasma arginine level Low to normal plasma citrulline level Low to normal urine orotic acid level *Note: The biochemical profile of NAGS deficiency is identical to the profile for carbamoyl phosphate synthetase 1 (CPS1) deficiency.8 PERFORM DNA TEST TO CONFIRM DIAGNOSIS DNA testing to identify mutations in the coding region of the NAGS gene can provide final confirmation. It is important to note that conventional mutation analysis does not detect mutations in the regulatory region of the NAGS gene. Although rare, these mutations may result in disease expression in affected individuals.12 CARBAGLU® (carglumic acid) MECHANISM OF ACTION CARBAGLU is the synthetic structural analogue of N-acetylglutamate (NAG) and acts as the replacement for NAG in NAGS deficiency patients.13 Acetyl CoA + NAG acts as an essential activator of Glutamate carbamoyl phosphate synthetase 1 NAGS (CPS1), an enzyme that catalyzes the NH + 4 Mitochondrium first biochemical reaction of the urea 13 N-acetylglutamate cycle. CPS1 Carbamoyl Phosphate NAGS: N-acetylglutamate synthase CPS1: carbamoyl phosphate synthetase 1 OTC OTC: ornithine transcarbamylase Ornithine Citrulline ASS: argininosuccinate synthetase ASL: argininosuccinate lyase Ornithine Citrulline ARG: arginase Urea Aspartate ARG ASS Cytosol Arginine Argininosuccinic acid ASL URINE Fumarate CARBAGLU DOSAGE AND ADMINISTRATION CARBAGLU should be initiated as soon as the diagnosis of NAGS deficiency is suspected, which may be as soon as at birth, and managed by a physician and medical team experienced in metabolic disorders. DOSING • Acute hyperammonemia: The recommended initial pediatric and adult dosage is 100 mg/kg/day to 250 mg/kg/day. Titrate based on plasma ammonia level and clinical symptoms. • Maintenance for chronic hyperammonemia: The recommended pediatric and adult maintenance dosage is 10 mg/kg/day to 100 mg/kg/day. Titrate to target normal plasma ammonia level for age. • Divide the total daily dose into two to four doses. • Monitor plasma ammonia and adjust the dosage to maintain the level within the normal range for age. PREPARATION AND ADMINISTRATION • Disperse CARBAGLU tablets in water. Do not swallow whole or crushed. • Take immediately before meals or feedings. • For instructions on administration orally or through a nasogastric tube, see the full prescribing information. See Full Prescribing Information, including Instructions for Use, for more information about admin- istering CARBAGLU. IMPORTANT SAFETY INFORMATION • Hyperammonemia: Monitor plasma ammonia level during treatment. Prolonged exposure to elevated plasma ammonia level can result in brain injury or death. Prompt use of all therapies necessary to reduce plasma ammonia level is essential. CARBAGLU® (carglumic acid) EFFICACY AND SAFETY The efficacy of CARBAGLU was evaluated in a retrospective study of 23 NAGS deficiency patients (14 males and 9 females) who received treatment for a median of 7.9 years (range 0.6 to 20.8 years).13 AMMONIA RESPONSE13 • Subset of 13 patients selected based on well documented plasma ammonia levels prior to and after long-term treatment NH3 Response • All 13 patients had abnormal ammonia levels at baseline 300 (overall mean baseline plasma ammonia level was 271 250 micromol/L) 200 (µmol/L) • By day 3 of treatment with CARBAGLU, normal plasma 3 150 ammonia levels were attained in patients for whom data were 100 Mean NH available 50 0 Baseline Day 2 Day 4 Day 6 Long-term GLUTAMINE RESPONSE Days • In 16 of 23 patients, glutamine levels were elevated before 14 treatment Glutamine Response • Rapid normalization occurred within 24 to 48 hours after 1000 15 treatment with CARBAGLU 800 Patients on long-term maintenance therapy with CARBAGLU 600 experienced15: 400 Mean GLN (µmol/L) • minimal to no restriction on protein intake 200 • improvement in growth parameters 0 • improvement from a previously affected neurological status Baseline Day 2 Day 4 Day 6 Long-term Days • maintenance of normal neurological and psychomotor development IMPORTANT SAFETY INFORMATION • Most common adverse reactions (>9%) are: vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache. • 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. • Pregnancy: No human data; decreased survival and growth in animal offspring. • Nursing Mothers: Breastfeeding is not recommended while taking CARBAGLU. IMPORTANT SAFETY INFORMATION • Hyperammonemia: Monitor plasma ammonia level during treatment. Prolonged exposure to elevated plasma ammonia level can result in brain injury or death. Prompt use of all therapies necessary to reduce plasma ammonia level is essential. • Most common adverse reactions (>9%) are: vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache. • 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. • Pregnancy: No human data; decreased survival and growth in animal offspring. • Nursing Mothers: Breastfeeding is not recommended while taking CARBAGLU. REFERENCES 1. Caldovic L, Morizano H, Tuchman M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. 2007;28(8): 754-759. 2. Cartagena A, Prasad AN, Rupar CA, Strong M, Tuchman M, Ah Mew N, Prasad C. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can J Neurol Sci. 2013;40:3-9. 3. Caldovic L, Morizono H, Panglao MG, Lopez GY, Shi D, Summar ML, Tuchman M. Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles. Hum Mutat. 2005;25:293-298. 4. Gessler P, Buchal P, Schwenk HU, Wermuth B. Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency. Eur J Pediatr. 2010;169(2):197-199. 5. Ah Mew N, Lanpher BC, Gropman A, Chapman KA, Simpson KL, Urea Cycle Disorders Consortium, Summar ML. Urea cycle disorders overview. In Pagon RA, Adam MP, Ardinger HH et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2017. http://www.ncbi.nlm.nih.gov/ books/NBK1217. Updated June 22, 2017. Accessed November 20, 2017. 6. Roth KS. N-acytylglutamate synthetase deficiency. Medscape. http://emedicine.medscape.com/article/941090-overview. Updated Nov 17, 2014. Accessed November 20, 2017. 7. Summar M, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr. 2001; 138(suppl):6-10.