Drug: Carbaglu

Carbaglu tablets for oral administration 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, practically insoluble in organic solvents. Chemically carglumic acid is N-carbamoyl-L-glutamic acid or (2S)-2-(carbamoylamino) pentanedioic acid, with a molecular weight of 190.16. The structural formula is: Molecular Formula: C6H10N2O5 The inactive ingredients of Carbaglu are microcrystalline cellulose, sodium lauryl sulfate, hypromellose, croscarmellose sodium, silica colloidal anhydrous, sodium stearyl fumarate.

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Retrospective Case Series Experience The most common adverse reactions (occurring in ≥ 13% of patients), regardless of causality, are: Infections, vomiting, abdominal pain, pyrexia, tonsilitis, anemia, ear infection, diarrhea, nasopharyngitis, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with Carbaglu in the retrospective case series. Because these reactions were reported retrospectively, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Table 1: Adverse Reactions Reported in ≥ 2 Patients in the Retrospective Case Series treated with Carbaglu
System Organ Class Preferred Term Number of Patients
(N) (%) TOTAL 23 (100) Blood and lymphatic system disorders   Anemia 3 (13) Ear and labyrinth disorders   Ear infection 3 (13) Gastrointestinal disorders   Abdominal pain 4 (17)   Diarrhea 3 (13)   Vomiting 6 (26)   Dysgeusia 2 (9) General disorders and administration site conditions   Asthenia 2 (9)   Hyperhidrosis 2 (9)   Pyrexia 4 (17) Infections and infestations   Infection 3 (13)   Influenza 2 (9)   Nasopharyngitis 3 (13)   Pneumonia 2 (9)   Tonsillitis 4 (17) Investigations   Hemoglobin decreased 3 (13)   Weight decreased 2 (9) Metabolism and nutrition disorders   Anorexia 2 (9) Nervous system disorders   Headache 3 (13)   Somnolence 2 (9) Skin and subcutaneous tissue disorders   Rash 2 (9) Read the Carbaglu (carglumic acid tablets) Side Effects Center for a complete guide to possible side effectsLearn More »

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Carbaglu treatment should be initiated by a physician experienced in metabolic disorders. Adult Dosage and Administration The recommended initial dose for acute hyperammonemia is 100 mg/kg/day to 250 mg/kg/day. Concomitant administration of other ammonia lowering therapies is recommended. Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms. The recommended maintenance dose should be titrated to target normal plasma ammonia level for age. Based on limited data in 22 patients receiving maintenance treatment with Carbaglu in a retrospective case series, maintenance doses were usually less than 100 mg/kg/day. The total daily dose should be divided into 2 to 4 doses and rounded to the nearest 100 mg (i.e., half of a Carbaglu Tablet). Preparation for Oral Administration in Adults Carbaglu tablets should not be swallowed whole or crushed. Disperse Carbaglu tablets in water immediately before use. Each 200 mg tablet should be dispersed in a minimum of 2.5 mL of water and taken immediately. Carbaglu tablets do not dissolve completely in water and undissolved particles of the tablet may remain in the mixing container. To ensure complete delivery of the dose, the mixing container should be rinsed with additional volumes of water and the contents swallowed immediately. USE IN OTHER FOODS AND LIQUIDS HAS NOT BEEN STUDIED CLINICALLY AND IS THEREFORE NOT RECOMMENDED. Preparation for Nasogastric Tube Administration in Adults For patients who have a nasogastric tube in place, Carbaglu should be administered as follows:
  • Mix each 200 mg tablet in a minimum of 2.5 mL of water. Shake gently to allow for quick dispersal.
  • Administer the dispersion immediately through the nasogastric tube
  • Flush with additional water to clear the nasogastric tube.
Pediatric Dosage and Administration The recommended initial dose for acute hyperammonemia is 100 mg/kg/day to 250 mg/kg/day. Concomitant administration of other ammonia lowering therapies is recommended. Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms. The recommended maintenance dose should be titrated to target normal plasma ammonia level for age. Based on limited data in 22 patients receiving maintenance treatment with Carbaglu in a retrospective case series, maintenance doses were usually less than 100 mg/kg/day. The total daily dose should be divided into 2 to 4 doses. Preparation for Oral Administration Using an Oral Syringe in Pediatrics For administration via oral syringe, Carbaglu should be administered as follows:
  • Mix each 200 mg tablet in 2.5 mL of water to yield a concentration of 80 mg/mL in a mixing container. Shake gently to allow for quick dispersal.
  • Draw up the appropriate volume of dispersion in an oral syringe and administer immediately. Discard the unused portion.
  • Refill the oral syringe with a minimum volume of water (1-2 mL) and administer immediately.
Preparation for Nasogastric Tube Administration in Pediatrics For patients who have a nasogastric tube in place, Carbaglu should be administered as follows:
  • Mix each 200 mg tablet in 2.5 mL of water to yield a concentration of 80 mg/mL in a mixing container. Shake gently to allow for quick dispersal.
  • Draw up the appropriate volume of dispersion and administer immediately through a nasogastric tube. Discard the unused portion.
  • Flush with additional water to clear the nasogastric tube.

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No information provided. Last reviewed on RxList: 8/16/2013
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Acute hyperammonemia in patients with NAGS deficiency Carbaglu is indicated as an 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 are recommended. Maintenance therapy for chronic hyperammonemia in patients with NAGS deficiency Carbaglu is indicated for maintenance therapy in pediatric and adult patients for chronic hyperammonemia due to the deficiency of the hepatic enzyme Nacetylglutamate synthase (NAGS). During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be reduced or discontinued based on plasma ammonia levels.

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NoneLast reviewed on RxList: 8/16/2013
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

One patient treated with 650 mg/kg/day of carglumic acid developed symptoms characterized as a monosodium glutamate intoxication-like syndrome: tachycardia, profuse sweating, increased bronchial secretion, increased body temperature and restlessness. These symptoms resolved upon reduction of dose. Repeated oral dosing of carglumic acid at 2000 mg/kg/day was lethal to most neonatal rats within 2-3 days of treatment. In adult rats, a single oral administration of carglumic acid was not lethal at doses up to 2800 mg/kg (1.8 times the maximum recommended starting dose based on a body surface area comparison to adult humans).

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Dosage Forms And Strengths Carbaglu is a white and elongated 200 mg tablet, scored and coded “C” on one side. Storage And Handling Carbaglu is a white and elongated tablet, scored and coded “C” on one side. Each tablet contains 200 mg of carglumic acid. Carbaglu is available in 5 or 60 tablets in a polypropylene bottle with polyethylene cap and desiccant unit. NDC 52276-312-05 Bottles of 5 tablets
NDC 52276-312-60 Bottles of 60 tablets Storage Before opening, store refrigerated at 2 – 8 °C (36 – 46 °F). After first opening of the container:
  • Do not refrigerate, do not store above 30 °C (86 °F).
  • Keep the container tightly closed in order to protect from moisture.
  • Write the date of opening on the tablet container.
  • Do not use after the expiration date stated on the tablet container.
  • Discard one month after first opening.
Manufactured For: Orphan Europe SARL, Paris, France. Distributed by: Accredo Health Group, Inc. 1680 Century Center Parkway Memphis, Tennessee 38134. Revised: August 2013Last reviewed on RxList: 8/16/2013
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Hyperammonemia Any episode of acute symptomatic hyperammonemia should be treated as a life-threatening emergency. Treatment of hyperammonemia may require dialysis, preferably hemodialysis, to remove a large burden of ammonia. Uncontrolled hyperammonemia can rapidly result in brain injury/damage or death, and prompt use of all therapies necessary to reduce plasma ammonia levels is essential. Management of hyperammonemia due to NAGS deficiency should be done in coordination with medical personnel experienced in metabolic disorders. Ongoing monitoring of plasma ammonia levels, neurological status, laboratory tests and clinical responses in patients receiving Carbaglu is crucial to assess patient response to treatment. Therapeutic Monitoring Plasma ammonia levels should be maintained within normal range for age via individual dose adjustment. Nutritional Management Since hyperammonemia is the result of protein catabolism, complete protein restriction is recommended to be maintained for 24 to 48 hours and caloric supplementation should be maximized to reverse catabolism and nitrogen turnover. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with carglumic acid. 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 (1.3 times the maximum recommended human starting dose based on body surface area). In a separate study, mating and fertility were unaffected in male rats at oral doses up to 1000 mg/kg/day (0.6 times the maximum recommended human starting dose based on body surface area). Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well controlled studies or available human data with Carbaglu® in pregnant women. Decreased survival and growth occurred in offspring born to animals that received carglumic acid at doses similar to the maximum recommended starting human dose during pregnancy and lactation. Because untreated N-acetylglutamate synthase (NAGS) deficiency results in irreversible neurologic damage and death, women with NAGS must remain on treatment throughout pregnancy. In embryo-fetal developmental toxicity studies, pregnant rats and rabbits received oral carglumic acid during organogenesis at doses up to 1.3 times the maximum recommended human starting dose based on body surface area (mg/m²). Actual doses were 500 and 2000 mg/kg/day (rats) and 250 and 1000 mg/kg/day (rabbits). The high doses resulted in maternal toxicity in both rats and rabbits. No effects on embryo-fetal development were observed in either species. In a peri-and post-natal developmental study, female rats received oral carglumic acid from organogenesis through day 21 post-partum at doses up to 1.3 times the maximum recommended starting human dose based on body surface area (mg/m²). Actual doses were 500 and 2000 mg/kg/day. A reduction in offspring survival was seen at the high dose and a reduction in offspring growth was seen at both doses. Nursing Mothers It is not known whether Carbaglu® is excreted in human milk. Carglumic acid is excreted in rat milk, and an increase in mortality and impairment of body weight gain occurred in neonatal rats nursed by mothers receiving carglumic acid. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Carbaglu®, human milk-feeding is not recommended. Treatment is continuous and life-long for NAGS deficiency patients. Pediatric Use The efficacy of Carbaglu for the treatment of hyperammonemia in patients with NAGS deficiency from birth to adulthood was evaluated in a retrospective review of the clinical course of 23 NAGS deficiency patients who all began Carbaglu treatment during infancy or childhood. There are no apparent differences in clinical response between adults and pediatric NAGS deficiency patients treated with Carbaglu, however, data are limited. Geriatric Use Carbaglu has not been studied in the geriatric population. Therefore, the safety and effectiveness in geriatric patients have not been established Last reviewed on RxList: 8/16/2013
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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