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近日，美国食品药品监督管理局（FDA）批准Carbaglu(carglumic acid)片剂用于治疗高氨血症。 CARBAGLU（carglumic酸）片剂处方 美国首次批准：2010 [孤儿欧洲，SARL] 由于肝酶N-乙酰合成酶（NAGS）的不足之处治疗急性高氨血症的辅助治疗。 成人剂量和给药方法 推荐的初始剂量范围为急性高氨血症是100毫克/千克/天到250毫克/公斤/天。 小儿剂量和给药方法 推荐的初始剂量范围为急性高氨血症是100毫克/千克/天到250毫克/公斤/天。 其他食物和液体中的临床研究，因此不推荐。 禁忌 营养管理：在初始治疗NAGS缺乏，蛋白质限制的建议。当血氨水平是标准化的，通常是饮食中蛋白质的摄入量可以重新提出。 报告疑似不良反应，接触Accredo健康集团有限公司1-888-454-8860，或FDA在1-800-FDA-1088或www.fda.gov / medwatch。 人奶喂养哺乳母亲：不推荐使用。 日期：2012年5月
FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Acute hyperammonemia in patients with NAGS deficiency Carbaglu treatment should be initiated by a physician experienced in metabolic disorders. 2.1 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). 2.2 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. 2.3 Preparation for Nasogastric Tube Administration in Adults For patients who have a nasogastric tube in place, Carbaglu should be administered as follows:
2.4 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. 2.5 Preparation for Oral Administration Using an Oral Syringe in Pediatrics For administration via oral syringe, Carbaglu should be administered as follows:
2.6 Preparation for Nasogastric Tube Administration in Pediatrics For patients who have a nasogastric tube in place, Carbaglu should be administered as follows:
3 DOSAGE FORMS AND STRENGTHS Carbaglu is a white and elongated 200 mg tablet, scored and coded “C” on one side. None 5 WARNINGS AND PRECAUTIONS 5.1 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. 5.2 Therapeutic Monitoring Plasma ammonia levels should be maintained within normal range for age via individual dose adjustment. 5.3 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. 6 ADVERSE REACTIONS 6.1 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
No drug interaction studies have been performed. 8 USE IN SPECIFIC POPULATIONS 8.1 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. 8.3 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. 8.4 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. 8.5 Geriatric Use Carbaglu has not been studied in the geriatric population. Therefore, the safety and effectiveness in geriatric patients have not been established. 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). 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. 12.1 Mechanism of Action Carglumic acid is a synthetic structural analogue of N-acetylglutamate (NAG), which is an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1) in liver mitochondria. CPS 1 is the first enzyme of the urea cycle, which converts ammonia into urea. NAG is the product of N-acetylglutamate synthase (NAGS), a mitochondrial enzyme. Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS 1. 12.2 Pharmacodynamics In a retrospective review of the clinical course in 23 patients with NAGS deficiency, carglumic acid reduced plasma ammonia levels within 24 hours when administered with and without concomitant ammonia lowering therapies. No dose response relationship has been identified. 12.3 Pharmacokinetics The pharmacokinetics of carglumic acid has been studied in healthy male volunteers using both radiolabeled and non-radiolabeled carglumic acid. Absorption The median Tmax of Carbaglu was 3 hours (range: 2-4). Absolute bioavailability has not been determined. Distribution The apparent volume of distribution was 2657 L (range: 1616-5797). Protein binding has not been determined. Metabolism A proportion of carglumic acid may be metabolized by the intestinal bacterial flora. The likely end product of carglumic acid metabolism is carbon dioxide, eliminated through the lungs. Elimination Median values for the terminal half-life was 5.6 hours (range 4.3-9.5), the apparent total clearance was 5.7 L/min (range 3.0-9.7), the renal clearance was 290 mL/min (range 204-445), and the 24-hour urinary excretion was 4.5% of the dose (range 3.5-7.5). Following administration of a single radiolabeled oral dose of 100 mg/kg of body weight, 9% of the dose was excreted unchanged in the urine and up to 60% of the dose was excreted unchanged in the feces. 13.1 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. 14.1 Responses of Patients with NAGS Deficiency to Acute and Chronic Treatment
The clinical observations in the 23 patient case series were retrospective, unblinded and uncontrolled and preclude any meaningful formal statistical analyses of the data. However, short-term efficacy was evaluated using mean and median change in plasma ammonia levels from baseline to days 1 to 3. Persistence of efficacy was evaluated using long-term mean and median change in plasma ammonia level. Table 3 summarizes the plasma ammonia levels at baseline, days 1 to 3 post-Carbaglu treatment, and long-term Carbaglu treatment for 13 evaluable patients. Of the 23 NAGS deficiency patients who received treatment with Carbaglu, a subset of 13 patients who had both well documented plasma ammonia levels prior to Carbaglu treatment and after long-term treatment with Carbaglu were selected for analysis. Table 3: Plasma ammonia levels at baseline and after treatment with Carbaglu
*13/23 patients with complete short-term and long-term plasma ammonia documentation 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: Ammonia response for 13 evaluable NAGS deficiency patients at baseline and after treatment with Carbaglu 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Carbaglu is a white and elongated tablet, scored and coded “C” on one side. NDC 52276-312-05 Bottle of 5 tablets 卡谷氨酸片Carbaglu—高氨血症患者新希望 高氨血症为罕见的遗传性疾病，是由于乙酰谷氨酸合酶（NAGS）缺乏所致的一种极为罕见的、持续终生并可危及生命的临床疾病，表现为血氨极度升高，进而引发永久性的中枢神经系统损害，不及时治疗NAGS缺乏引起的高氨血症会危及患者生命。 2010年3月，意大利Recordati公司血液疾病治疗新药Carbaglu(卡谷氨酸片剂)获美国FDA批准，用于急性高氨血症的辅助治疗及慢性高氨血症的维持治疗。卡谷氨酸片治疗急性高氨血症的初次剂量建议为100至250mg/kg*d。 药理显示，卡谷氨酸片剂可变构活化性线粒体内的氨甲酰磷酸合酶1，在酶促作用下将氨转化化为尿素排出体外，给药24小时内能有效降低体内氨水平。 一项用药期为6个月-21年不等的包含23名NAGS缺乏患者的临床研究评估了Carbaglu的安全性和有效性。在这些患者在24小时内开始使血氨水平降低，并在3天内降至标准水平。大多数患者的用药结果显示，长期使用Carbaglu可使血氨浓度维持在正常水平。 卡谷氨酸片常见的不良反应有呕吐、腹痛、发热、扁桃体炎、贫血、耳部感染、腹泻、鼻咽喉炎症和头痛。 高氨血症是临床难治性疾病，目前缺乏根治性药物，运用药物控制患者体内血氨浓度是最主要有效的方法，Carbaglu(卡谷氨酸片)的出现，给高氨血症患者带来了新的希望。卡谷氨酸片有望能更有效的控制病情，延长患者生命，提高患者生活质量。
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卡谷氨酸片剂|CARBAGLU(carglumic acid Tablet）简介：
近日，美国食品药品监督管理局（FDA）批准Carbaglu(carglumic acid)片剂用于治疗高氨血症。人体因N-乙酰谷氨酸合酶（NAGS）缺乏而导致体内血氨水平较高，从而导致永久性的中枢神经系统损害，为罕见的遗 ... 责任编辑：admin |
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