部份中文苯基丁酸钠处方资料（仅供参考） Ammonaps（苯基丁酸钠片） 药品名称 （包括商品名、通用名） 苯基丁酸钠 药品英文名 Sodium Phenylbutyrate 药品别名 苯基丁酸钠、Ammonaps、Buphenyl 药物剂型 片剂：500mg 药理作用 本药为乙酸苯酯的前体药物，主要用于尿素循环障碍的附加治疗。通过调整饮食中氮摄入量及使用本类药物以排泄体内的废氮产物，可以减少尿素循环障碍患者的尿素合成。其具体作用机制如下：本药在体内经β-氧化代谢成乙酸苯酯，乙酸苯酯继而与谷氨酰氨共轭生成苯乙酰谷氨酰氨，上述2步反应均较快而完全。苯乙酰谷氨酰氨作为尿素的替代废氮产物，可通过肾脏排泄，与尿素在摩尔水平上相比，两者每摩尔均含有2摩尔氮(即1摩尔本药也可以清除2摩尔氨基酸来源的氮)。据报道，使用本药治疗尿素循环障碍患者(联合控制饮食氮摄入量)，血氨及血谷氨酸水平可有降低甚至达正常水平。 药动学 本药片剂及粉剂口服后达峰时间分别为1.35h及1h，静脉注射达峰时间为30～60min。女性的苯丁酸及乙酸苯酯的血药浓度峰值及曲线下面积(AUC)高于男性(高30%～50%)，苯乙酰谷氨酰胺药动学未见明显性别差异。表观分布容积为0.2L/kg。主要经肝脏及肾脏迅速代谢为乙酸苯酯及苯乙酰谷氨酰氨。绝大部分药物可在24h内以苯乙酰谷氨酰氨的形式从尿中排泄，少量以药物本体及乙酸苯酯形式排泄(少于口服剂量的1%)。总体清除率为18mg/(kg·h)，母体化合物的消除半衰期为0.8h，乙酸苯酯的消除半衰期为1.2h。 适应证 用于尿素循环障碍的治疗。 禁忌证 1.对本药或乙酸苯酯过敏者。 2.禁用于急性高氨血症的紧急处理。 3.重度高血压、心力衰竭、肾功能不全者。 注意事项 1.本药片剂或粉剂应在进餐时服用，配方粉剂应与食物(固体或液体)混匀服用，并避免与酸性饮料同服。本药自身无臭，但经体内代谢的产物可引起身体异味，影响本药服药依从性(尤其是成人患者)。本药片剂适用于成人及体重20kg以上儿童。配方粉剂可用于口服、经胃造瘘术后、鼻饲。本药应为终身服用，除非通过肝移植进行治疗。 2.慎用： (1)轻、中度高血压、心力衰竭、肾功能不全者或其他与钠潴留有关的水肿状态。 (2)肝功能不全者。 (3)肥胖患者。 3.药物对儿童的影响：有报道儿童服用本药可产生无法预知的不良反应；儿童用药，其自身严重症状及脑损伤仍可能继续加剧。 4.药物对妊娠的影响：国内尚无孕妇用药相关资料，美国药品和食品管理局(FDA)对本药的妊娠安全性分级为C级。 5.药物对哺乳的影响：哺乳妇女用药研究尚不充分，应权衡利弊后用药。 6.用药前后及用药时应当检查或监测： (1)常规应监测血清蛋白及血浆中氨、谷氨酸、精氨酸水平。 (2)必要时应监测肝肾功、血清白蛋白、总蛋白、动脉血气分析、血电解质浓度，白细胞分类及计数，血小板计数、尿液分析。 7. 贮法：避光，室温保存。 不良反应 常见呼吸频率改变、情绪变化、肌肉疼痛或痉挛、恶心、呕吐、神经过敏或烦躁、踝部及外周水肿等。 国外不良反应参考： 1.心血管系统：可致踝部及外周水肿，血压改变较少见，罕见心律失常及昏厥。 2.精神神经系统：可致头痛及抑郁。3.代谢/内分泌系统：可引起低白蛋白血症(约10%)、代谢性酸中毒(14%)、碱中毒(7%)、高氯血症(7%)，也可致高尿酸血症、低钾血症、低磷血症、高磷血症、高钠血症(发生率低于6%)。 4.泌尿生殖系统：常引起女性月经周期不规则，甚至停经(发生率约23%)。罕见本药引起肾小管酸中毒。 5.肝脏：可引起血清氨基转移酶、胆红素、碱性磷酸酶水平升高，尚无本药致肝毒性的报道。 6.胃肠道：常见食欲缺乏(约4%)，还可引起味觉不佳、腹痛、恶心、呕吐、胃炎，罕见本药引起消化性溃疡、直肠出血、便秘、胰腺炎。 7.血液：可能引起贫血(包括再生障碍性贫血)、白细胞减少或增多、血小板减少，罕见本药引起血小板增多。 8.皮肤：偶有皮疹。 9.其他：本药服用后，可能引起身体异味。 用法用量 成人常规剂量： 口服给药：通常每日给药4～6次，进餐时服用，每日给药总量低于20g。一天给药总量超过20g的安全性及有效性尚未确定。 儿童常规剂量：口服给药：体重小于20kg儿童，一天450～600mg/kg，分4～6次给药，进餐时服用，每天给药总量低于20g。推荐服用苯丁酸钠粉，不推荐服用苯丁酸钠片。体重大于20kg者，用量同成人。 国外用法用量参考： 成人常规剂量：口服给药：一天9.9～13g/m2，一天总量超过20g的安全性及有效性尚未确定。肝功能不全时剂量：有实验表明，未患尿素循环障碍的肝功能不全者，本药的代谢及排泄不受影响，尚无资料建议肝功能不全者需调整剂量，但有待进一步研究。儿童常规剂量：口服给药：体重小于20kg儿童，一天450～600mg/kg；体重大于20k者，用量同成人。 药物相应作用 1.与氟哌啶醇、丙戊酸盐、皮质类固醇类药物合用，可能导致高氨血症，合用时应谨慎。 2.与丙磺舒合用可影响苯丁酸盐代谢产物的肾脏排泄，合用时应谨慎。 AMMONAPS 500 mg tablets AMMONAPS 940 mg/g granules ------------------------------------------------- AMMONAPS 500 mg tablets 1. Name of the medicinal product AMMONAPS 500 mg tablets. 2. Qualitative and quantitative composition Each tablet contains 500 mg sodium phenylbutyrate. Each AMMONAPS tablet contains 62 mg of sodium. For a full list of excipients, see section 6.1. 3. Pharmaceutical form Tablet. The tablets are off-white, oval and embossed with “UCY 500”. 4. Clinical particulars 4.1 Therapeutic indications AMMONAPS is indicated as adjunctive therapy in the chronic management of urea cycle disorders, involving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase or argininosuccinate synthetase. It is indicated in all patients with neonatal-onset presentation (complete enzyme deficiencies, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzyme deficiencies, presenting after the first month of life) who have a history of hyperammonaemic encephalopathy. 4.2 Posology and method of administration AMMONAPS treatment should be supervised by a physician experienced in the treatment of urea cycle disorders. The use of AMMONAPS tablets is indicated for adults and children who are able to swallow tablets. AMMONAPS is also available as granules for infants, children who are unable to swallow tablets and for patients with dysphagia. The daily dose should be individually adjusted according to the patient's protein tolerance and the daily dietary protein intake needed to promote growth and development. The usual total daily dose of sodium phenylbutyrate in clinical experience is: • 450 - 600 mg/kg/day in children weighing less than 20 kg • 9.9 - 13.0 g/m2/day in children weighing more than 20 kg, adolescents and adults. The safety and efficacy of doses in excess of 20 g/day (40 tablets) have not been established. Therapeutic monitoring: Plasma levels of ammonia, arginine, essential amino acids (especially branched chain amino acids), carnitine and serum proteins should be maintained within normal limits. Plasma glutamine should be maintained at levels less than 1,000 µmol/l. Nutritional management: AMMONAPS must be combined with dietary protein restriction and, in some cases, essential amino acid and carnitine supplementation. Citrulline or arginine supplementation is required for patients diagnosed with neonatal-onset form of carbamyl phosphate synthetase or ornithine transcarbamylase deficiency at a dose of 0.17 g/kg/day or 3.8 g/m2/day. Arginine supplementation is required for patients diagnosed with deficiency of argininosuccinate synthetase at a dose of 0.4 - 0.7 g/kg/day or 8.8 - 15.4 g/m2/day. If caloric supplementation is indicated, a protein-free product is recommended. The total daily dose of AMMONAPS should be divided into equal amounts and given with each meal (e.g. three times per day). The tablets should be taken with a large volume of water. 4.3 Contraindications − Pregnancy. − Breast-feeding. − Hypersensitivity to the active substance or to any of the excipients. 4.4 Special warnings and precautions for use AMMONAPS tablets should not be used in patients with dysphagia due to the potential risk of oesophageal ulceration if tablets are not promptly delivered to the stomach. Each AMMONAPS tablet contains 62 mg (2.7 mmol) of sodium, corresponding to 2.5 g (108 mmol) of sodium per 20 g of sodium phenylbutyrate, which is the maximum daily dose. AMMONAPS should therefore be used with caution in patients with congestive heart failure or severe renal insufficiency, and in clinical conditions where there is sodium retention with oedema. Since the metabolism and excretion of sodium phenylbutyrate involves the liver and kidneys, AMMONAPS should be used with caution in patients with hepatic or renal insufficiency. Serum potassium should be monitored during therapy since renal excretion of phenylacetylglutamine may induce a urinary loss of potassium. Even on therapy, acute hyperammonaemic encephalopathy may occur in a number of patients. AMMONAPS is not recommended for the management of acute hyperammonaemia, which is a medical emergency. In children unable to swallow tablets, it is recommended to use AMMONAPS granules instead. 4.5 Interaction with other medicinal products and other forms of interaction Concurrent administration of probenecid may affect renal excretion of the conjugation product of sodium phenylbutyrate. There have been published reports of hyperammonaemia being induced by haloperidol and by valproate. Corticosteroids may cause the breakdown of body protein and thus increase plasma ammonia levels. More frequent monitoring of plasma ammonia levels is advised when these medications have to be used. 4.6 Fertility, pregnancy and lactation Pregnancy The safety of this medicinal product for use in human pregnancy has not been established. Evaluation of experimental animal studies has shown reproductive toxicity, i.e. effects on the development of the embryo or the foetus. Prenatal exposure of rat pups to phenylacetate (the active metabolite of phenylbutyrate) produced lesions in cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number. The significance of these data in pregnant women is not known; therefore the use of AMMONAPS is contra-indicated during pregnancy (see section 4.3). Effective contraceptive measures must be taken by women of child-bearing potential. Lactation When high doses of phenylacetate (190 - 474 mg/kg) were given subcutaneously to rat pups, decreased proliferation and increased loss of neurons were observed, as well as a reduction in CNS myelin. Cerebral synapse maturation was retarded and the number of functioning nerve terminals in the cerebrum was reduced, which resulted in impaired brain growth. It has not been determined if phenylacetate is secreted in human milk and therefore the use of AMMONAPS is contra-indicated during lactation (see section 4.3). 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. 4.8 Undesirable effects In clinical trials with AMMONAPS, 56 % of the patients experienced at least one adverse event and 78 % of these adverse events were considered as not related to AMMONAPS. Adverse reactions mainly involved the reproductive and gastrointestinal system. The adverse reactions are listed below, by system organ class and by frequency. Frequency is defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Blood and lymphatic system disorders Common: Anaemia, thrombocytopenia, leukopenia, leukocytosis, thrombocytosis Uncommon: Aplastic anaemia, ecchymosis Metabolism and nutrition disorders Common: Metabolic acidosis, alkalosis, decreased appetite Psychiatric disorders Common: Depression, irritability Nervous system disorders Common: Syncope, headache Cardiac disorders Common: Oedema Uncommon: Arrhythmia Gastrointestinal disorders Common: Abdominal pain, vomiting, nausea, constipation, dysgeusia Uncommon: Pancreatitis, peptic ulcer, rectal haemorrhage, gastritis Skin and subcutaneous tissue disorders Common: Rash, abnormal skin odour Renal and urinary disorders Common: Renal tubular acidosis Reproductive system and breast disorders Very common: Amenorrhoea, irregular menstruation Investigations Common: Decreased blood potassium, albumin, total protein and phosphate. Increased blood alkaline phosphatase, transaminases, bilirubin, uric acid, chloride, phosphate and sodium. Increased weight. A probable case of toxic reaction to AMMONAPS (450 mg/kg/d) was reported in an 18-year old anorectic female patient who developed a metabolic encephalopathy associated with lactic acidosis, severe hypokalaemia, pancytopaenia, peripheral neuropathy, and pancreatitis. She recovered following dose reduction except for recurrent pancreatitis episodes that eventually prompted treatment discontinuation. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. 4.9 Overdose One case of overdose occurred in a 5-month old infant with an accidental single dose of 10 g (1370 mg/kg). The patient developed diarrhoea, irritability and metabolic acidosis with hypokalaemia. The patient recovered within 48 hours after symptomatic treatment. These symptoms are consistent with the accumulation of phenylacetate, which showed dose-limiting neurotoxicity when administered intravenously at doses up to 400 mg/kg/day. Manifestations of neurotoxicity were predominantly somnolence, fatigue and light-headedness. Less frequent manifestations were confusion, headache, dysgeusia, hypacusis, disorientation, impaired memory and exacerbation of a pre-existing neuropathy. In the event of an overdose, discontinue the treatment and institute supportive measures. Haemodialysis or peritoneal dialysis may be beneficial. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: various alimentary tract and metabolism products, ATC code: A16A X03. Sodium phenylbutyrate is a pro-drug and is rapidly metabolised to phenylacetate. Phenylacetate is a metabolically active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine which is then excreted by the kidneys. On a molar basis, phenylacetylglutamine is comparable to urea (each containing 2 moles of nitrogen) and therefore provides an alternate vehicle for waste nitrogen excretion. Based on studies of phenylacetylglutamine excretion in patients with urea cycle disorders it is possible to estimate that, for each gram of sodium phenylbutyrate administered, between 0.12 and 0.15 g of phenylacetylglutamine nitrogen are produced. As a consequence, sodium phenylbutyrate reduces elevated plasma ammonia and glutamine levels in patients with urea cycle disorders. It is important that the diagnosis is made early and treatment is initiated immediately to improve the survival and the clinical outcome. Previously, neonatal-onset presentation of urea cycle disorders was almost universally fatal within the first year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen-free analogues. With haemodialysis, use of alternative waste nitrogen excretion pathways (sodium phenylbutyrate, sodium benzoate and sodium phenylacetate), dietary protein restriction, and, in some cases, essential amino acid supplementation, the survival rate in new-borns diagnosed after birth (but within the first month of life) increased to almost 80 % with most deaths occurring during an episode of acute hyperammonaemic encephalopathy. Patients with neonatal-onset disease had a high incidence of mental retardation. In patients diagnosed during gestation and treated prior to any episode of hyperammonaemic encephalopathy, survival was 100 %, but even in these patients, many subsequently demonstrated cognitive impairment or other neurologic deficits. In late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, who recovered from hyperammonaemic encephalopathy and were then treated chronically with dietary protein restriction and sodium phenylbutyrate, the survival rate was 98 %. The majority of the patients who were tested had an IQ in the average to low average/borderline mentally retarded range. Their cognitive performance remained relatively stable during phenylbutyrate therapy. Reversal of pre-existing neurologic impairment is not likely to occur with treatment, and neurologic deterioration may continue in some patients. AMMONAPS may be required life-long unless orthotopic liver transplantation is elected. 5.2 Pharmacokinetic properties Phenylbutyrate is known to be oxidised to phenylacetate which is enzymatically conjugated with glutamine to form phenylacetylglutamine in the liver and kidney. Phenylacetate is also hydrolysed by esterases in liver and blood. Plasma and urine concentrations of phenylbutyrate and its metabolites have been obtained from fasting normal adults who received a single dose of 5 g of sodium phenylbutyrate and from patients with urea cycle disorders, haemoglobinopathies and cirrhosis receiving single and repeated oral doses up to 20 g/day (uncontrolled studies). The disposition of phenylbutyrate and its metabolites has also been studied in cancer patients following intravenous infusion of sodium phenylbutyrate (up to 2 g/m²) or phenylacetate. Absorption Phenylbutyrate is rapidly absorbed under fasting conditions. After a single oral dose of 5 g of sodium phenylbutyrate, in the form of tablets, measurable plasma levels of phenylbutyrate are detected 15 minutes after dosing. The mean time to peak concentration is 1.35 hour and the mean peak concentration 218 µg/ml. The elimination half-life was estimated to be 0.8 hours. The effect of food on absorption is unknown. Distribution The volume of distribution of phenylbutyrate is 0.2 l/kg. BiotransformationMetabolism After a single dose of 5 g of sodium phenylbutyrate, in the form of tablets, measurable plasma levels of phenylacetate and phenylacetylglutamine are detected 30 and 60 minutes respectively after dosing. The mean time to peak concentration is 3.74 and 3.43 hours, respectively, and the mean peak concentration is 48.5 and 68.5 µg/ml, respectively. The elimination half-life was estimated to be 1.2 and 2.4 hours, respectively. Studies with high intravenous doses of phenylacetate showed non linear pharmacokinetics characterised by saturable metabolism to phenylacetylglutamine. Repeated dosing with phenylacetate showed evidence of an induction of clearance. In the majority of patients with urea cycle disorders or haemoglobinopathies receiving various doses of phenylbutyrate (300 - 650 mg/kg/day up to 20 g/day) no plasma level of phenylacetate could be detected after overnight fasting. In patients with impaired hepatic function the conversion of phenylacetate to phenylacetylglutamine may be relatively slower. Three cirrhotic patients (out of 6) who received repeated oral administration of sodium phenylbutyrate (20 g/day in three doses) showed sustained plasma levels of phenylacetate on the third day that were five times higher than those achieved after the first dose. In normal volunteers gender differences were found in the pharmacokinetic parameters of phenylbutyrate and phenylacetate (AUC and Cmax about 30 - 50 % greater in females), but not phenylacetylglutamine. This may be due to the lipophilicity of sodium phenylbutyrate and consequent differences in volume of distribution. EliminationExcretion Approximately 80 - 100 % of the medicinal product is excreted by the kidneys within 24 hours as the conjugated product, phenylacetylglutamine. 5.3 Preclinical safety data Sodium phenylbutyrate was negative in 2 mutagenicity tests, i.e. the Ames test and the micronucleus test. Results indicate that sodium phenylbutyrate did not induce any mutagenic effects in the Ames test with or without metabolic activation. Micronucleus test results indicate that sodium phenylbutyrate was considered not to have produced any clastogenic effect in rats treated at toxic or non-toxic dose levels (examined 24 and 48 hours after a single oral administration of 878 to 2800 mg/kg). Carcinogenicity and fertility studies have not been conducted with sodium phenylbutyrate. 6. Pharmaceutical particulars 6.1 List of excipients Microcrystalline cellulose Magnesium stearate Colloidal anhydrous silica 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Do not store above 30°C. 6.5 Nature and contents of container HDPE bottles, with child resistant caps, containing 250 or 500 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Swedish Orphan Biovitrum International AB SE-112 76 Stockholm Sweden 8. Marketing authorisation number(s) EU/1/99/120/001 (250 tablets) EU/1/99/120/002 (500 tablets) 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 08/12/1999 Date of latest renewal: 08/12/2009 10. Date of revision of the text March 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/