英文药名：ORFADIN Capsules(nitisinone) 中文药名：尼替西农胶囊（别名：欧佛定） 生产厂家：Swedish Orphan 药品介绍 美国食品及药品管理局(Food and Drug Administration)批准了一种称为“nitisinone胶囊”的新的药物。它能够治疗一种罕见的、可引起进展性肝衰和肝癌的儿科疾病——I型遗传性酪氨酸血症(HT-1)。 美国的I型遗传性酪氨酸血症(HT-1)患儿少于100例。如果不进行肝移植的话,HT-1患儿将因肝衰和肝癌在20岁前死亡。但是,如果患儿早期足量服用nitisinone,肝衰和肝癌的发病率明显降低。超过180例患儿参与研究,开始治疗的平均年龄为9个月。同时采用药物与限制饮食时,出生后2个月内确诊的患儿的4年存活率为88%。文献表明,仅采用限制饮食进行治疗的同期存活率为29%。应用nitisinone时,饮食必须限制酪氨酸和苯丙氨酸。高酪氨酸水平对眼、皮肤和神经系统具有毒性作用。该药的最常见副作用与患儿进食不当引起的酪氨酸水平升高有关。除此之外,还有少量病例出现血小板和白细胞计数的轻度降低。 FDA指出,nitisinone应由具有治疗I型遗传性酪氨酸血症经验的医师开具处方,每例患儿都应按照特异性生化检验调整到合适的剂量。他们补充说,治疗中非常重要的一部分就是,应由营养学医师为具有先天性代谢缺陷的患儿制订合适的低蛋白食物。 研发与上市厂商 瑞典Swedish Orphan公司研制开发，2002年4月首次在美国上市。 商品名 Orfadin 适应证 本品适用于罕见儿科1型遗传性酪氨酸血症 (HT-1) 的治疗。作为酪氨酸和苯丙氨酸饮食限制的辅助用药。 药理 本品是羟苯丙酮酸二氧酶的竞争性抑制剂，该酶在酪氨酸分解代谢途径中可上调延胡索酰乙酰乙酸酶(FAH)。通过抑制HT-1患者酪氨酸的正常代谢，本品可预防代谢中间体马来酰乙酰乙酸盐和延胡索酰乙酰乙酸盐的累积。在HT-1患者中，这些代谢中间体被转换成毒性代谢物琥珀酰丙酮和琥珀酰乙酰乙酸盐，造成肝、肾毒性。琥珀酰丙酮还可抑制卟啉合成途径，导致5-氨基酮戊酸盐积累。作为羟苯丙酮酸二氧酶抑制剂，推测受本品影响的生化学参数包括尿琥珀酰丙酮、血浆琥珀酰丙酮和胆色素原 (PBG) 合酶的活性。 大鼠口服本品生物利用度在90%以上，且分布于各器官中，特别是在肝脏和肾脏，在这2个脏器中放射活性保持至给药后7天。在大鼠体内，本品经生物转换后经尿液排泄。 在19～39岁 (中位数32岁) 的健康男性志愿者中进行了本品单一剂量的药动学研究。以胶囊或液体制剂形式给予本品1mg/kg，血药浓度达峰时间分别为：胶囊制剂3小时，液体制剂15分钟。以药时曲线下面积和最大血药浓度分析，胶囊和液体制剂是生物等效的。平均终末半衰期为54小时。 临床评价 生化学作用 在25个国家的87家医院进行了一项开放性研究，为期6年以上，有207例HT-1患者参与，患者年龄中位数为9个月 (刚出生至21.7岁)。大多数患者 (87%) 的血浆琥珀酰丙酮水平减低到参照水平 (可检测水平) 以下，正常化时间的中位数为3.9个月；180例患者的PBG合酶活性增加到参照水平 (可检测水平) 内，正常化时间的中位数为0.3个月，这些参数的变化与治疗前相比具统计学意义 (P<0.001)。 对总体存活率的影响 数据显示，2个月以下单用饮食限制方法治疗的HT-1患者，2和4年的存活率均为29%。而本研究中，2个月以下接受饮食限制和本品治疗的患者，2和4年的存活率均为88%；6个月以下单用饮食限制方法治疗的HT-1患者，2和4年存活率分别为74%和60%，而本研究中，6个月以下接受饮食限制和本品治疗的HT-1患者的相应存活率均为94%。 不良反应 在用本品治疗的207例HT-1患者中，最常见的不良反应涉及肝胆系统 (肝肿瘤8%，肝功能衰竭7%)、视觉系统 (结膜炎2%，角膜混浊2%，畏光2%，眼睑炎1%，眼痛1%，白内障1%)、血液和淋巴系统(血小板减少3%，粒细胞减少3%，鼻衄1%)、皮肤系统(瘙痒1%，剥落性皮炎1%，斑丘疹1%，脱发1%)。 其他低于1%的不良反应包括死亡、癫痫、脑肿瘤、头痛、运动过度、紫绀、腹痛、腹泻、胃肠炎、消化道出血、牙齿变色、肝酶水平升高、肝功能障碍、肝肿大、脱水、低血糖、口渴、感染、败血症、支气管炎、呼吸衰竭、病理性骨折、停经、神经质和嗜睡。 注意事项 未适当限制酪氨酸和苯丙氨酸的摄入可导致血浆酪氨酸水平升高。血浆酪氨酸水平必须保持低于500mmol/L，以避免对眼 (角膜溃疡、角膜混浊、角膜炎、结膜炎、眼痛和畏光)、皮肤 (足底和手掌痛性过度角化) 和神经系统 (不同程度的智力低下和发育迟缓)的毒性作用。对于大多数患者，眼部症状是暂时的，持续不超过1周。有6例患者发病延续16～672天。本品治疗期间需进行眼科检查，如有不良反应症状出现，需立即检查血浆酪氨酸浓度。如果血浆酪氨酸水平超过500mmol/L，须采取更为严格的饮食限制。本品的剂量需进行调整以降低血浆酪氨酸浓度。 在用本品和饮食限制治疗的患者中观察到发生一过性血小板减少(3%)、粒细胞减少 (3%) 或两者同时发生 (1.5%)，其中1例发生这2种不良反应的患者在本品剂量从2mg/kg减少至1mg/kg后症状改善，另1例血小板减少的患者停药2周，血小板计数在其后的3个月里继续下降，5个月后逐渐恢复正常，其余患者的血小板和粒细胞计数在未改变本品剂量的情况下均逐渐正常化。此外，未见因这2种不良反应而发生感染或出血。本品治疗期间建议常规监测血小板和粒细胞计数。另外，还应常规监测肝功能。 用量与用法 本品的用量需个体化。推荐的起始剂量为一日1mg/kg，分早、晚2次在就餐前至少1小时给药。 先天性代谢缺陷儿童需由专业营养师设计低蛋白饮食。对于幼童，可在服药前将胶囊打开，将内含物混合于少量水、配方饮料或苹果酱中。 本品治疗必须使卟啉代谢正常化。如果治疗1个月内生化参数 (尿琥珀酰丙酮) 未正常化，剂量可增加至一日1.5mg/kg。而血浆琥珀酰丙酮要在治疗后3个月才会恢复正常。在治疗开始时和急性发作时，必须更为密切地监测各生化参数。特别是对于婴儿，一旦肝功能改善，剂量可增大至一日2mg/kg，这一剂量被认为是所有患者的最大剂量。 制剂 白色不透明的硬胶囊口服制剂，有2、5和10mg三种规格。 Orfadin® capsules are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1). Treatment with nitisinone should be initiated by a physician experienced in the treatment of hereditary tyrosinemia type 1. The dose of nitisinone should be adjusted in each patient. The recommended initial dose is 1 mg/kg/day divided for morning and evening administration. Since an effect of food is unknown, nitisinone should be taken at least one hour before a meal. Because of the long half-life of nitisinone, the total dose may be split unevenly as convenient in order to limit the total number of capsules given at each administration. A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine. For young children, capsules may be opened and the contents suspended in a small amount of water, formula or apple sauce immediately before use. Nitisinone treatment should block the flux through the tyrosine degradation pathway at the level of 4-hydroxy-phenylpyruvate dioxygenase. Treatment should lead to normalized porphyrin metabolism (i.e., normal erythrocyte PBG- synthase activity and urine 5 ALA). Succinylacetone should not be detectable in urine or plasma. If the biochemical parameters (except plasma succinylacetone) are not normalized within one month after start of nitisinone treatment, the dose should be increased to 1.5 mg/kg/day. For plasma succinylacetone, it may take up to three months before the level is normalized after the start of nitisinone treatment. Since plasma nitisinone concentration, plasma succinylacetone, urine 5-ALA and erythtocyte PBG-synthase activity are not routinely available, it is appropriate during regular monitoring to follow urine succinylacetone, liver function tests, alpha-fetoprotein, and serum tyrosine and phenylalanine levels. However, during the initiation of therapy and during acute exacerbations, it may be necessary to follow more closely all available biochemical parameters (see Laboratory Tests). A dose of 2 mg/kg/day may be needed, especially in infants, once liver function has improved. This dose should be considered as a maximal dose for all patients. None known. Inadequate restriction of tyrosine and phenylalanine intake can result in elevations in plasma tyrosine. Plasma tyrosine levels should be kept below 500 µmol/L in order to avoid toxic effects to the eyes (corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia), skin (painful hyperkeratotic plaques on the soles and palms) and nervous system (variable degrees of mental retardation and developmental delay). In most patients, eye symptoms were transient, lasting less than one week. Six patients had prolonged episodes lasting 16 to 672 days (see WARNINGS and PRECAUTIONS, Ophthalmologic Care of Patients Treated with Nitisinone). Patients treated with nitisinone and dietary restriction in clinical trials were observed to develop transient thrombocytopenia (3%), leucopenia (3%) or both (1.5%). One patient, who developed both leucopenia and thrombocytopenia, improved after the dose of nitisinone was decreased from 2 mg/kg to 1 mg/kg. Another patient, who developed thrombocytopenia, had nitisinone stopped for 2 weeks, but platelet values continued to be low for 3 months and slowly returned to normal after 5 months. In all other patients, platelet values and white blood cell counts normalized gradually without documented change in nitisinone dose. No patients developed infections or bleeding as a result of the episodes of leucopenia and thrombocytopenia. Platelet and white blood cell counts should be monitored regularly during nitisinone therapy. Patients with hereditary tyrosinemia type 1 are at increased risk of developing porphyric crises, liver failure, or hepatic neoplasms requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 0.5%). Regular liver monitoring by imaging (ultrasound, computerized tomography, magnetic resonance imaging) and laboratory tests, including serum alpha-fetoprotein concentration is recommended. An increase in serum alpha-fetoprotein concentration may be a sign of inadequate treatment, but patients with increasing alpha-fetoprotein or signs of nodules of the liver during treatment with nitisinone should always be evaluated for hepatic malignancy. In a clinical trial of 207 patients treated with nitisinone for HT-1, the most frequent adverse effects, regardless of causality assessment, occurred in the following organ systems: Liver and Biliary System:hepatic neoplasm 8%, liver failure 7%. Visual System:conjunctivitis 2%, corneal opacity 2%, keratitis 2%, photophobia 2%, blepharitis 1%, eye pain 1%, cataracts 1%. Hemic and Lymphatic:thrombocytopenia 3%, leucopenia 3%, porphyria 1%, epistaxis 1%. Skin and Appendages:pruritis 1%, exfoliative dermatitis 1%, dry skin 1%, maculopapular rash 1%, alopecia 1%. Adverse reactions that occurred in less than 1% of the patients, regardless of causality assessment, are: Body as a Whole:death. Nervous System:seizures, brain tumor, encephalopathy, headache, hyperkinesia. Cardiovascular:cyanosis. Digestive System:abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, tooth discoloration. Liver and Biliary System:elevated hepatic enzymes, hepatic function disorder, liver enlargement. Metabolic and Nutritional Disorders:dehydration, hypoglycemia, thirst. Resistance Mechanism Disorder:infection, septicemia, otitis. Respiratory:bronchitis, respiratory insufficiency. Musculoskeletal System:pathologic fracture. Female Reproductive:amenorrhea. Psychiatric:nervousness, somnolence. No drug-drug interaction studies have been conducted with nitisinone. Nitisinone has been shown to have adverse effects on skeletal ossification in animals when given in doses providing exposures less than the human therapeutic dose of 1 mg/kg/day based on body surface area. There are no adequate and well controlled studies in pregnant women. Nitisinone should be used during pregnancy only if the potential benefit justified the potential risk to the fetus. In pregnant mice given oral gavage doses of 5, 50, 250 mg/kg/day from gestation day 7 through 16, incomplete skeletal ossification of fetal bones was observed with doses ≥5mg/kg/day (exposures less than the human therapeutic dose of 1 mg/kg/day based on relative body surface area). In pregnant mice given the same doses from gestation day 7 through weaning, gestation length increased in mice given ≥50 mg/kg/day (exposure 4 times the human systemic exposure after 1 mg/kg/day oral dose based on relative body surface area). Decreased pup survival by 9% compared to 5% in untreated controls was observed at 5 mg/kg/day (exposures less than the human systemic exposure after 1 mg/kg/day oral dose based on relative body surface area). In pregnant rabbits given oral gavage doses of 5, 12, 25 mg/kg/day from gestation day 7 through 19, maternal toxicity and incomplete skeletal ossification of fetal bones was observed with doses of ≥5 mg/kg/day (exposures less than the human therapeutic dose of 1 mg/kg/day based on the body surface area). Although the exposure was not quantified, naive pups that were exposed to Orfadin® via breast milk showed signs of ocular toxicity and lower body weight. This suggests that Orfadin® is excreted via breast milk in rats. It is not known whether nitisinone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitisinone is administrated to a nursing woman. Nitisinone has been studied in patients ranging in age from birth to 21.7 years. The median age of enrollment in a study of 207 patients with HT-1 was 9 months. Clinical studies of nitisinone did not include any subjects aged 65 and over to determine whether they respond differently from younger subjects. HT-1 is presently a disease of the pediatric population. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this patient population. Accidental ingestion of this drug by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. In volunteers given a single 1 mg/kg dose of nitisinone, the plasma tyrosine level reached a maximum of 1200 µmol/L from 48 to 120 hours after dosing. After a washout period of 14 days, the mean value of plasma tyrosine was still 808 µmol/L. Fasted follow-up samples obtained from volunteers several weeks later showed tyrosine values back to normal. Nitisinone was generally well tolerated in these studies. There were no reports of changes in vital signs or laboratory data of any clinical significance. One patient did report sensitivity to sunlight. Tyrosinemia has been associated with toxicity to eyes, skin, and the nervous system (see WARNINGS). No information about specific treatment of overdose is available. Restriction of tyrosine and phenylalanine in the diet should limit toxicity associated with tyrosinemia. Patients should be monitored for potential adverse events (see ADVERSE REACTIONS). Orfadin® capsules contain nitisinone, which is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase used in the treatment of hereditary tyrosinemia type 1 (HT-1). Nitisinone occurs as white to yellowish-white, crystalline powder. It is practically insoluble in water, soluble in 2M sodium hydroxide and in methanol, and sparingly soluble in alcohol. Chemically, nitisinone is 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione, and the structural formula is: Figure 1. The molecular formula is CHFNO with a relative mass of 329.23 Orfadin® is a hard white-opaque capsule, marked as 2 mg, 5 mg or 10 mg strengths of nitisinone and is intended for oral administration. Each capsule contains 2 mg, 5 mg or 10 mg nitisinone, plus pregelatinized starch. The capsule shell is gelatin and titanium dioxide and the imprint is an iron oxide. --------------------------------------------------------- 注：以下产品不同规格和不同价格，购买以咨询为准！ --------------------------------------------------------- 中文参考药品译名： 尼替西农 原产地英文药品名： NITISINONE 中文参考商品译名： 欧佛定 2毫克/胶囊 60胶囊/瓶 原产地英文商品名： ORFADIN 2mg/Cap 60Caps/bottle 生产厂家中文参考译名： RARE DIS 生产厂家英文名： RARE DIS --------------------------------------------------------------- 中文参考药品译名： 尼替西农 原产地英文药品名： NITISINONE 中文参考商品译名： 欧佛定 5毫克/胶囊 60胶囊/瓶 原产地英文商品名： ORFADIN 5mg/Cap 60Caps/bottle 生产厂家中文参考译名： RARE DIS 生产厂家英文名： RARE DIS --------------------------------------------------------------- 中文参考药品译名： 尼替西农 原产地英文药品名： NITISINONE 中文参考商品译名： 欧佛定 10毫克/胶囊 60胶囊/瓶 原产地英文商品名： ORFADIN 10mg/Cap 60Caps/bottle 生产厂家中文参考译名： RARE DIS 生产厂家英文名： RARE DIS