Orfadin胶囊是一种罕见病用药--作为治疗先天性I型酪氨酸血症(HTI)时，对苯丙氨酸和酪氨酸进行饮食控制时的附加剂。这种产品在1995年5月16日被FDA授予罕见病用药。先天性I型酪氨酸血症是一种罕见的遗传性代谢性病症，其特征是患者体内缺乏能够分解酪氨酸的酶。 这种病症最常见的形式是急性I型酪氨酸血症,如果不能治愈，在新生儿刚出生的第一年会有致命的危险。这种病还有一种慢性和次慢性的形式，表现为病程较长，如果得不到治愈，同样有致命危险。 Orfadin胶囊(nitisinone)没有已知的禁忌症。如果不能充分地限制对酪氨酸和苯丙氨酸的吸收，就会造成血浆中的酪氨酸水平升高，导致对皮肤、眼睛，及神经系统的毒害作用。 临床实验中，用Orfadin进行治疗和饮食控制的病人，能产生暂时性的血小板减少症(3%)和白细胞减少症(3%)或者两者同时发生(1.5%)。在治疗时，血小板和白细胞数量要有规律地进行监控。由于治疗时已发生了肝肿瘤和肝衰竭，因此建议治疗时要通过成像术和实验室检测进行有规律的肝监控，这其中也包括对血清的α-胎儿球蛋白的监控。 【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。 药品英文名 Nitisinone 药品别名 Orfadin 药物剂型 尼替西农胶囊：2mg/粒；5mg/粒；10mg/粒。2～8℃冰箱保存。 药理作用 本品是羟苯丙酮酸二氧酶的竞争性抑制剂。羟苯丙酮酸二氧酶在酪氨酸分解代谢途径中可上调延胡酰乙酰乙酸酶(FAH)。 1型遗传性酪氨酸血症(HT-1)患者酪氨酸代谢产生代谢中间体马来酰乙酰乙酸盐和延胡索乙酰乙酸盐，这些代谢中间体进而转化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-氨基酮戊酸盐累积。 本品通过抑制羟苯丙酮酸二氧酶进而抑制延胡酰乙酰乙酸酶，抑制HT-1患者酪氨酸的代谢，预防代谢中间体的蓄积以及由此造成的肝、肾毒性。 本品还可能影响尿琥珀酰丙酮、血浆琥珀酰丙酮和胆色素原(PBG)合酶的活性。 研究显示，HT-1患者服用本品后，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；多数患者的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。 药动学 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，在这两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出。健康男性志愿者一次服用本品1mg/kg，其胶囊和液体制剂血药浓度达峰时间分别为3h和15min，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54h。 适应证 本品可作为酪氨酸和苯丙氨酸饮食限制的辅助用药，用于罕见儿科1型遗传性酪氨酸血症(HT-1)的治疗。 禁忌证 对本品过敏者禁用。 注意事项 1.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500μmol/L，以避免对眼(角膜溃疡、角膜浑浊、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。 2.对于大多数患者，眼部症状是暂时的，持续不超过1周。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500μmol/L，需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。 3.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。 4.本品治疗期间建议常规监测血小板和粒细胞计数。 5.本品治疗期间应常规监测肝功能。 6.先天性代谢缺陷儿童需由专业营养师设计低蛋白饮食。 7.慎用： (1)本品生殖安全分为C，孕妇慎用。 (2)尚不知本品是否经乳汁分泌，哺乳期妇女慎用。 不良反应 1.最常见的不良反应涉及肝胆系统(包括肝肿瘤8%，肝功能衰竭7%)、视觉系统(包括结膜炎2%，角膜浑浊2%，畏光2%，眼睑炎1%，眼痛1%，白内障1%)、血液和淋巴系统(包括血小板减少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%)。 2.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。 用法用量 本品的用量需个体化，推荐的起始剂量为一天1mg/kg，分早、晚2次在就餐前至少1h给药。如果治疗1个月内生化参数(尿琥珀酰丙酮)未正常化，剂量可增加至一天1.5mg/kg。在治疗开始时和急性发作时，一旦肝功能改善，最大剂量可增至一天2mg/kg。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服用。 药物相应作用 尚无药物相互作用研究资料。 ORFADIN® (nitisinone)Capsule INDICATIONS AND USAGE Orfadin® capsules are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1). DOSAGE and ADMINISTRATION 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. Dose Adjustment 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. CONTRAINDICATIONS None known. WARNINGS and PRECAUTIONS High Plasma Tyrosine Levels 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). Transient Thrombocytopenia and Leucopenia 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. Ophthalmologic Care of Patients Treated with Nitisinone •Slit-lamp examination of the eyes should be performed before initiation of nitisinone treatment. •Patients who develop photophobia, eye pain or signs of inflammation such as redness, swelling, or burning of the eyes during treatment with nitisinone should undergo slit-lamp reexamination and immediate measurement of the plasma tyrosine concentration. •A more restricted diet should be implemented if the plasma tyrosine level is above 500 µmol/L. •Nitisinone dosage should not be adjusted in order to lower the plasma tyrosine concentration, since the HT-1 metabolic defect may result in deterioration of the patient's clinical condition. Risk of Porphyric Crises, Liver Failure, and Hepatic Neoplasms 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. Laboratory Tests •Plasma nitisinone concentration, urine and plasma succinylacetone levels, urine 5-ALA levels, and erythrocyte PBG-synthase activity were used during clinical trials to guide drug dosage. The probability of recurrence of abnormal values of urine succinylacetone was 1% at a nitisinone concentration of 37 µmol/L (95% confidence interval: 23-51 µmol/L). Assays for plasma nitisinone concentration, plasma succinyl acetone, urine 5-ALA, and erythrocyte PBG-synthase activity are not routinely available in the U.S. However, urine succinylacetone levels can be used to guide drug dose adjustment (see DOSAGE and ADMINISTRATION). •Serum alpha-fetoprotein concentrations are generally markedly elevated at the time of diagnosis, and gradually decrease during the course of nitisinone treatment. Increases during therapy may be a sign of inadequate treatment. An exponential increase in serum alpha-fetoprotein concentration should be promptly evaluated for potential liver neoplasia. •Platelet and white blood cell counts should be monitored regularly because of the risk of transient thrombocytopenia and leukopenia (see WARNINGS). •Serum phosphate should be measured as a screening test for patients with renal involvement at risk of secondary hypophosphatemia and rickets. •Plasma tyrosine levels should be kept below 500 µmol/L in order to avoid toxic effects (see WARNINGS). ADVERSE REACTIONS 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. DRUG INTERACTIONS No drug-drug interaction studies have been conducted with nitisinone. USE IN SPECIFIC POPULATIONS Use In Specific Populations (Pregnancy) 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). Use In Specific Populations (Nursing Mothers) 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. Use In Specific Populations (Pediatric Use) 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. Use In Specific Populations (Geriatric Use) 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. OVERDOSAGE 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). DESCRIPTION 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: Nitisinone structural formula. Figure 1. The molecular formula is C14H10F3NO5 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. Orfadin (nitisinone) capsules 2 mg bottle label 60 capsules. Orfadin (nitisinone) capsules 5 mg bottle label 60 capsules. Orfadin (nitisinone) capsules 10 mg bottle label 60 capsules. Orfadin (nitisinone) https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5d449b73-d503-4132-b978-d890491975df --------------------------------------------------------------- 以下产品不同规格和不同价格，购买以咨询为准备 --------------------------------------------------------------- 产地国家：美国 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 ----------------------------------------------------------------- 产地国家：美国 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 --------------------------------------------------------------- 产地国家：美国 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