nitisinone膠囊(orfadin)批准用於第一型遺傳性酪氨酸血症(HT-1)
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。
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。
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。
注：本品属瑞典原研药品，采购以咨询为准
Orfadin 2mg 10mg hard capsule
1. Name of the medicinal product
Orfadin 2 mg hard capsules
2. Qualitative and quantitative composition
Each capsule contains 2 mg nitisinone.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Hard capsule.
White, opaque capsules (6x16 mm) imprinted “NTBC 2mg” in black on the body of the capsule.
The capsules contain a white to off white powder.
4. Clinical particulars
4.1 Therapeutic indications
Treatment of adult and paediatric (in any age range) patients with confirmed diagnosis of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.
4.2 Posology and method of administration
Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of HT-1 patients.
Posology
Treatment of all genotypes of the disease should be initiated as early as possible to increase overall survival and avoid complications such as liver failure, liver cancer and renal disease. Adjunct to the nitisinone treatment, a diet deficient in phenylalanine and tyrosine is required and should be followed by monitoring of plasma amino acids (see sections 4.4 and 4.8).
The recommended initial dose in the paediatric and adult population is 1 mg/kg body weight/day divided in 2 doses administered orally. The dose of nitisinone should be adjusted individually.
Dose adjustment
During regular monitoring, it is appropriate to follow urine succinylacetone, liver function test values and alpha-fetoprotein levels (see section 4.4). If urine succinylacetone is still detectable one month after the start of nitisinone treatment, the nitisinone dose should be increased to 1.5 mg/kg body weight/day divided in 2 doses. A dose of 2 mg/kg body weight/day may be needed based on the evaluation of all biochemical parameters. This dose should be considered as a maximal dose for all patients.
If the biochemical response is satisfactory, the dose should be adjusted only according to body weight gain.
However, in addition to the tests above, during the initiation of therapy or if there is a deterioration, it may be necessary to follow more closely all available biochemical parameters (i.e. plasma succinylacetone, urine 5-aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity).
Special populations
There are no specific dose recommendations for elderly or patients that have renal or hepatic impairment.
Paediatric population
The dose recommendation in mg/kg body weight is the same in children and adults.
Method of administration
The capsule may be opened and the content suspended in a small amount of water or formula diet immediately before intake.
Orfadin is also available as a 4 mg/ml oral suspension for paediatric patients who have difficulties swallowing capsules.
It is recommended that if nitisinone treatment is initiated with food, this should be maintained on a routine basis, see section 4.5.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Mothers receiving nitisinone must not breast-feed (see sections 4.6 and 5.3).
4.4 Special warnings and precautions for use
Monitoring of plasma tyrosine levels
It is recommended that a slit-lamp examination of the eyes is performed before initiation of nitisinone treatment. A patient displaying visual disorders during treatment with nitisinone should without delay be examined by an ophthalmologist. It should be established that the patient is adhering to his/her dietary regimen and the plasma tyrosine concentration should be measured. A more restricted tyrosine and phenylalanine diet should be implemented in case the plasma tyrosine level is above 500 micromol/l. It is not recommended to lower the plasma tyrosine concentration by reduction or discontinuation of nitisinone, since the metabolic defect may result in deterioration of the patient's clinical condition.
Liver monitoring
The liver function should be monitored regularly by liver function tests and liver imaging. It is recommended to also monitor serum alpha-fetoprotein concentrations. Increase in serum alpha-fetoprotein concentration may be a sign of inadequate treatment. Patients with increasing alpha-fetoprotein or signs of nodules in the liver should always be evaluated for hepatic malignancy.
Platelet and white blood cell (WBC) monitoring
It is recommended that platelet and WBC counts are monitored regularly, as a few cases of reversible thrombocytopenia and leucopenia were observed during clinical evaluation.
Monitoring visits should be performed every 6 months; shorter intervals between visits are recommended in case of adverse events.
4.5 Interaction with other medicinal products and other forms of interaction
No formal interaction studies with other medicinal products have been conducted.
Nitisinone is metabolised in vitro by CYP 3A4 and dose-adjustment may therefore be needed when nitisinone is co-administered with inhibitors or inducers of this enzyme.
Based on in vitro studies, nitisinone is not expected to inhibit CYP 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4-mediated metabolism.
No formal food interactions studies have been performed with Orfadin hard capsules. However, nitisinone has been co-administered with food during the generation of efficacy and safety data. Therefore, it is recommended that if nitisinone treatment with Orfadin hard capsules is initiated with food, this should be maintained on a routine basis, see section 4.2.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of nitisinone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Orfadin should not be used during pregnancy unless the clinical condition of the woman requires treatment with nitisinone.
Breast-feeding
It is unknown whether nitisinone is excreted in human breast milk. Animal studies have shown adverse postnatal effects via exposure of nitisinone in milk. Therefore, mothers receiving nitisinone must not breast-feed, since a risk to the suckling child cannot be excluded (see sections 4.3 and 5.3).
Fertility
There are no data on nitisinone affecting fertility.
4.7 Effects on ability to drive and use machines
Orfadin has minor influence on the ability to drive and use machines. Adverse reactions involving the eyes (see section 4.8) can affect the vision. If the vision is affected the patient should not drive or use machines until the event has subsided.
4.8 Undesirable effects
Summary of the safety profile
By its mode of action, nitisinone increases tyrosine levels in all nitisinone treated patients. Eye-related adverse reactions, such as conjunctivitis, corneal opacity, keratitis, photophobia, and eye pain, related to elevated tyrosine levels are therefore common. Other common adverse reactions include thrombocytopenia, leucopenia, and granulocytopenia. Exfoliative dermatitis may occur uncommonly.
Tabulated list of adverse reactions
The adverse reactions listed below by MedDRA system organ class and absolute frequency, are based on data from a clinical trial and post-marketing use. 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, adverse reactions are presented in order of decreasing seriousness.

MedDRA system organ class	Frequency	Adverse reaction
Blood and lymphatic system disorders	Common	Thrombocytopenia, leucopenia, granulocytopenia
	Uncommon	Leukocytosis
Eye disorders	Common	Conjunctivitis, corneal opacity, keratitis, photophobia, eye pain
	Uncommon	Blepharitis
Skin and subcutaneous tissue disorders	Uncommon	Exfoliative dermatitis, erythematous rash, pruritus
Investigations	Very common	Elevated tyrosine levels

Description of selected adverse reactions
Nitisinone treatment leads to elevated tyrosine levels. Elevated levels of tyrosine have been associated with eye-related adverse reactions, such as e.g. corneal opacities and hyperkeratotic lesions. Restriction of tyrosine and phenylalanine in the diet should limit the toxicity associated with this type of tyrosinemia by lowering tyrosine levels (see section 4.4).
In clinical studies, granulocytopenia was only uncommonly severe (<0.5x109/L) and not associated with infections. Adverse reactions affecting the MedDRA system organ class 'Blood and lymphatic system disorders' subsided during continued nitisinone treatment.
Paediatric population
The safety profile is mainly based on the paediatric population since nitisinone treatment should be started as soon as the diagnosis of hereditary tyrosinemia type 1 (HT-1) has been established. From clinical study and post marketing data there are no indications that the safety profile is different in different subsets of the paediatric population or different from the safety profile in adult patients.
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:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
4.9 Overdose
Accidental ingestion of nitisinone by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. Elevated tyrosine levels have been associated with toxicity to eyes, skin, and the nervous system. Restriction of tyrosine and phenylalanine in the diet should limit toxicity associated with this type of tyrosinemia. No information about specific treatment of overdose is available.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract and metabolism products, ATC code: A16A X04.
Mechanism of action
The biochemical defect in hereditary tyrosinemia type 1 (HT-1) is a deficiency of fumarylacetoacetate hydrolase, which is the final enzyme of the tyrosine catabolic pathway. Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme which precedes fumarylacetoacetate hydrolase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate. Succinylacetone inhibits the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate.
Pharmacodynamic effects
Nitisinone treatment leads to normalised porphyrin metabolism with normal erythrocyte porphobilinogen synthase activity and urine 5-aminolevulinate, decreased urinary excretion of succinylacetone, increased plasma tyrosine concentration and increased urinary excretion of phenolic acids. Available data from a clinical study indicates that in more than 90% of the patients urine succinylacetone was normalized during the first week of treatment. Succinylacetone should not be detectable in urine or plasma when the nitisinone dose is properly adjusted.
Clinical efficacy and safety
When compared to data for historical controls, it can be seen that treatment with nitisinone together with dietary restriction results in a higher survival probability in all HT-1 phenotypes. This is seen in the following table:

Age at start of treatment or diagnosis	Survival probability
	Nitisinone treatment		Dietary control
	5 years	10 years	5 years	10 years
< 2 months	82	--	28	--
> 2-6 months	95	95	51	34
> 6 months	92	86	93	59

Treatment with nitisinone was also found to result in reduced risk for the development of hepatocellular carcinoma (2.3 to 3.7-fold) compared to historical data on treatment with dietary restriction alone. It was found that the early initiation of treatment resulted in a further reduced risk for the development of hepatocellular carcinoma (13.5-fold when initiated prior to the age of 12 months).
5.2 Pharmacokinetic properties
Formal absorption, distribution, metabolism and elimination studies have not been performed with nitisinone. In 10 healthy male volunteers, after administration of a single dose of nitisinone capsules (1 mg/kg body weight) the terminal half-life (median) of nitisinone in plasma was 54 hours (ranging from 39 to 86 hours). A population pharmacokinetic analysis has been conducted on a group of 207 HT-1 patients. The clearance and half-life were determined to be 0.0956 l/kg body weight/day and 52.1 hours respectively.
In vitro studies using human liver microsomes and cDNA-expressed P450 enzymes have shown limited CYP 3A4-mediated metabolism.
5.3 Preclinical safety data
Nitisinone has shown embryo-foetal toxicity in the mouse and rabbit at clinically relevant dose levels. In the rabbit, nitisinone induced a dose-related increase in malformations (umbilical hernia and gastroschisis) from a dose level 2.5-fold higher than the maximum recommended human dose (2 mg/kg/day).
A pre- and postnatal development study in the mouse showed statistically significantly reduced pup survival and pup growth during the weaning period at dose levels 125- and 25-fold higher, respectively, than the maximum recommended human dose, with a trend toward a negative effect on pup survival starting from the dose of 5 mg/kg/day. In rats, exposure via milk resulted in reduced mean pup weight and corneal lesions.
No mutagenic but a weak clastogenic activity was observed in in vitro studies. There was no evidence of in vivo genotoxicity (mouse micronucleus assay and mouse liver unscheduled DNA synthesis assay). Carcinogenicity studies have not been performed.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule content
Starch, pregelatinised (maize)
Capsule shell
gelatin
titanium dioxide (E 171)
Printing ink
black iron oxide (E 172)
shellac
propylene glycol
ammonium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
During the shelf life, the patient may store the capsules for a single period of 2 months at a temperature not above 25°C, after which the medicinal product must be discarded.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
6.5 Nature and contents of container
HDPE bottle with a tamper-proof closure of LDPE, containing 60 capsules.
Each pack contains 1 bottle.
6.6 Special precautions for disposal and other handling
Any unused medicinal 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/1/04/303/001
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 21/02/2005
Date of latest renewal: 21/02/2010
10. Date of revision of the text
19.06.15
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
注：附其他资料：
Orfadin 20mg Hard Capsule（https://www.medicines.org.uk/emc/medicine/30534）
Orfadin 10 mg hard capsules（https://www.medicines.org.uk/emc/medicine/21408）
Orfadin 5mg capsules（https://www.medicines.org.uk/emc/medicine/21410）