英文药名: 水甜菜碱半胱氨酸 Cystadane
Cystadane P. for oral sol 180g (Betaine anhydrous)
ＣＹＳＴＡＤＡＮＥ 口服溶液 180 公克（無水甜菜鹼）
药品名称
通用名:
无水甜菜碱
用法用量
一般一次口服本品3g（可混合溶解在大约450ml水中服用），2次/d。某些病人可能需要高达20g/d。对3岁以下的儿童起始剂量按100mg/kg，然后每周增加100mg/kg。用药期间应监测血浆中高半胱氨酸浓度，直到血浆中测不出或只有微量高半胱氨酸。
药理作用
本品对治疗高半胱氨酸血症（这是一种遗传性疾病）具有明显的效果。高半胱氨酸血症的病人常有过早的动脉粥样硬化和血栓栓塞，也可能有骨骼畸形和精神迟钝。高半胱氨酸是由必需氨基酸蛋氨酸代谢的中间过程形成的，或者转变成半胱氨酸也可能再导入甲基还原成蛋氨酸。在高半胱氨酸转化成半胱氨酸的过程中需要维生素B6作为辅助因子。此外，还需要维生素B12作为辅助因子，而叶酸是这两种之一的再还原过程中的基质。本品由胆碱转化而来，是再环化的底物。缺乏不同的酶或维生素辅助因子，可引起高半胱氨酸血症和高半胱氨酸尿症。给高半胱氨酸血症的病人辅助因子或基质，可降低高半胱氨酸血浆中浓度。本品应用于对单纯用维生素B6治疗无效的病人，已经出现良好效果。在一项临床报告中，应用本品治疗10例高半胱氨酸血症病人（对维生素B6和叶酸无效），导致血浆高半胱氨酸浓度降低。在另一项试验中，应用本品治疗10年的病人未出现血管血栓的并发症。本品实际上降低高半胱氨酸血症病人血浆中高半胱氨酸浓度，长期研究表明，本品治疗可防止代谢异常引起的严重血管血栓的并发症。
适应症
高半胱氨酸血症和高半胱酸尿症。
不良反应
本品不良反应少见。偶有恶心、腹泻和胃肠道不适。 
注意事项
在血浆中高半胱氨酸浓度中度增加，尚无高半胱氨酸尿症时，就可能出现动脉粥样硬化和冠状动脉病的发生率增加。口服叶酸、维生素B6和维生素B12可降低某些中等度高半胱氨酸血症病人血浆中浓度，甚至降至正常。但是否能降低心血管病的发病率仍然不能肯定。本品属妊娠C类药物，只有当妊娠期明显必要时才可应用。还不清楚是否能进入人乳汁中。
制剂
本品为粉末剂，每瓶含本品180g。盒内附有药匙1只，每匙1g。
生产厂家:
Orphan Europe 
Cystadane半胱氨酸1x180g

Cystadane 1g oral powder
1. Name of the medicinal product
Cystadane 1 g oral powder
2. Qualitative and quantitative composition
1 g of powder contains 1 g of betaine anhydrous.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Oral powder.
White crystalline free flowing powder.
4. Clinical particulars
4.1 Therapeutic indications
Adjunctive treatment of homocystinuria, involving deficiencies or defects in:
• cystathionine beta-synthase (CBS),
• 5,10-methylene-tetrahydrofolate reductase (MTHFR),
• cobalamin cofactor metabolism (cbl).
Cystadane should be used as supplement to other therapies such as vitamin B6 (pyridoxine), vitamin B12 (cobalamin), folate and a specific diet.
4.2 Posology and method of administration
Cystadane treatment should be supervised by a physician experienced in the treatment of patients with homocystinuria.
Posology
Adult
The recommended total daily dose in adult is 6 g per day administered orally in divided doses of 3g two times per day.
Paediatric population
The recommended total daily dose in paediatric patients over 10 years of age is the same as adult. However, dose titration may be preferable in paediatric patients.
In paediatric patients less than 10 years of age, the usual effective dose regimen is 100 mg/kg/day given in 2 doses daily; increasing the frequency above twice daily and/or the dose above 150 mg/kg/day does not improve the homocysteine-lowering effect.
Special populations
Hepatic or renal impairment
Experience with betaine anhydrous therapy in patients with renal insufficiency or non-alcoholic hepatic steatosis has demonstrated no need to adapt the dose regimen of Cystadane.
Method of administration
The bottle should be lightly shaken before opening. Three measuring spoons are provided which dispense either 100 mg, 150 mg or 1 g of betaine anhydrous. It is recommended that a heaped measuring spoon is removed from the container and a flat surface e.g. base of a knife is drawn across the top of the measure. This will give the following doses: small measure 100 mg, middle size measure 150 mg and large measure 1 g of betaine anhydrous.
The powder should be mixed with water, juice, milk, formula or food until completely dissolved and ingested immediately after mixing.
Therapeutic monitoring
The aim of treatment is to keep plasma levels of total homocysteine below 15 µM or as low as possible. The steady-state response usually occurs within a month.
4.3 Contraindications
Hypersensitivity to the active substance.
4.4 Special warnings and precautions for use
 Uncommon cases of severe cerebral oedema and hypermethioninemia were reported within 2 weeks to 6 months of starting betaine anhydrous therapy (see section 4.8). Complete recovery was seen after treatment discontinuation:
- Plasma methionine level should be monitored, at start of treatment and periodically thereafter. The plasma methionine concentrations should be kept below 1000 µM.
- If any symptoms of cerebral oedema like morning headaches with vomiting and/or visual changes appear, plasma methionine level and compliance to the diet should be checked and treatment with Cystadane interrupted.
- If symptoms of cerebral oedema recur after re-introduction of treatment then betaine anhydrous therapy should be discontinued indefinitely.
To minimise the risk of potential drug interactions, it is advisable to leave 30 minutes between the intake of betaine anhydrous and amino acids mixtures and/or medicinal products containing vigabatrin and GABA analogues (see section 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
Based on in vitro data, betaine anhydrous might interact with amino acids mixtures and medicinal products containing vigabatrin and GABA analogues.
4.6 Fertility, pregnancy and lactation
Pregnancy
Data on a limited number of exposed pregnancies indicate no adverse event of betaine anhydrous on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiologic data are available. Animal reproduction studies have not been conducted. During pregnancy, administering betaine anhydrous in addition to pyridoxine, folate, anticoagulant and diet under close monitoring of plasma homocysteine would be compatible with good maternal and foetal outcomes. However, Cystadane should not be used during pregnancy unless clearly necessary.
Breastfeeding
It is not known whether betaine anhydrous is excreted in human milk (although its metabolic precursor, choline, occurs at high levels in human milk). Because of lack of data, caution should be exercised when prescribing Cystadane to breast-feeding women.
Fertility
No data is available
4.7 Effects on ability to drive and use machines
Cystadane has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
In general, adverse reactions seen with betaine anhydrous therapy appeared to be not serious and are mainly related to the gastrointestinal system. Gastrointestinal disorders like diarrhoea, glossitis, nausea, stomach discomfort, vomiting and dental disorders may occur uncommonly.
The most commonly reported adverse reaction during treatment is blood methionine increased. Complete recovery was seen after treatment discontinuation (see section 4.4).
Tabulated summary of adverse reactions
Reported adverse reactions are listed below, by system organ class and by frequency.
Frequencies are 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Metabolism and nutrition disorders	Uncommon: anorexia
Psychiatric disorders	Uncommon: agitation, depression, irritability, personality disorder, sleep disturbed
Nervous system disorders	Uncommon: brain oedema*
Gastrointestinal disorders	Uncommon: dental disorders, diarrhoea, glossitis, nausea, stomach discomfort, vomiting
Skin and subcutaneous tissue disorders	Uncommon: hair loss, hives, skin odour abnormal
Renal and urinary disorders	Uncommon: urinary incontinence
Investigations	Very common: blood methionine increased*

Description of selected adverse reactions
*Uncommon cases of severe cerebral oedema and hypermethioninemia were reported within 2 weeks to 6 months of starting betaine anhydrous therapy, with complete recovery after treatment discontinuation.
Symptoms of cerebral oedema include morning headaches with vomiting and/or visual changes
High increases in plasma methionine levels in a range from 1,000 to 3,000 µM were noted in these patients. As cerebral oedema has also been reported in patients with hypermethioninemia, secondary hypermethioninemia due to betaine anhydrous therapy has been postulated as a possible mechanism of action.
For specific recommendations, refer to section 4.4.
4.9 Overdose
No case of overdose has been reported.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, ATC code: A16AA06.
Mechanism of action
Betaine anhydrous was shown to lower plasma homocysteine levels in the three types of homocystinuria, i.e. CBS deficiency; MTHFR deficiency and cbl defect. The extent of this effect was dependent on the absolute degree of hyperhomocysteinemia, being higher in severe hyperhomocysteinemia.
Pharmacodynamic effects
Betaine anhydrous acts as a methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. As a result, plasma levels of homocysteine should decrease in these patients, to 20-30 % of pre-treatment levels.
Betaine anhydrous has also been shown to increase plasma methionine and S-adenosyl methionine (SAM) levels in patients with MTHFR deficiency and cbl defects. In CBS-deficient patients without dietary restriction of methionine, excessive accumulation of methionine has been observed.
Betaine anhydrous supplementation was shown to improve the metabolic abnormalities in the cerebrospinal fluid of patients with homocystinuria.
Clinical efficacy and safety
Elevated homocysteine plasma levels are associated with cardiovascular events (such as thrombosis), osteoporosis, skeletal abnormalities, and optic lens dislocation. In observational studies, clinical improvement (cardiovascular and neurodevelopmental) was reported by the treating physician in about 75% of patients taking betaine anhydrous. Most of these patients were also receiving other treatments such as vitamin B6 (pyridoxine), vitamin B12 (cobalamin) and folate with variable biochemical responses. In most cases, adding betaine anhydrous resulted in a further reduction in plasma homocysteine level. It is likely that due to the multiple nature of therapy (dietary, pharmaceutical, supportive) in these patients, there may be an element of overestimation in the clinical effects of betaine anhydrous treatment. Late detection of homocystinuria in symptomatic state is responsible for residual morbidity due to irreversible damage to connective tissue (ophtalmological, skeletal) that cannot be corrected by further therapy. The available clinical data do not allow correlating posology and clinical efficacy. There is no evidence of development of tolerance.
In a few cases, increased plasma methionine levels were associated with cerebral oedema (see sections 4.4 and 4.8).
Monitoring plasma homocysteine levels has demonstrated that the onset of action of betaine anhydrous occurred within several days and that a steady-state response was achieved within one month.
Paediatric population
In paediatric patients less than 10 years of age, the usual effective dose regimen is 100 mg/kg/day given in 2 doses daily; increasing the frequency above twice daily and/or the dose above 150 mg/kg/day does not improve the homocysteine-lowering effect.
Monitoring betaine plasma concentrations does not help to define the efficacy of treatment, since these concentrations do not directly correspond to the flux through the cytosolic betaine homocysteine methyl transferase pathway.
5.2 Pharmacokinetic properties
The pharmacokinetic data of homocystinuric patients on long-term betaine anhydrous supplementation are very similar to those of healthy volunteers. This demonstrates that differences in betaine anhydrous kinetics are most probably due to betaine anhydrous depletion in untreated homocystinuria and are only meaningful for the initial treatment.
Absorption
The absolute bioavailability of betaine anhydrous has not been determined. In healthy adult volunteers (age between 21 to 49 years), after a single oral dose of betaine anhydrous (50 mg/kg), absorption was rapid (tmax = 0.9 ± 0.3 hours and a Cmax= 0.9 ± 0.2 mM).
After a repeated dose regimen of 100 mg/kg/day for 5 days, the absorption kinetics did not change.
Distribution
Betaine anhydrous was rapidly distributed into a relatively large volume (V/F = 1.3 l/kg).
After a repeated dose regiment of 100 mg/kg/day for 5 days, the distribution half life was prolonged significantly (up to 36 h), indicating saturable transport and redistribution processes.
Biotransformation
Betaine anhydrous is a methyl group donor
Elimination
With a slow elimination rate (mean half life= 14 h, mean total body clearance, CL/F, = 84 ml/h/kg), renal clearance is negligible (5% of total body clearance), assuming 100% bioavailability.
5.3 Preclinical safety data
At high doses, a CNS depressant effect and irritation of the gastrointestinal tract was seen in rats. Long-term carcinogenicity and reproductive toxicity studies have not been conducted on betaine anhydrous. A standard battery of genotoxicity test reveals no specific hazard for humans.
6. Pharmaceutical particulars
6.1 List of excipients
None.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Unopened bottle: 3 years
After the first opening: 3 months.
6.4 Special precautions for storage
Do not store above 25°C.
Keep the bottle tightly closed in order to protect from moisture.
For storage conditions after first opening of the medicinal product, see section 6.3.
6.5 Nature and contents of container
HDPE bottles with a child resistant closure.
Each pack contains 1 bottle with 180 g of powder.
Three measuring spoons are included in each pack.
Three measuring spoons (pink, blue, green) dispense, respectively, 1 g, 150 mg and 100 mg of betaine anhydrous.
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
Orphan Europe SARL
Immeuble “Le Wilson”
70 Avenue du General de Gaulle
F-92 800 Puteaux
France
8. Marketing authorisation number(s)
EU/1/06/379/001
9. Date of first authorisation/renewal of the authorisation
15/02/2007
10. Date of revision of the text
20/03/2013
甜菜碱（甘氨酸三甲胺内盐）是胆碱的天然代谢中间体，可显著增加S-腺苷蛋氨酸的水平，从理论上讲可能对脂肪肝有益处。10例非酒精性脂肪肝患者接受无水甜菜碱口服制剂 (Cystadane)治疗 12月。其中7例完成1年的治疗， 结果表明，血清AST、ALT水平在治疗后显著下降，7例中有3例转氨酶恢复正常，3例下降50％以上，另1例转氨酶水平无明显改变。血清转氨酶水平显著下降 (ALT -39%; AST -38%)也可见于未完成1年疗程的患者中。同样，在甜菜碱治疗1年后，脂肪变性的程度、炎症坏死分级和纤维化分 期也显著改善。4例出现短暂的消化道副反应，但无需减量或停用甜菜碱。最近，在一项双盲随机对照的前瞻性临床研究中，191例NASH患者中，96例患者接受葡萄糖醛酸甜菜碱每日两次口服治疗，其余95例患者口服安慰剂，疗程为8周。治疗组中，25%的患者脂肪变性改善(p < 0.01)，6%的患者肝肿大改善 (p < 0.05)，而对照组无明显疗效。治疗组尚对改善右上腹不适有效。治疗组医生评价的总体疗效“非常好”或“好”者占48％，而对照组为17％（P= 9 10-6）。治疗组患者自己评价为“非常好”或“好”的占52％，对照组为34％（P= 0.017）。甜菜碱使血清ALT、AST和GGT水平显著下降，而对照组无明显改变。治疗组和对照组的副反应发生率分别为10％和7％，无显著差别。两组中，副反应均较轻微和短暂，一般无须停药。上述结果表明，甜菜碱是一种可显著改善NASH患者生化和组织学改变的安全有效的药物，值得临床应用。