部份中文安归宁处方资料（仅供参考） 原发性血小板过多症治疗新药 商品名：安归宁 通用名：盐酸阿那格雷 英文名：Agrylin 主要成分 盐酸阿那格雷 作用机制 阿那格雷为环磷腺苷磷酸二酯酶III抑制剂。高浓度时可抑制血小板的生成和聚集。本药原用作抑制血小板聚集，有抗血栓效果，但近年应用低剂量时发现其有降低血小板作用。作用机制可能是影响巨核细胞细胞周期后期（有丝分裂后）分化成熟，使血小板生成减少。不影响DNA、RNA的合成及巨核细胞增殖分裂，因而无潜在致癌性。 适应证 美国FDA批准安归宁用于特发性血小板增多症及真性红细胞增多症并发血小板增多。但对于由其他骨髓增殖性疾病如骨髓纤维化和骨髓增生异常综合征伴随血小板增高亦可应用。 用法用量 成人:盐酸阿那格雷：初始剂量1mg/天，分2次给药，1周，然后每周加量不超过0.5mg/天，直到血小板计数在正常水平。常规维持剂量：1-3mg/天。最大剂量：10mg/天和2.5mg/剂。 儿童:初始剂量：0.5mg/天。维持剂量：同成人。最大剂量：10mg/天和2.5mg/剂。 肝损害:中重度肝损害：避免使用。 Xagrid 0.5mg hard capsule 1. Name of the medicinal product Xagrid 0.5 mg hard capsules. 2. Qualitative and quantitative composition Each hard capsule contains 0.5 mg anagrelide (as anagrelide hydrochloride). Excipient(s) with known effect: Each hard capsule contains lactose monohydrate (53.7 mg) and anhydrous lactose (65.8 mg). For the full list of excipients, see section 6.1. 3. Pharmaceutical form Hard capsule. An opaque white hard capsule imprinted with S 063. 4. Clinical particulars 4.1 Therapeutic indications Xagrid is indicated for the reduction of elevated platelet counts in at risk essential thrombocythaemia (ET) patients who are intolerant to their current therapy or whose elevated platelet counts are not reduced to an acceptable level by their current therapy. An at risk patient An at risk essential thrombocythaemia patient is defined by one or more of the following features: • > 60 years of age or • a platelet count > 1000 x 109/l or • a history of thrombo-haemorrhagic events. 4.2 Posology and method of administration Treatment with Xagrid should be initiated by a clinician with experience in the management of essential thrombocythaemia. Posology The recommended starting dose of anagrelide is 1 mg/day, which should be administered orally in two divided doses (0.5 mg/dose). The starting dose should be maintained for at least one week. After one week the dose may be titrated, on an individual basis, to achieve the lowest effective dose required to reduce and/or maintain a platelet count below 600 x 109/l and ideally at levels between 150 x 109/l and 400 x 109/l. The dose increment must not exceed more than 0.5 mg/day in any one-week and the recommended maximum single dose should not exceed 2.5 mg (see section 4.9). During clinical development doses of 10 mg/day have been used. The effects of treatment with anagrelide must be monitored on a regular basis (see section 4.4). If the starting dose is > 1 mg/day platelet counts should be performed every two days during the first week of treatment and at least weekly thereafter until a stable maintenance dose is reached. Typically, a fall in the platelet count will be observed within 14 to 21 days of starting treatment and in most patients an adequate therapeutic response will be observed and maintained at a dose of 1 to 3 mg/day (for further information on the clinical effects refer to section 5.1). Elderly The observed pharmacokinetic differences between elderly and young patients with ET (see section 5.2) do not warrant using a different starting regimen or different dose titration step to achieve an individual patient-optimised anagrelide regimen. During clinical development approximately 50% of the patients treated with anagrelide were over 60 years of age and no age specific alterations in dose were required in these patients. However, as expected, patients in this age group had twice the incidence of serious adverse events (mainly cardiac). Renal impairment There are limited pharmacokinetic data for this patient population. The potential risks and benefits of anagrelide therapy in a patient with impairment of renal function should be assessed before treatment is commenced (see section 4.3). Hepatic impairment There are limited pharmacokinetic data for this patient population. However, hepatic metabolism represents the major route of anagrelide clearance and liver function may therefore be expected to influence this process. Therefore it is recommended that patients with moderate or severe hepatic impairment are not treated with anagrelide. The potential risks and benefits of anagrelide therapy in a patient with mild impairment of hepatic function should be assessed before treatment is commenced (see sections 4.3 and 4.4). Paediatric population The safety and efficacy of anagrelide in children has not been established. The experience in children and adolescents is very limited; anagrelide should be used in this patient group with caution. In the absence of specific paediatric guidelines, WHO diagnostic criteria for adult diagnosis of ET are considered to be of relevance to the paediatric population. Diagnostic guidelines for essential thrombocythemia should be followed carefully and diagnosis reassessed periodically in cases of uncertainty, with effort made to distinguish from hereditary or secondary thrombocytosis, which may include genetic analysis and bone marrow biopsy. Typically cytoreductive therapy is considered in high risk paediatric patients. Anagrelide treatment should only be initiated when the patient shows signs of disease progression or suffers from thrombosis. If treatment is initiated, the benefits and risks of treatment with anagrelide must be monitored regularly and the need for ongoing treatment evaluated periodically. Platelet targets are assigned on an individual patient basis by the treating physician. Discontinuation of treatment should be considered in paediatric patients who do not have a satisfactory treatment response after approximately 3 months. Currently available data are described in sections 4.4, 4.8, 5.1 and 5.2, but no recommendation on a posology can be made. Method of Administration For oral use. The capsules must be swallowed whole. Do not crush or dilute the contents in a liquid. 4.3 Contraindications Hypersensitivity to anagrelide or to any of the excipients listed in section 6.1. Patients with moderate or severe hepatic impairment. Patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min). 4.4 Special warnings and precautions for use Hepatic impairment The potential risks and benefits of anagrelide therapy in a patient with mild impairment of hepatic function should be assessed before treatment is commenced. It is not recommended in patients with elevated transaminases (> 5 times the upper limit of normal) (see sections 4.2 and 4.3). Renal impairment The potential risks and benefits of anagrelide therapy in a patient with impairment of renal function should be assessed before treatment is commenced (see sections 4.2 and 4.3). Monitoring Therapy requires close clinical supervision of the patient which will include a full blood count (haemoglobin and white blood cell and platelet counts), assessment of liver function (ALT and AST), renal function (serum creatinine and urea) and electrolytes (potassium, magnesium and calcium). Platelets The platelet count will increase within 4 days of stopping treatment with anagrelide and will return to pre-treatment levels within 10 to 14 days. Cardiovascular Serious cardiovascular adverse events including cases of torsade de pointes, ventricular tachycardia, cardiomyopathy, cardiomegaly and congestive heart failure have been reported (see section 4.8). Caution should be taken when using anagrelide in patients with known risk factors for prolongation of the QT interval, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and hypokalaemia. Care should also be taken in populations that may have a higher maximum plasma concentration (Cmax) of anagrelide or its active metabolite, 3-hydroxy-anagrelide, e.g. hepatic impairment or use with CYP1A2 inhibitors (see section 4.5). Close monitoring for an effect on the QTc interval is advisable. A pre-treatment cardiovascular examination, including a baseline ECG and echocardiography is recommended for all patients prior to initiating therapy with anagrelide. All patients should be monitored regularly during treatment (e.g. ECG or echocardiography) for evidence of cardiovascular effects that may require further cardiovascular examination and investigation. Hypokalaemia or hypomagnesaemia must be corrected prior to anagrelide administration and should be monitored periodically during therapy. Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III and because of its positive inotropic and chronotropic effects, anagrelide should be used with caution in patients of any age with known or suspected heart disease. Moreover, serious cardiovascular adverse events have also occurred in patients without suspected heart disease and with normal pre-treatment cardiovascular examination. Anagrelide should only be used if the potential benefits of therapy outweigh the potential risks. Paediatric population Very limited data are available on the use of anagrelide in the paediatric population and anagrelide should be used in this patient group with caution (see sections 4.2, 4.8, 5.1 and 5.2). As with the adult population, a full blood count and assessment of cardiac, hepatic and renal function should be undertaken before treatment and regularly during treatment. The disease may progress to myelofibrosis or AML. Although the rate of such progression is not known, children have a longer disease course and may, therefore, be at increased risk for malignant transformation, relative to adults. Children should be monitored regularly for disease progression according to standard clinical practices, such as physical examination, assessment of relevant disease markers, and bone marrow biopsy. Any abnormalities should be evaluated promptly and appropriate measures taken, which may also include dose reduction, interruption or discontinuation. Clinically relevant interactions Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III (PDE III). Concomitant use of anagrelide with other PDE III inhibitors such as milrinone, amrinone, enoximone, olprinone and cilostazol is not recommended. Use of concomitant anagrelide and acetylsalicylic acid has been associated with major haemorrhagic events (see section 4.5). Excipients Xagrid contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Limited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between anagrelide and other medicinal products have been conducted. Effects of other active substances on anagrelide • Anagrelide is primarily metabolised by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine and enoxacin, and such medicinal products could theoretically adversely influence the clearance of anagrelide. • In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the pharmacokinetic properties of anagrelide. Effects of anagrelide on other active substances • Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other co-administered medicinal products sharing that clearance mechanism e.g. theophylline. • Anagrelide is an inhibitor of PDE III. The effects of medicinal products with similar properties such as the inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by anagrelide. • In vivo interaction studies in humans have demonstrated that anagrelide does not affect the pharmacokinetic properties of digoxin or warfarin. • At the doses recommended for use in the treatment of essential thrombocythaemia, anagrelide may potentiate the effects of other medicinal products that inhibit or modify platelet function e.g. acetylsalicylic acid. • A clinical interaction study performed in healthy subjects showed that co-administration of repeat-dose anagrelide 1 mg once daily and acetylsalicylic acid 75 mg once daily may enhance the anti-platelet aggregation effects of each active substance compared with administration of acetylsalicylic acid alone. In some ET patients concomitantly treated by acetylsalicylic acid and anagrelide, major haemorrhages occurred. Therefore, the potential risks of the concomitant use of anagrelide with acetylsalicylic acid should be assessed, particularly in patients with a high risk profile for haemorrhage before treatment is initiated. • Anagrelide may cause intestinal disturbance in some patients and compromise the absorption of hormonal oral contraceptives. Food interactions • Food delays the absorption of anagrelide, but does not significantly alter systemic exposure. • The effects of food on bioavailability are not considered clinically relevant to the use of anagrelide. Paediatric population Interaction studies have only been performed in adults. 4.6 Fertility, pregnancy and lactation Women of child-bearing potential Women of child-bearing potential should use adequate birth-control measures during treatment with anagrelide. Pregnancy There are no adequate data from the use of anagrelide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore Xagrid is not recommended during pregnancy. If anagrelide is used during pregnancy, or if the patient becomes pregnant while using the medicinal product, she should be advised of the potential risk to the foetus. Breast-feeding It is unknown whether anagrelide/metabolites are excreted in human milk. Available data in animals have shown excretion of anagrelide/metabolites in milk. A risk to the newborn/infant cannot be excluded. Breast-feeding should be discontinued during treatment with anagrelide. Fertility No human data on the effect of anagrelide on fertility are available. In male rats, there was no effect on fertility or reproductive performance with anagrelide. In female rats, using doses in excess of the therapeutic range, anagrelide disrupted implantation (see section 5.3). 4.7 Effects on ability to drive and use machines In clinical development, dizziness was commonly reported. Patients are advised not to drive or operate machinery while taking anagrelide if dizziness is experienced. 4.8 Undesirable effects Summary of the safety profile The safety of anagrelide has been examined in 4 open label clinical studies. In 3 of the studies 942 patients who received anagrelide at a mean dose of approximately 2 mg/day were assessed for safety. In these studies 22 patients received anagrelide for up to 4 years. In the later study 3660 patients who received anagrelide at a mean dose of approximately 2 mg/day were assessed for safety. In this study 34 patients received anagrelide for up to 5 years. The most commonly reported adverse reactions associated with anagrelide were headache occurring at approximately 14%, palpitations occurring at approximately 9%, fluid retention and nausea both occurring at approximately 6%, and diarrhoea occurring at 5%. These adverse drug reactions are expected based on the pharmacology of anagrelide (inhibition of PDE III). Gradual dose titration may help diminish these effects (see section 4.2). Tabulated list of adverse reactions Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneous reports are presented in the table below. Within the system organ classes they are listed under the following headings: 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. Paediatric population 48 patients aged 6-17 years (19 children and 29 adolescents) have received anagrelide for up to 6.5 years either in clinical studies or as part of a disease registry (see section 5.1). The majority of adverse events observed were among those listed in the SmPC. However, safety data are limited and do not allow a meaningful comparison between adult and paediatric patients to be made (see section 4.4). 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose Post-marketing case reports of intentional overdose with anagrelide have been received. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative management. Anagrelide, at higher than recommended doses, has been shown to produce reductions in blood pressure with occasional instances of hypotension. A single 5 mg dose of anagrelide can lead to a fall in blood pressure usually accompanied by dizziness. A specific antidote for anagrelide has not been identified. In case of overdose, close clinical supervision of the patient is required; this includes monitoring of the platelet count for thrombocytopenia. Dose should be decreased or stopped, as appropriate, until the platelet count returns to within the normal range. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other antineoplastic agents, ATC Code: L01XX35. Mechanism of action The specific mechanism of action by which anagrelide reduces platelet count is not yet fully understood although it has been confirmed that anagrelide is platelet selective from in vitro and in vivo study information. In vitro studies of human megakaryocytopoiesis established that anagrelide's inhibitory actions on platelet formation in man are mediated via retardation of maturation of megakaryocytes, and reducing their size and ploidy. Evidence of similar in vivo actions was observed in bone marrow biopsy samples from treated patients. Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III. Clinical efficacy and safety The safety and efficacy of anagrelide as a platelet lowering agent have been evaluated in four open-label, non-controlled clinical trials (study numbers 700-012, 700-014, 700-999 and 13970-301) including more than 4000 patients with myeloproliferative disorders (MPDs). In patients with essential thrombocythaemia complete response was defined as a decrease in platelet count to ≤ 600 x 109/l or a ≥ 50% reduction from baseline and maintenance of the reduction for at least 4 weeks. In studies 700-012, 700-014, 700-999 and study 13970-301 the time to complete response ranged from 4 to 12 weeks. Clinical benefit in terms of thrombohaemorrhagic events has not been convincingly demonstrated. Effects on heart rate and QTc interval The effect of two dose levels of anagrelide (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval was evaluated in a double-blind, randomised, placebo- and active-controlled, cross-over study in healthy adult men and women. A dose-related increase in heart rate was observed during the first 12 hours, with the maximum increase occurring around the time of maximal concentrations. The maximum change in mean heart rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg. A transient increase in mean QTc was observed for both doses during periods of increasing heart rate and the maximum change in mean QTcF (Fridericia correction) was +5.0 msec occurring at 2 hours for 0.5 mg and +10.0 msec occurring at 1 hour for 2.5 mg. Paediatric population In an open-label clinical study in 8 children and 10 adolescents (including patients who were anagrelide treatment naïve or who had been receiving anagrelide for up to 5 years pre-study), median platelet counts were decreased to controlled levels after 12 weeks of treatment. The average daily dose tended to be higher in adolescents. In a paediatric registry study, median platelet counts were reduced from diagnosis and maintained for up to 18 months in 14 paediatric ET patients (4 children, 10 adolescents) with anagrelide treatment. In earlier, open-label studies, median platelet count reductions were observed in 7 children and 9 adolescents treated for between 3 months and 6.5 years. The average total daily dose of anagrelide across all studies in paediatric ET patients was highly variable, but overall the data suggest that adolescents could follow similar starting and maintenance doses to adults and that a lower starting dose of 0.5 mg/day would be more appropriate for children over 6 years (see sections 4.2, 4.4, 4.8, 5.2). In all paediatric patients, careful titration to a patient-specific daily dose is needed. This medicinal product has been authorised under “exceptional circumstances”. This means that due to the rarity of this disease it has not been possible to obtain complete information on this medicine. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary. 5.2 Pharmacokinetic properties Absorption Following oral administration of anagrelide in man, at least 70% is absorbed from the gastrointestinal tract. In fasted subjects, peak plasma levels occur about 1 hour after administration. Pharmacokinetic data from healthy subjects established that food decreases the Cmax of anagrelide by 14%, but increases the AUC by 20%. Food also decreased the Cmax of the active metabolite, 3-hydroxy-anagrelide, by 29%, although it had no effect on the AUC. Biotransformation Anagrelide is primarily metabolised by CYP1A2 to form, 3-hydroxy anagrelide, which is further metabolised via CYP1A2 to the inactive metabolite, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline. Elimination The plasma half-life of anagrelide is short, approximately 1.3 hours and as expected from its half-life, there is no evidence for anagrelide accumulation in the plasma. Less than 1% is recovered in the urine as anagrelide. The mean recovery of 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in urine is approximately 18-35% of the administered dose. Additionally these results show no evidence of auto-induction of the anagrelide clearance. Linearity Dose proportionality has been found in the dose range 0.5 mg to 2 mg. Paediatric population Pharmacokinetic data from exposed fasting children and adolescents (age range 7 - 16 years) with essential thrombocythaemia indicate that dose normalised exposure, Cmax and AUC, of anagrelide tended to be higher in children/adolescents compared with adults. There was also a trend to higher dose-normalised exposure to the active metabolite. Elderly Pharmacokinetic data from fasting elderly patients with ET (age range 65 - 75 years) compared to fasting adult patients (age range 22 - 50 years) indicate that the Cmax and AUC of anagrelide were 36% and 61% higher respectively in elderly patients, but that the Cmax and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the elderly patients. These differences were likely to be caused by lower presystemic metabolism of anagrelide to 3-hydroxy anagrelide in the elderly patients. 5.3 Preclinical safety data Repeated dose toxicity Following repeated oral administration of anagrelide in dogs, subendocardial haemorrhage and focal myocardial necrosis was observed at 1mg/kg/day or higher in males and females with males being more sensitive. The no observed effect level (NOEL) for male dogs (0.3mg/kg/day) corresponds to 0.1, 0.1, and 1.6-fold the AUC in humans for anagrelide at 2mg/day, and the metabolites BCH24426 and RL603, respectively. Reproductive toxicology Fertility In male rats, anagrelide at oral doses up to 240 mg/kg/day (>1000 times a 2mg/day dose, based on body surface area) was found to have no effect on fertility and reproductive performance. In female rats increases in pre- and post-implantation losses and a decrease in the mean number of live embryos was observed at 30 mg/kg/day. The NOEL (10mg/kg/day) to this effect was 143, 12 and 11-fold higher than the AUC in humans administered a dose of anagrelide 2 mg/day, and the metabolites BCH24426 and RL603, respectively. Embryofoetal development studies Maternally toxic doses of anagrelide in rats and rabbits were associated with increased embryo resorption and foetal mortality. In a pre- and post-natal development study in female rats, anagrelide at oral doses of ≥10 mg/kg produced a non-adverse increase in gestational duration. At the NOEL dose (3mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and RL603 were 14, 2 and 2-fold higher than the AUC in humans administered an oral dose of anagrelide 2mg/day. Anagrelide at ≥60 mg/kg increased parturition time and mortality in the dam and foetus respectively. At the NOEL dose (30mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and RL603 were 425-, 31- and 13-fold higher than the AUC in humans administered an oral dose of anagrelide 2 mg/day, respectively. Mutagenic and carcinogenic potential Studies on the genotoxic potential of anagrelide did not identify any mutagenic or clastogenic effects. In a two-year rat carcinogenicity study, non-neoplastic and neoplastic findings were observed and related or attributed to an exaggerated pharmacological effect. Among them, the incidence of adrenal phaeochromocytomas was increased relative to control in males at all dose levels (≥ 3 mg/kg/day) and in females receiving 10 mg/kg/day and above. The lowest dose in males (3 mg/kg/day) corresponds to 37 times the human AUC exposure after a 1 mg twice daily dose. Uterine adenocarcinomas, of epigenetic origin, could be related to an enzyme induction of CYP1 family. They were observed in females receiving 30 mg/kg/day, corresponding to 572 times the human AUC exposure after a 1 mg twice daily dose. 6. Pharmaceutical particulars 6.1 List of excipients Capsule contents Povidone (E1201) Lactose, anhydrous Lactose monohydrate Cellulose, microcrystalline (E460) Crospovidone Magnesium stearate Capsule shell Gelatin Titanium dioxide (E171) Printing ink Shellac Strong ammonium solution Potassium hydroxide (E525) Black iron oxide (E172) 6.2 Incompatibilities Not applicable 6.3 Shelf life 4 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container High-density polyethylene (HDPE) bottles with child-resistant closures and desiccant containing 100 capsules. 6.6 Special precautions for disposal and other handling No special requirements. 7. Marketing authorisation holder Shire Pharmaceutical Contracts Ltd Hampshire International Business Park Chineham Basingstoke Hampshire RG24 8EP United Kingdom 8. Marketing authorisation number(s) EU/1/04/295/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 16 November 2004 Date of latest renewal: 16 November 2014 10. Date of revision of the text 04/2015 Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu http://www.info.pmda.go.jp/go/pack/4291428A1029_1_03/ 原发性血小板过多症治疗新药-Xagrid(Anagrelide hard capsule) Agrylin安归宁，主要成分是anagrelide hydrochloride，原有抑制血小板凝集的作用，有抗血栓效果，但以低剂量处方时则意外发现有降低血小板数的功效，主要是减慢骨髓内血小板母细胞（megakaryocyte）分化成熟度，使血小板产量减少，但并非影响血小板母细胞的分裂增殖，对DNA、RNA无伤害，故不会有致癌性，其可抗血小板凝集作用则间接因为减少血小板产生cAMP（cyclic adenosine monophosphate）之故，但其作用所需剂量约为降低血小板数剂量的十倍以上，安归宁目前以口服啶剂问世，最适合需长期治疗的门诊病患，用以治疗原发性血小板过多症无白血球降低及引起贫血之虞，但其心脏血管效应则会有头痛、心悸、眩晕、水肿、呕心、腹痛、腹泻、胸痛等副作用，此心脏血管副作用有种别差异，动物试验中并无此效应，再次反应新药临床试验的重要性，其中以头痛发生率最高达四成五，多在开始用药的前二周内发生可以scanol缓和症状，副作用多再二周后慢慢消失但有三分之一的患者会因副作用而须暂停用药，用以治疗有心脏疾病的病患应特别小心，药物经肝脏代谢尿液中排出，故肝肾功能异常的患者亦须审慎处方。 目前上市的啶剂分别有0.5毫克1毫克，起始每日剂量为二毫克可以0.5毫克啶分四次给予或1毫克两次服用，逐渐调剂至血小板数降至六十万以下或栓塞出血症状消失，每日递增剂量已0.5毫克为限，每日最高剂量不得超过十毫克，每次口服剂量应在2.5毫克以下，通常每日有效剂量为1.5至3毫克，服药后约7日血小板开始下降，百分之七十病患可获满意疗效，其余百分之十患者可部分缓解，临床试验显示纵使对hydroxyurea治疗效果不佳的病患对安归宁亦有良好疗效，多在服药后二至四周达到完全疗效其后可递减至维持剂量，可长期使用因无致癌的危险性，特别适用于年轻的患者，但可穿越胎盘不可使用于怀孕的妇女，高雄荣总血液肿瘤科目前共发现七名年龄低于三十岁的原发性血小板过多症患者，男性居多共六男一女，最低年龄13岁诊断时血小板计数自八十万至一百五十五万，脾脏略肿大或正常皆无临床栓塞出血现象，血小板超过百万者皆接受hydroxyurea治疗，无短期副作用，但新药安归宁的问世肯定是此些年轻患者的福音。 本品已经在美国及另外10个国家以Agrylin或Xagrid为商品名上市。 资料:血小板过多症即血中血小板计数超过四十万称之，临床诊断分为两大类： 一、反应性血小板过多症，亦称续发性血小板过多症（secondary thrombcytosis）。 二、原发性血小板增多症（primary thrombocytosis），临床多属绩发性者，约占87%病例，其病因顺序包括组织伤害（tissue tauma）、感染（infection）、肿瘤（malignancy）及慢性炎症（chronic inflammation）。百分之十的临床病童有反应性血小板增多症，其中百分之七十五因感染所导致，以肺炎、胃肠炎及横川氏症（Kawasaki’s disease）引起者最多件。续发性血小板增多程度与病因有关，于发病四日内见血小板增高，往往介乎六十至百万之间，增多症随病因去除而缓和，通常在一至三周内恢复正常，由于续发性血小板增多为时短暂，多不致发生栓塞或出血等并发症，故良性血小板增多症绝无需治疗之必要。但对有特殊危险因子的患者应小心处理，包括有消化性溃疡出血、脑血管疾病、心肌梗塞病史的病患。原发性血小板过多症属骨髓异常增生性疾病（myeloproliferative disease）的一种，平均发病年龄为55岁，偶发于年轻患者，骨髓增生性疾病除原发性血小板过多症外（essential thrombocythemia），尚包括多血症（polytcythemia vera）、慢性骨髓球白血病（chronic myelocytic leukemia）、骨髓纤维化（agnogenic myeloid metaplasia or idiopathic myelofibrosis，AMM），致病机制在于造血干细胞促族群异常，导致过度增生现象，临床表现循环血球过多迹象，包括红血球、白血球、血小板三类血球，可产生高代谢率症候群，常有疲劳、低烧、食欲不振、体重下降、腹胀等症状，亦会有脾脏肿大、微血管栓塞或出血现象。 此等骨髓增生性疾病中因原发性血小板过多症只有血小板异常表现，通常预后极佳，死亡率极低，但有百分之五的患者发生异常出血，约五分之一的患者有栓塞症状，其中脑血管疾病，急性心肌梗塞可致命，因此目前治疗原则为使用化学治疗或放射性同位素以压制骨髓细胞增殖，放射性磷、hydroxyurea、干扰素（IFN-a）、busulfan、melphalan是常用的药物，但此等药物纵然能抑制各类血液细胞的增殖，但有各类的副作用，如hydroxyurea、busulfan、melphala可导致皮肤色素沉着、皮肤溃疡、肺脏纤维化，更甚者是会引发续发癌，使用达十年以上者有百分之十发生急性白血病的危险性。干扰素虽无明显致癌的可能，但疗效慢，治疗期间严重影响病患的生活质量，包括发热、疲乏、食欲不振、冷颤、肌肉疼痛、昏眩等，此类药品用以治疗原发性血小板过多症时最困扰者莫过于会同时导致白血球及红血球的减少，产生诸多的并发症，治疗医师常遭遇血小板仍处过高状态，但因白血球过低而被迫暂停治疗。 ----------------------------------------------- 产地国家： 德国 原产地英文商品名: Xagrid 0.5mg/cap 100caps/box 原产地英文药品名: Anagrelide 中文参考商品译名: 安归宁 0.5毫克/胶囊 100胶囊/盒 中文参考药品译名: 阿那格雷 生产厂家中文参考译名: 西尔公司 生产厂家英文名: Shire -------------------------------------------------- 产地国家： 日本 原产地英文商品名: AGRYLIN Capsules （アグリリンカプセル）0.5mg/cap 100caps/box 原产地英文药品名: Anagrelide Hydrochloride Hydrate 中文参考商品译名: 安归宁（アグリリンカプセル）0.5毫克/胶囊 100胶囊/盒 中文参考药品译名: 阿那格雷 生产厂家中文参考译名: Shire Japan KK 生产厂家英文名: Shire Japan KK