安归宁（Agrylin）
【一】
其他名：
1、 中文名： 阿那格雷
2、 英文名：Anagrelide
3、 缩写： Agrylin
【二】 来源：
化学合成，结构为活性奎宁唑啉。
【三】 作用机制：
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。
【四】 药代动力学：
【五】 相互作用：
硫糖铝可以干扰安归宁吸收。
【六】适应证：
美国FDA批准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。
【七】 单药有效率：
治疗有效率报告为60%~93%，平均70%，另10%患者可部分缓解。
【八】 剂型以及剂量：
【九】 给药途径：
口服。
【十】 配伍：
无相关资料。
【十一】 禁忌证：
1、 对安归宁过敏者禁用。
2、 妊娠或有预期妊娠妇女禁用。
3、 有严重心血管及肝肾疾病者慎用。
【十二】 不良反应：
1、 心血管系统：乏力、心悸、水肿，个别可发生心律紊乱。
2、 消化系统：腹痛、恶心、腹胀，发生率为10%左右。肝脏转氨酶升高。
3、 呼吸系统：气短、肺纤维化和肺浸润。
4、 神经系统：头疼（发生率在亚洲可达一半），眩晕、无力，视物模糊或视力有严重影响。
5、 血液
【十三】 临床使用规程：
1、 告知女性患者服药期间应采取避孕措施。
2、告知患者服药初期可能会发生头疼、心悸，多于用药第2周内出现，继续用药可逐渐消失，症状明显可对症用止痛药。
3、有严重心脑血管病患者用时必须定期监测心脏功能，因本药可有水潴留作用。
4、 血小板降低症状多在用药1周
【十四】 贮存：
15~20℃，避光。
生产商:西尔公司
在欧洲上市的
商品名:xagrid
西尔公司在美国和加拿大销售阿那格雷的商标为Agrylin, 在欧洲销售的商标为Xagrid。Agrylin是治疗原发性血小板血症（ET）的药物，ET是骨髓的一种慢性疾病，该病与血小板生成增多相关。
1. NAME OF THE MEDICINAL PRODUCT
Xagrid 0.5mg hard capsule
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 0.5 mg anagrelide (as 0.61 mg anagrelide
hydrochloride)
For a full list of excipients, see section 6.1
3. PHARMACEUTICAL FORM
Capsule, hard
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 administrationTreatment with Xagrid capsules should be initiated by a clinician with experience in the management of essential thrombocythaemia.The recommended starting dosage of anagrelide is 1mg/day, which shouldbeadministered orally in two divided doses (0.5mg/dose).The starting dose should be maintained for at least one week. After one week the dosage may be titrated, on an individual basis, to achieve the lowest effective dosage 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 dosage increment must not exceed more than 0.5mg/day in any one-week and the recommended maximum single dose should not exceed 2.5mg (see section 4.9). During clinical development dosages of 10mg/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>1mg/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 dosage of 1 to 3mg/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 dosage 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
Currently, there are no specific pharmacokinetic data for this patient population and the potential risks and benefits of anagrelide therapy in a patient with impairment of renal function should be assessed before treatment is commenced.
Hepatic impairment
Currently, there are no specific pharmacokinetic data for this patient population. However, hepatic metabolism represents the major route of drug 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).
Children and adolescents:
The experience in children is limited.
4.3 Contraindications
Hypersensitivity to anagrelide or to any of the excipients of the medicinal product.Patients with moderate or severe hepatic impairment. Patients with moderate or severe renal impairment (creatinine clearance <50ml/min).
4.4 Special warnings and precautions for useHepatic impairment: (see sections 4.2 and 4.3) 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).Renal impairment: (see sections 4.2 and 4.3) the potential risks and benefits of anagrelide therapy in a patient with impairment of renal function should be assessed before treatment is commenced.General: therapy requires close clinical supervision of the patient which
will include a full blood count (haemoglobin and white blood cell and platelet counts), and assessment of liver function (ALT and AST) and renal function (serum creatinine and urea) tests.Platelets: the platelet count will increase within 4 days of stopping treatment with Xagrid capsules and will return to pre-treatment levels within 10 to 14 days.Cardiovascular: Cases of cardiomegaly and congestive heart failure have been reported (see section 4.8). Anagrelide should be used with caution in
patients of any age with known or suspected heart disease, and only if the potential benefits of therapy outweighthepotential risks. Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III and because of its positive inotropiceffects, a pre-treatment cardiovascular examination (including further investigation such asechocardiography,electrocardiogramisrecommended. Patients should be monitored during treatment for evidence of cardiovascular effects that may require further cardiovascular examination and investigation.Paediatric patients: (see section 5.1) limited data are available on the use of anagrelide in the paediatric population and anagrelide should be used in this patient group with caution.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. Excipients: This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interactionLimited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between anagrelide and other medicinal products have been conducted.
Drug interactions: effects of other substances on anagrelide • Anagrelide is primarily metabolised by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine and omeprazole, 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.
Drug interactions: effects of anagrelide on other 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 theoretically 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 1mg once daily and acetylsalicylic acid 75mg once daily may enhance the anti-platelet aggregation effects of each drug compared with administration of acetylsalicylic acid alone. Therefore, due to the lack of data in ET patients, 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.
4.6 Pregnancy and lactation
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.Use of Xagrid during pregnancy is not recommended. If Xagrid is used during pregnancy, or if the patient becomes pregnant while using the drug, she should be advised of the potential risk to the foetus.Women of child-bearing potential should use adequate birth-control measures during treatment with anagrelide.Lactation: It is not known whether anagrelide hydrochloride is excreted in milk. Since many medicinalproducts are excreted in human milk and because of the potential for adverse reactions inbreastfeedinginfants,mothersshoulddiscontinue breast-feeding when taking Xagrid.
4.7 Effects on ability to drive and use machinesNo studies on the effects on the ability to drive and use machines have
been performed. In clinical development, dizziness was commonly reported.Patients are advised not to drive or operate machinery while taking Xagrid if dizziness is experienced.
4.8 Undesirable effectsThe 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 2mg/day were assessed for safety. In these studies22patients received anagrelide for up to 4 years. In the later study 3660 patients who received anagrelide at a mean dose ofpproximately 2mg/day were assessed for safety. In this study 34 patients received anagrelide for up to 5 years.The most commonly reported drug related adverse reactions 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).The following convention was used for frequency of adverse drug reactions: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); not known (cannot be estimated from the
available data).Blood and lymphatic system disordersCommon: AnaemiaUncommon: Thrombocytopenia, pancytopenia, ecchymosis, haemorrhageMetabolism and nutrition disordersCommon: Fluid retentionUncommon: Oedema, weight lossRare: Weight gainNervous system disordersVery common: HeadacheCommon: DizzinessUncommon: Paraesthesia, insomnia, depression, confusion, hypoaesthesia, nervousness, dry mouth, amnesiaRare: Somnolence, abnormal coordination, dysarthria, migraineSpecial sensesRare: Vision abnormal, tinnitus, diplopiaCardiac disordersCommon: Palpitations, tachycardiaUncommon: Congestive heartfailure,hypertension, arrhythmia, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, syncopeRare:Anginapectoris,myocardial infarction, cardiomegaly, cardiomyopathy, pericardial effusion, vasodilatation, postural hypotension
Respiratory and thoracic disordersUncommon: Dyspnoea, epistaxis, pleural effusion, pneumoniaRare: Pulmonary hypertension, pulmonary infiltratesNot known: Allergic alveolitisGastrointestinal disordersCommon: Nausea, diarrhoea, abdominal pain, flatulence, vomitingUncommon: Dyspepsia, anorexia, pancreatitis, constipation, gastrointestinal haemorrhage, gastrointestinal disorderRare: Colitis, gastritis, gingival bleedingHepatobiliary disordersUncommon:HepaticenzymesincreasedSkinandsubcutaneous tissueCommon:RashUncommon:Alopecia,skindiscoloration,pruritusRare:DryskinMusculoskeletalandconnectivetissuedisordersUncommon: Myalgia, arthralgia, back painUrogenitalUncommon: ImpotenceRare: Nocturia, renal failureInvestigations Rare: Blood creatinine increasedGeneral disorders and administration site conditionsCommon: FatigueUncommon: Chest pain, weakness, chills, malaise, feveryRare: Asthenia, pain, flu-like syndrome
4.9 Overdose
There have been a small number of post-marketing case reports of intentional overdose with anagrelide. Reported symptoms include sinus 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. Dosage should be decreased or stopped, as appropriate, until the platelet count returns to within the normal range. Xagrid, at higher than recommended doses, has been shown to produce reductions in blood pressure with occasional instances of hypotension. A single 5mg dose of anagrelide can lead to a fall in blood pressure usually accompanied by dizziness.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic propertiesPharmacotherapeutic group: ATC Code: L01XX35 (Other Antineoplastic Agents)The specificmechanism 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.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.
Children and adolescents:
An open label clinical study with a 3 month treatment period didnotraiseanysafetyconcernsforanagrelidein17children/adolescent patients with ET (age range 7-14 years) compared to 18 adult patients. Earlier during clinical development a limited number (12) of children (age range 5 - 17 years) with essential thrombocythaemia were treated with anagrelide.
5.2 Pharmacokinetic properties
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 a 0.5mg dose; the plasma half-life is short, approximately 1.3 hours. Dose proportionality has been found in the dose range 0.5mg to 2mg. Anagrelide is primarily metabolised by CYP1A2; less than 1% is recovered in the urine as anagrelide. Two major urinary metabolites, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline and
N-(5,6-dichloro-3,4-dihydroquinazalin-2-yl)-2-oxoacetamide have been identified. The mean recovery of 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in urine is approximately 18-35% of the administered dose.Pharmacokinetic data from healthy subjects established that food decreases the Cmax of anagrelide by 14%, but increases the AUC by 20%. Food had a more significant effect on the active metabolite and decreased the Cmax by 29%, although it had no effect on the AUC.As expected from its half-life, there is no evidence for anagrelide accumulation in the plasma. Additionally these results show no evidence of
auto-induction of the anagrelide clearance.
Special populations
Children and adolescentsPharmacokinetic data from fasting children and adolescents (age range 7 - 14 years) with essential thrombocythaemia indicate that dose and body weight normalisedexposure,CmaxandAUC,ofanagrelidewerelowerinchildren/adolescents compared to adults. There was also a trend to lower exposure to the active metabolite. These observations may be a reflection
of more efficient metabolic clearance in younger subjects.
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, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline, were 42%and37lowerrespectively in the elderly patients. These differences were likely to be caused by lower presystemic metabolism of anagrelide to
2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in the elderly patients.
5.3 Preclinical safety data
Repeated dose toxicity.Following repeated administration of anagrelide, at doses of 1mg/kg/day or higher, subendocardial haemorrhage and focal myocardial necrosis occurred in dogs. Reproductive toxicology.Maternally toxic doses of anagrelide (60 mg/kg/day and above) in rats and rabbits were associated with increased embryo resorption and foetal mortality.
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.Currently, there is no clinical evidence that these findings are of relevance to human use.
美国上市的
商品名:Agrylin
通用名称：盐酸阿那格雷
英文名称：Agrylin、Anagrelide Hydrochloride
中文别名：氯喹咪唑酮、盐酸阿那格利
2.作用机制
阿那格雷主要作用于巨核细胞，可抑制环磷腺苷（cAMP）磷酸二酯酶的活性，增加血小板内cAMP水平，从而抑制血小板的聚集及形态变化，抑制巨核细胞的成熟。大量研究结果发现，阿那格雷在体内外都能影响巨核细胞的成熟，导致细胞体变小和形态特征的变化，并认为阿那格雷减少血小板的数量主要是因为干预巨核细胞的成熟。体外实验发现，阿那格雷可以通过减少巨核细胞的大小和倍性而抑制巨核细胞克隆的发展或者是破坏和阻止巨核细胞的成熟，这些作用出现在巨核细胞发展的后一阶段、非分裂期。
3.适应症
治疗原发血小板增生症。
4.用法用量
起始每日剂量为2mg可以0.5mg分四次给予或1mg两次服用，逐渐调至血小板数降至六十万以下或栓塞出血症状消失，每日递增剂量以0.5mg为限，每日最高剂量不得超过10mg，每次口服剂量应在2.5mg以下，通常每日有效剂量为1.5至3mg，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。
5.剂型及规格
片剂0.5mg，胶囊0.5mg、1mg。