英文药名: Agrylin (Anagrelide Capsules)

中文药名: 安归宁(阿那格雷胶囊）

品牌药生产厂家: Shire

药品名称

中文药名: 阿那格雷(安归宁)
中文别名：氯喹咪唑酮、盐酸阿那格利
英文名：Anagrelide
缩写： Agrylin
化学合成，结构为活性奎宁唑啉。
简介

在欧洲上市的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。
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。
相互作用

硫糖铝可以干扰安归宁吸收。
适应症

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。
禁忌

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。
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。

注意事项

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
贮存

15~20℃，避光。
补充说明

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，约佔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，於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，通常在一至三週内恢復正常，由於续发性血小板增多为时短暂，多不致发生栓塞或出血等併发症，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，偶发於年轻患者，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），致病机制在於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跡象，包括红血球、白血球、血小板三类血球，可產生高代谢率症候群，常有疲劳、低烧、食慾不振、体重下降、腹胀等症状，亦会有脾臟肿大、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可导致皮肤色素沉著、皮肤溃疡、肺臟纤维化，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品质，包括发热、疲乏、食慾不振、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於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。

此种情况自1997年三月美国通过临床使用一种有选择性降血小板的药剂后得以改善，此药名称为Agrylin安归宁，主要成分是anagrelide hydrochloride阿那格雷，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（cyclicadenosine 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週内发生可以scanol缓和症状，副作用多再二週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，特别适用於年轻的患者，但可穿越胎盘不可使用於怀孕的妇女，高雄荣总血液肿瘤科目前共发现七名年龄低於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.

原发性血小板增多症　

原发性或特发性血小板增多症(Primary or idiopathic thrombocythemia)属于骨髓增生性疾病中的一种。其特征为外周血中血小板明显增多，且有功能不正常，骨髓中巨核细胞过度增殖，临床有自发出血倾向及或有血栓形成，约半数病人有脾大。由于本病常有反复出血，故又称原发性出血性血小板增多症(Primary hemorrhagic thrombocythemia)。

病因及发病机制：

本病也是多能干细胞的克隆性疾病。其出血机理是由于血小板量虽多，但有功能缺陷，如血小板粘附及聚集功能减退、释放功能异常、血小板第三因子降低、5-羟色胺减少等；部分病人有凝血功能的异常，如纤维蛋白原、凝血酶原、因子V、因子Ⅷ的减少，可能是由于凝血因子消耗过多引起；由于本病大部分发生在老年患者，可能合并血管退行性改变，易形成血栓，造成血管远端梗塞，梗塞区破溃出血。

因血小板过多，活化的血小板产生血栓素，引起血小板强烈的聚集及释放反应，形成微血管栓塞，进一步发展为血栓。

晚期原发性血小板增多症，可有肝脏和其他脏器的髓外造血。

临床表现：

原发性血小板增多症，每年发病率为0．1／10万人口。中数发病年龄60岁(范围2～90岁)，好发于50～70岁。女︰男=1．3︰1。起病缓慢。约有20％的病人，尤其年轻患者，发病时无症状，偶尔因血小板增多及脾大进一步检查而确诊。1／3的病人就诊时表现功能性或者血管舒缩性症状包括血管性头痛、头昏、视觉模糊、手掌及足底灼痛感，末梢麻木。80％病人可表现有原因不明的出血及血栓形成而就诊。出血常为自发性，可反复发作，以胃肠道出血常见，也可有鼻、齿龈出血、血尿、呼吸道出血、皮肤、粘膜瘀斑，但紫癜少见。有时可因手术后出血不止而被发现。偶有脑出血，引起死亡。血栓发生率较出血少。国外报告血栓形成较国内多见。国内统计30％有动脉或静脉血栓形成。静脉以脾、肠系膜及下肢静脉为血栓好发部位。下肢血管栓塞后，可表现肢体麻感、疼痛、甚至坏疽。也有表现红斑性肢痛病，间歇性跛行。肠系膜血管血栓形成可致呕吐、腹痛。肺、肾、肾上腺或脑内如发生栓塞可引起相应临床症状，可成为致死的原因。脾大见于80％以上的病例，一般为轻到中度肿大，少数病人有肝肿大。

实验室检查：
(一)血象
血小板计数多在1000～3000×109／L．之间，最高可达20000×109／L。血小板形态一般正常，但有巨大型、小型及畸形，常聚集成堆，偶尔见到巨核细胞碎片及裸核。白细胞计数可正常或增高，多在(10～30)×109／L，偶尔可达到(40～50)×109／L，一般不超过50×109／L，分类以中性分叶核粒细胞增多。因失血少数病人可致低色素性贫血，红细胞大小不均、中心淡染、多染性、嗜碱性点彩及豪-胶小体。
(二)骨髓象
有核细胞增生活跃或明显活跃，巨核细胞增生尤为显著，原始及幼稚巨核增多，有大量血小板聚集成堆。
(三)出、凝血试验
出血时间延长，凝血酶原消耗时间缩短，血块退缩不良。血小板粘附功能及肾上腺素和ADP诱导的聚集功能均降低，但对胶原聚集反应一般正常。凝血酶原时间正常或延长，白陶土部分凝血活酶时间延长。
(四)血尿酸、乳酸脱氢酶、血清酸性磷酸酶均增高，中性粒细胞碱性磷酸酶活性也增高。部分病人因血小板破坏，大量钾离子释放到血中，引起假性高血钾症。
(五)其他
染色体检查部分病人有21号染色体长臂缺失(2lq-)，也有报告21号染色体长臂大小不一的变异。骨髓祖细胞培养有自发的巨核细胞或红细胞克隆形成。

诊断和鉴别诊断：

原因不明的血小板持续性增多(>600×109／L)，骨髓中巨核细胞显著增加，并有大量血小板形成，结合脾大、出血或血栓形成等表现应考虑本病的诊断。但需与继发性(或反应性)血小板增多症及其他骨髓增生性疾病相鉴别。　　

真性红细胞增多症研究组提出最新诊断标准：
①血小板计数>600×109／L；
②血细胞比容<0．4或红细胞容量(RCM)正常；
③骨髓可染铁存在或血清铁蛋白正常或红细胞MCV正常；
④无Ph染色体或bcr／abl基因重排；
⑤骨髓胶原纤维无增生，如<1／3活检面积，常无显著脾大及外周血出现幼粒幼红细胞；
⑥无骨髓增生异常综合征的形态学及细胞遗传学的证据；
⑦无引起反应性血小板增多的原因。　　

原发性血小板增多症主要与下列疾病鉴别：
(一)其他骨髓增生性疾病 真性红细胞增多症、慢性粒细胞白血病及骨髓纤维化等骨髓增生性疾病，皆可伴有血小板增多。但真性红细胞增多症以红细胞增多为突出表现。慢性粒细胞白血病以粒细胞系列为主，血中白细胞显著增多，出现幼稚粒细胞，中性粒细胞碱性磷酸酶积分明显降低，染色体检查可见到Ph染色体。骨髓纤维化的病人外周血中有幼红、幼粒细胞，红细胞大小不等及见到泪滴样红细胞增多，骨髓大多干抽，骨髓活检有纤维化的表现。
(二)继发性血小板增多症 见于脾切除后、脾萎缩、急或慢性失血、外伤及手术后。慢性感染、类风湿性关节炎、风湿病、坏死性肉芽肿、溃疡性结肠炎、恶性肿瘤、分娩、肾上腺素等药物反应也可引起血小板增多。骨髓细胞培养，原发性血小板增多症有自发性巨核细胞集落形成，可与继发性区别。　　

治疗：
治疗的目的要求血小板减少至正常或接近正常，以预防血栓及出血的发生。

病程与预后：
根据血小板增多的程度，病程不一。大多数病例进展缓慢，中位生存期10～15年。约25％病人可转为骨髓纤维化，部分病例可转为真性红细胞增多症或慢性粒细胞白血病。重要脏器有血栓形成及出血，常为本症致死的主要原因。

预防常识：
原发性血小板增多症必须与症状性(继发性)血小板增多症仔细鉴别。脾大不显著，骨髓和血片无白血病细胞，中性粒细胞碱性磷酸酶积分升高，无Ph染色体可与慢粒鉴别；外周血无明显的幼红、幼粒细胞增多、骨骼x线片无显著的骨质硬化征象，骨髓活检无明显的胶元纤维及网状纤维增生等可与骨髓纤维化鉴别；临床无多血质表现，外周血中红细胞和血红蛋白不升高而血小板极度升高，骨髓象无明显的红细胞系统增生而巨核细胞系统却增生极度活跃可与真性红细胞增多症鉴别；无切脾病史，出血时间，血小板粘附和聚集功能降低等可与脾切除术后的血小板增多症鉴别。本病自然病程长，预后良好，根据血小板数值决定用药情况。病人需经常就诊，监测外周血象变化，及时调整用药，并了解疾病演变过程。注意自我保护，防止外伤出血。治疗以化疗、同位素32P为主，血小板单采术可迅速降低血小板、改善症状、有条件可用干扰素治疗。

【原产地英文商品名】AGRYLIN 1mg/capsules 100 capsules/bottle
【原产地英文药品名】ANAGRELIDE HCL
【中文参考商品译名】
注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
·安归宁 0.5毫克/胶囊 100胶囊/瓶
·安归宁 1毫克/胶囊 100胶囊/瓶
【中文参考药品译名】盐酸阿那格雷
【生产厂家中文参考译名】西尔
【生产厂家英文名】shire
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【原产地英文商品名】ANAGRELIDE HCL(AGRYLIN GENERIC) 0.5mg/capsule 30capsules/bottle
【原产地英文药品名】ANAGRELIDE HCL
【中文参考商品译名】
注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
·盐酸阿那格雷(安归宁仿制药) 0.5毫克/胶囊 30胶囊/瓶
·盐酸阿那格雷(安归宁仿制药) 1毫克/胶囊 30胶囊/瓶
【中文参考药品译名】盐酸阿那格雷

AGRYLIN - anagrelide hydrochloride capsule 
Shire US Manufacturing Inc.

DESCRIPTION

Name: AGRYLIN® (anagrelide hydrochloride)

Dosage Form: 0.5 mg capsules for oral administration

Active Ingredient: AGRYLIN® Capsules contain 0.5 mg of anagrelide base (as anagrelide hydrochloride).

Inactive Ingredients: Anhydrous Lactose NF, Crospovidone NF, Lactose Monohydrate NF, Magnesium stearate NF, Microcrystalline cellulose NF, Povidone USP.

Pharmacological Classification: Platelet-reducing agent.

Chemical Name: 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride monohydrate.

Molecular formula: C10H7Cl2N3O•HCl•H2O

Molecular weight: 310.55

Structural formula:

Appearance:	Off-white powder
Solubility:	Water	Very slightly soluble
	Dimethyl Sulfoxide	Sparingly soluble
	Dimethylformamide	Sparingly soluble

Clinical Pharmacology

The mechanism by which anagrelide reduces blood platelet count is still under investigation. Studies in patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically insignificant effect on red cell parameters. Anagrelide inhibits cyclic AMP phosphodiesterase III (PDEIII).  PDEIII inhibitors can also inhibit platelet aggregation.  However, significant inhibition of platelet aggregation is observed only at doses of anagrelide higher than those required to reduce platelet count.

Following oral administration of 14C-anagrelide in people, more than 70% of radioactivity was recovered in urine. Based on limited data, there appears to be a trend toward dose linearity between doses of 0.5 mg and 2.0 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours. The available plasma concentration time data at steady state in patients showed that anagrelide does not accumulate in plasma after repeated administration.

Two major metabolites have been identified (RL603 and 3-hydroxy anagrelide).

There were no apparent differences between patient groups (pediatric versus adult patients) for tmax and t1/2 for anagrelide, 3-hydroxy anagrelide, or RL603.

Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide in the fed and fasted states showed that administration of a 1 mg dose of anagrelide with food decreased the Cmax by 14%, but increased the AUC by 20%.

Pharmacokinetic (PK) data from pediatric (age range 7-14 years) and adult (age range 16-86 years) patients with thrombocythemia secondary to a myeloproliferative disorder (MPD), indicate that dose- and body weight-normalized exposure, Cmax and AUCτ, of anagrelide were lower in the pediatric patients compared to the adult patients (Cmax 48%, AUCτ 55%).

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.

A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment (creatinine clearance <30ml/min) showed no significant effects on the pharmacokinetics of anagrelide.

A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic impairment showed an 8-fold increase in total exposure (AUC) to anagrelide.

CLINICAL STUDIES

A total of 942 patients with myeloproliferative disorders including 551 patients with Essential Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic Myelogenous Leukemia (CML), and 96 patients with other myeloproliferative disorders (OMPD), were treated with anagrelide in three clinical trials. Patients with OMPD included 87 patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had unknown myeloproliferative disorders.

Clinical Studies

Patients with ET, PV, CML, or MMM were diagnosed based on the following criteria:

ET

• Platelet count ≥ 900,000/μL on two determinations

• Profound megakaryocytic hyperplasia in bone marrow

• Absence of Philadelphia chromosome

• Normal red cell mass

• Normal serum iron and ferritin and normal marrow iron stores

CML

• Persistent granulocyte count ≥ 50,000/μL without evidence of infection

• Absolute basophil count ≥ 100/μL

• Evidence for hyperplasia of the granulocytic line in the bone marrow

• Philadelphia chromosome is present

• Leukocyte alkaline phosphatase ≤ lower limit of the laboratory normal range

PV+

• A1 Increased red cell mass

• A2 Normal arterial oxygen saturation

• A3 Splenomegaly

• B1 Platelet count ≥ 400,000/μL, in absence of iron deficiency or bleeding

• B2 Leukocytosis (≥ 12,000/μL, in the absence of infection)

• B3 Elevated leukocyte alkaline phosphatase

• B4 Elevated serum B12

+ Diagnosis positive if A1, A2, and A3 present; or, if no splenomegaly, diagnosis is positive if A1 and A2 are present with any two of B1, B2, or B3.

MMM

• Myelofibrotic (hypocellular, fibrotic) bone marrow

• Prominent megakaryocytic metaplasia in bone marrow

• Splenomegaly

• Moderate to severe normo-chromic normocytic anemia

• White cell count may be variable; (80,000-100,000/μL)

• Increased platelet count

• Variable red cell mass; teardrop poikilocytes

• Normal to high leukocyte alkaline phosphatase

• Absence of Philadelphia chromosome

Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/μL on two occasions or ≥ 650,000/μL on two occasions with documentation of symptoms associated with thrombocythemia. The mean duration of anagrelide therapy for ET, PV, CML, and OMPD patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for 2 years. Patients were treated with anagrelide starting at doses of 0.5-2.0 mg every 6 hours. The dose was increased if the platelet count was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000-400,000/μL). The criteria for defining subjects as "responders" were reduction in platelets for at least 4 weeks to ≤600,000/μL, or by at least 50% from baseline value. Subjects treated for less than 4 weeks were not considered evaluable. The results are depicted graphically below:

 *x 103/μL

+ Nine hundred and forty-two subjects with myeloproliferative disorders were enrolled in three research studies. Of these, 923 had platelet counts over the duration of the studies.

AGRYLIN® was effective in phlebotomized patients as well as in patients treated with other concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and alkylating agents.

Indications and Usage

AGRYLIN® Capsules are indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events (see CLINICAL STUDIES, DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

Anagrelide is contraindicated in patients with severe hepatic impairment. Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment (see CLINICAL PHARMACOLOGY). Use of anagrelide in patients with severe hepatic impairment has not been studied (see also WARNINGS: Hepatic).

WARNINGS

Cardiovascular

Anagrelide should be used with caution in patients with known or suspected heart disease, and only if the potential benefits of therapy outweigh the potential risks. Because of the positive inotropic effects and side-effects of anagrelide, a pre-treatment cardiovascular examination is recommended along with careful monitoring during treatment. In humans, therapeutic doses of anagrelide may cause cardiovascular effects, including vasodilation, tachycardia, palpitations, and congestive heart failure.

Hepatic

Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment (see CLINICAL PHARMACOLOGY ). Use of anagrelide in patients with severe hepatic impairment has not been studied. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate impairment of hepatic function should be assessed before treatment is commenced. In patients with moderate hepatic impairment, dose reduction is required and patients should be carefully monitored for cardiovascular effects (see DOSAGE AND ADMINISTRATION for specific dosing recommendations).

Interstitial Lung Diseases

Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been reported to be associated with the use of anagrelide in post-marketing reports. Most cases presented with progressive dyspnea with lung infiltrations. The time of onset may range from 1 week to several years after initiating anagrelide. In most cases, the symptoms improved after discontinuation of anagrelide (See ADVERSE REACTIONS).

PRECAUTIONS

Laboratory Tests:

Anagrelide therapy requires close clinical supervision of the patient. While the platelet count is being lowered (usually during the first two weeks of treatment), blood counts (hemoglobin, white blood cells), and renal function (serum creatinine, BUN) should be monitored. Cases of clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and elevations greater than three times the ULN) have been reported in post-marketing surveillance. Measure liver function tests (ALT, AST) before initiating anagrelide treatment and during therapy.

In 9 subjects receiving a single 5 mg dose of anagrelide, standing blood pressure fell an average of 22/15 mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure were observed following a dose of 2 mg.

Cessation of AGRYLIN® Treatment:

In general, interruption of anagrelide treatment is followed by an increase in platelet count. After sudden stoppage of anagrelide therapy, the increase in platelet count can be observed within four days.

Drug Interactions:

Limited PK and/or PD studies investigating possible interactions between anagrelide and other medicinal products have been conducted. In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the PK properties of anagrelide, nor does anagrelide affect the PK properties of digoxin or warfarin.

In two clinical interaction studies in healthy subjects, co-administration of single-dose anagrelide 1mg and aspirin 900mg or repeat-dose anagrelide 1mg once daily and aspirin 75mg once daily showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone.  Co-administered anagrelide 1mg and aspirin 900mg single-doses had no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT). 

The potential risks and benefits of concomitant use of anagrelide with aspirin should be assessed, particularly in patients with a high risk profile for haemorrhage, before treatment is commenced.

Drug interaction studies have not been conducted with the other common medications used concomitantly with anagrelide in clinical trials which were acetaminophen, furosemide, iron, ranitidine, hydroxyurea, and allopurinol.

Anagrelide is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine, and such medicinal products could theoretically adversely influence the clearance of anagrelide. 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 cyclic AMP PDE III. The effects of medicinal products with similar properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by anagrelide.

There is a single case report which suggests that sucralfate may interfere with anagrelide absorption.

Food has no clinically significant effect on the bioavailability of anagrelide.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

In a two year rat carcinogenicity study a higher incidence of uterine adenocarcinoma, relative to controls, was observed in females receiving 30mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose). Adrenal phaeochromocytomas were increased relative to controls in males receiving 3mg/kg/day and above, and in females receiving 10mg/kg/day and above (at least 10 and 18 times respectively human AUC exposure after a 1mg twice daily dose). Anagrelide hydrochloride was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (1,440 mg/m2/day, 195 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male rats. However, in female rats, at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on body surface area) or higher, it disrupted implantation when administered in early pregnancy and retarded or blocked parturition when administered in late pregnancy.

Pregnancy:

Pregnancy Category C.

(i) Teratogenic Effects

Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day (5,400 mg/m2/day, 730 times the recommended maximum human dose based on body surface area) and in pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m2/day, 32 times the recommended maximum human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to anagrelide hydrochloride.

(ii) Nonteratogenic Effects

A fertility and reproductive performance study performed in female rats revealed that anagrelide hydrochloride at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on body surface area) or higher disrupted implantation and exerted adverse effect on embryo/fetal survival.

A perinatal and postnatal study performed in female rats revealed that anagrelide hydrochloride at oral doses of 60 mg/kg/day (360 mg/m2/day, 49 times the recommended maximum human dose based on body surface area) or higher produced delay or blockage of parturition, deaths of nondelivering pregnant dams and their fully developed fetuses, and increased mortality in the pups born.

There are however, no adequate and well controlled studies with anagrelide hydrochloride in pregnant women. Because animal reproduction studies are not always predictive of human response, anagrelide hydrochloride should be used during pregnancy only if clearly needed.

Nonclinical toxicology:

In the 2-year rat study, a significant increase in non-neoplastic lesions were observed in anagrelide treated males and females in the adrenal (medullary hyperplasia), heart (myocardial hypertrophy and chamber distension), kidney (hydronephrosis, tubular dilation and urothelial hyperplasia) and bone (femur enostosis). Vascular effects were observed in tissues of the pancreas (arteritis/periarteritis, intimal proliferation and medial hypertrophy), kidney (arteritis/periarteritis, intimal proliferation and medial hypertrophy), sciatic nerve (vascular mineralization), and testes (tubular atrophy and vascular infarct) in anagrelide treated males.

Five women became pregnant while on anagrelide treatment at doses of 1 to 4 mg/day. Treatment was stopped as soon as it was realized that they were pregnant. All delivered normal, healthy babies. There are no adequate and well-controlled studies in pregnant women. Anagrelide hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Anagrelide is not recommended in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of child-bearing potential should be instructed that they must not be pregnant and that they should use contraception while taking anagrelide. Anagrelide may cause fetal harm when administered to a pregnant woman.

Nursing Mothers:

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reaction in nursing infants from anagrelide hydrochloride, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:

Myeloproliferative disorders are uncommon in pediatric patients and limited data are available in this population. An open label safety and PK/PD study (see CLINICAL PHARMACOLOGY) was conducted in 17 pediatric patients 7-14 years of age (8 patients 7-11 years of age and 9 patients 11-14 years of age, mean age of 11 years; 8 males and 9 females) with thrombocythemia secondary to ET as compared to 18 adult patients (mean age of 63 years, 9 males and 9 females). Prior to entry on to the study, 16 of 17 pediatric patients and 13 of 18 adult patients had received anagrelide treatment for an average of 2 years. The median starting total daily dose, determined by retrospective chart review, for pediatric and adult ET patients who had received anagrelide prior to study entry was 1mg for each of the three age groups (7-11 and 11-14 year old patients and adults). The starting dose for 6 anagrelide-naive patients at study entry was 0.5 mg once daily. At study completion, the median total daily maintenance doses were similar across age groups, median of 1.75 mg for patients of 7-11 years of age, 2 mg in patients 11-14 years of age, and 1.5 mg for adults.

The study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anagrelide, including platelet counts (see CLINICAL PHARMACOLOGY).

The frequency of adverse events observed in pediatric patients was similar to adult patients. The most common adverse events observed in pediatric patients were fever, epistaxis, headache, and fatigue during a 3-months treatment of anagrelide in the study. Adverse events that had been reported in these pediatric patients prior to the study and were considered to be related to anagrelide treatment based on retrospective review were palpitation, headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps. Episodes of increased pulse rate and decreased systolic or diastolic blood pressure beyond the normal ranges in the absence of clinical symptoms were observed in some patients. Reported AEs were consistent with the known pharmacological profile of anagrelide and the underlying disease. There were no apparent trends or differences in the types of adverse events observed between the pediatric patients compared with those of the adult patients. No overall difference in dosing and safety were observed between pediatric and adult patients.

In another open-label study, anagrelide had been used successfully in 12 pediatric patients (age range 6.8 to 17.4 years; 6 male and 6 female), including 8 patients with ET, 2 patients with CML, 1 patient with PV, and 1 patient with OMPD. Patients were started on therapy with 0.5 mg qid up to a maximum daily dose of 10 mg. The median duration of treatment was 18.1 months with a range of 3.1 to 92 months. Three patients received treatment for greater than three years. Other adverse events reported in spontaneous reports and literature reviews include anemia, cutaneous photosensitivity and elevated leukocyte count.

Geriatric Use:

Of the total number of subjects in clinical studies of AGRYLIN®, 42.1% were 65 years and over, while 14.9% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS

Analysis of the adverse events in a population consisting of 942 patients in 3 clinical studies diagnosed with myeloproliferative diseases of varying etiology (ET: 551; PV: 117; OMPD: 274) has shown that all disease groups have the same adverse event profile. While most reported adverse events during anagrelide therapy have been mild in intensity and have decreased in frequency with continued therapy, serious adverse events were reported in these patients. These include the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis, pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal ulceration, and seizure.

Of the 942 patients treated with anagrelide for a mean duration of approximately 65 weeks, 161 (17%) were discontinued from the study because of adverse events or abnormal laboratory test results. The most common adverse events for treatment discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain. Overall, the occurrence rate of all adverse events was 17.9 per 1,000 treatment days. The occurrence rate of adverse events increased at higher dosages of anagrelide.

The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative disease) in clinical trials were:

Headache 43.5%

Palpitations 26.1%

Diarrhea 25.7%

Asthenia 23.1%

Edema, other 20.6%

Nausea 17.1%

Abdominal Pain 16.4%

Dizziness 15.4%

Pain, other 15.0%

Dyspnea 11.9%

Flatulence 10.2%

Vomiting 9.7%

Fever 8.9%

Peripheral Edema 8.5%

Rash, including urticaria 8.3%

Chest Pain 7.8%

Anorexia 7.7%

Tachycardia 7.5%

Pharyngitis 6.8%

Malaise 6.4%

Cough 6.3%

Paresthesia 5.9%

Back Pain 5.9%

Pruritus 5.5%

Dyspepsia 5.2%

Adverse events with an incidence of 1% to < 5% included:

Body as a Whole System: Flu symptoms, chills, photosensitivity.

Cardiovascular System: Arrhythmia, hemorrhage, hypertension, cardiovascular disease, angina pectoris, heart failure, postural hypotension, thrombosis, vasodilatation, migraine, syncope.

Digestive System: Constipation, GI distress, GI hemorrhage, gastritis, melena, aphthous stomatitis, eructation.

Hemic & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy.

Platelet counts below 100,000/μL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction below 50,000/μL occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide therapy. Thrombocytopenia promptly recovered upon discontinuation of anagrelide.

Hepatic System: Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during anagrelide therapy.

Musculoskeletal System: Arthralgia, myalgia, leg cramps.

Nervous System: Depression, somnolence, confusion, insomnia, nervousness, amnesia.

Nutritional Disorders: Dehydration.

Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma.

Skin and Appendages System: Skin disease, alopecia.

Special Senses: Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.

Urogenital System: Dysuria, hematuria.

Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with OMPD experienced renal failure (approximately 1%) while on anagrelide treatment; in 4 cases, the renal failure was considered to be possibly related to anagrelide treatment. The remaining 11 were found to have pre-existing renal impairment. Doses ranged from 1.5-6.0 mg/day, with exposure periods of 2 to 12 months. No dose adjustment was required because of renal insufficiency.

The adverse event profile for patients in three clinical trials on anagrelide therapy (in 5% or greater of 942 patients with myeloproliferative diseases) is shown in the following bar graph:

Cases of interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) and clinically significant hepatotoxicity have been reported (See WARNINGS, Interstitial Lung Diseases and PRECAUTIONS, Laboratory Tests).

OVERDOSAGE

Acute Toxicity and Symptoms

Single oral doses of anagrelide hydrochloride at 2,500, 1,500 and 200 mg/kg in mice, rats and monkeys, respectively, were not lethal. Symptoms of acute toxicity were: decreased motor activity in mice and rats and softened stools and decreased appetite in monkeys.

There have been postmarketing case reports of intentional overdose with anagrelide hydrochloride. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative management. Platelet reduction from anagrelide therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage. Should overdosage occur, cardiac and central nervous system toxicity can also be expected.

Management and Treatment

In case of overdosage, close clinical supervision of the patient is required; this especially 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.

DOSAGE AND ADMINISTRATION

Treatment with AGRYLIN® Capsules should be initiated under close medical supervision. The recommended starting dosage of AGRYLIN® for adult patients is 0.5 mg qid or 1 mg bid (2 capsules of 0.5 mg twice a day), which should be maintained for at least one week. Starting doses in pediatric patients have ranged from 0.5 mg per day to 0.5 mg qid. As there are limited data on the appropriate starting dose for pediatric patients, an initial dose of 0.5 mg per day is recommended. In both adult and pediatric patients, dosage should then be adjusted to the lowest effective dosage required to reduce and maintain platelet count below 600,000/μL, and ideally to the normal range. The dosage should be increased by not more than 0.5 mg/day in any one week. Maintenance dosing is not expected to be different between adult and pediatric patients. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose (see PRECAUTIONS).

There are no special requirements for dosing the geriatric population.

It is recommended that patients with moderate hepatic impairment start anagrelide therapy at a dose of 0.5 mg/day and be maintained for a minimum of one week with careful monitoring of cardiovascular effects. The dosage increment must not exceed more than 0.5 mg/day in any one-week. The potential risks and benefits of anagrelide therapy in a patient with mild or moderate impairment of hepatic function should be assessed before treatment is commenced. Use of anagrelide in patients with severe hepatic impairment has not been studied. Use of anagrelide in patients with severe hepatic impairment is contraindicated (see CONTRAINDICATIONS).

To monitor the effect of anagrelide and prevent the occurrence of thrombocytopenia, platelet counts should be performed every two days during the first week of treatment and at least weekly thereafter until the maintenance dosage is reached.

Typically, platelet count begins to respond within 7 to 14 days at the proper dosage. The time to complete response, defined as platelet count ≤ 600,000/μL, ranged from 4 to 12 weeks. Most patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Patients with known or suspected heart disease, renal insufficiency, or hepatic dysfunction should be monitored closely.

HOW SUPPLIED

AGRYLIN® is available as:

0.5 mg, opaque, white capsules imprinted "S063" in black ink:

NDC 54092-063-01 = bottle of 100

Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), [See USP Controlled Room Temperature]. Store in a light resistant container.