Xagrid

HOS-093594 · has-adverse-reaction-information · PDF-Seite 7

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. MedDRA Frequency of adverse reactions System Organ Very Common Uncommon Rare Not known Class common Blood and Anaemia Pancytopenia lymphatic Thrombocytopenia system Haemorrhage disorders Ecchymosis Metabolism and Fluid Oedema Weight gain nutrition retention Weight loss disorders Nervous system Headache Dizziness Depression Migraine Cerebral disorders Amnesia Dysarthria infarction* Confusion Somnolence Insomnia Abnormal Paraesthesia coordination

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HOS-093590 · has-contraindication-information · PDF-Seite 3

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). 3

HOS-093589 · has-indication-information · PDF-Seite 2

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.

HOS-093592 · has-interaction-information · PDF-Seite 5

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  In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the pharmacokinetic properties of anagrelide. CYP1A2 inhibitors  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. CYP1A2 inducers  CYP1A2 inducers (such as omeprazole) could decrease the exposure of anagrelide (see section 5.2). The consequences on the safety and efficacy profile of anagrelide are not established. Therefore, clinical and biological monitoring is recommended in patients taking concomitant CYP1A2 inducers. If needed, anagrelide dose adjustment could be made. 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. 5  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 patients with ET concomitantly treated by acetylsalicylic acid and anagrelide, major haemorrhages occurred. Therefore, the potential risks of the concomitant

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HOS-093593 · has-pregnancy-information · PDF-Seite 6

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).

HOS-093591 · has-warning-information · PDF-Seite 4

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). Thrombotic Risk Abrupt treatment discontinuation should be avoided due to the risk of sudden increase in platelet counts, which may lead to potentially fatal thrombotic complications, such as cerebral infarction. Patients should be advised how to recognize early signs and symptoms suggestive of thrombotic complications, such as cerebral infarction, and if symptoms occur to seek medical assistance. Treatment discontinuation In the event of dosage interruption or treatment withdrawal, the rebound in platelet count is variable, but the platelet count will start to increase within 4 days of stopping treatment with anagrelide and will return to pre-treatment levels within 10 to 14 days, possibly rebounding above baseline values. Therefore, platelets should be monitored frequently (see section 4.2). 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). 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 rec

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