Core Safety Profile. Pharmaceutical form(s)/strength: Capsules, 0.5 mg AT/H/PSUR/0028/001 Date of FAR:

Transcription

1 Core Safety Profile Active substance: Anagrelide hydrochloride Pharmaceutical form(s)/strength: Capsules, 0.5 mg P-RMS: AT/H/PSUR/0028/001 Date of FAR:

2 4.3 Contraindications Hypersensitivity to anagrelide or to any of the excipients of the medicinal product Cardiovascular disease grade 3 with a negative benefit/risk assessment or grade 4 (South West Oncology Group) Severe renal insufficiency (creatinine clearance < 30ml/min) moderate to severe hepatic insufficiency 4.4 Special warnings and precautions for use General The therapy requires close clinical supervision of the patient including complete blood count (haemoglobin, white blood cells and platelet counts) and tests regarding liver function (e.g. GPT/ALAT and GOT/ASAT) and renal function (serum creatinine). Cardiovascular effects During treatment with anagrelide cases of cardiomegaly and cardiac insufficiency were reported (see section 4.8 Undesirable effects). In patients with known or suspected heart diseases anagrelide must be administered with caution independently of the age of the patient and only after a positive benefit/risk assessment. Anagrelide inhibits cyclic AMP-phosphodiesterase III and because of its positive inotropic effect cardiovascular examinations (including e.g. echocardiography and electrocardiogram) before start of the therapy is recommended. During the therapy patients should be monitored for cardiovascular changes that may require further cardiovascular examinations. Palpitations and headache were often observed mainly at the beginning of a therapy (see section 4.8). These undesired effects can be reduced by a slow increase of the dosage with a starting dose of 0.5 to 1.0 mg per day and normally abate within few weeks. Hepatic impairment (see sections 4.2 and 4.3) In patients with impaired liver function frequent liver function tests especially at the beginning of the therapy are necessary. Renal impairment (see sections 4.2 and 4.3) In patients with impaired renal function frequent kidney function tests especially at the beginning of the therapy are necessary. Lactose-Warning Anagrelide contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 2/7

3 4.5 Interaction with other medicinal products and other forms of interaction Until now limited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between anagrelide and other medicinal products have been conducted. The following drugs were used concomitantly with anagrelide: acetylsalicylic acid, acetaminophen, -blocker, ACE-inhibitors, clopridogrel, coumarine, folic acid, amlodipine, carbamazepine, hydrochlorothiazide, indapamide, furosemide, iron, isosorbide mononitrate, levothyroxin-na, simvastatin, ticlopidin, ranitidine, hydroxyurea, allopurinol and digoxin. With exception of acetylsalicylic acid (elevated risk for bleeding) no significant interactions could be observed. 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. 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. An in vitro study in human whole blood demonstrated that the antiaggregatory effects of acetylsalicylic acid were additively, but not synergistically increased by the presence of anagrelide. 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. Co-administration of repeat-dose anagrelide and acetylsalicylic acid 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 Effects of anagrelide on other medical products 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. 3/7

4 It has been demonstrated that grapefruit juice inhibits CYP1A2 and thus may reduce the clearance of anagrelide. 4.6 Pregnancy and lactation Pregnancy There are insufficient data in humans regarding administration during pregnancy. Studies in animals have shown reproductive toxicity at very high dosages. Therefore anagrelide is not recommended during pregnancy. If anagrelide 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 is excreted in milk. Since many medicinal products are excreted in human milk and because of the potential for adverse reactions in breast-feeding infants, mothers should discontinue breast-feeding when taking anagrelide. 4.7 Effects on ability to drive and use machines No 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 anagrelide if dizziness is experienced. 4.8 Undesirable effects The most frequent undesirable effects of anagrelide, which were mostly slight in intensity and decreased during proceeding of the therapy, were: headache, palpitation, oedemas, nausea and diarrhoea. These undesired effects are expected due to the pharmacologic effect of anagrelide. By a slow increase of the dosage with a starting dose of 0.5 to 1.0 mg per day these effects can be reduced. The following undesirable effects are ranked according to system organ class and to their frequency: Very common ( 1/10) Common ( 1/100 to < 1/10) Uncommon ( 1/1.000 to < 1/100) Rare ( 1/ to < 1/1.000) Very rare (< 1/10.000) 4/7

5 Blood and the lymphatic system disorders anaemia, ecchymosis thrombocytopenia, bleeding, haematoma Metabolism and nutrition disorders oedema weight gain Nervous system disorders Very common: headache vertigo, paraesthesia, insomnia depression, nervousness, xerostomia, migraine Eye disorders vision anomalia, conjunctivitis Ear and labyrinth disorders tinnitus Cardiac disorders palpitation, tachycardia, hypertonia cardiac insufficiency, arrhythmia, supraventricular tachycardia, ventricular tachycardia, syncope atrial fibrillation, angina pectoris, myocardial infarction, orthostatic hypotonia 5/7

6 Respiratory, thoracic and mediastinal disorders epistaxis dyspnoea, respiratory infection pleura effusion, pneumonia, asthma Gastrointenstinal disorders nausea, diarrhoea, dyspepsia vomiting, flatulence, obstipation, abdominal pain gastritis, loss of appetite Skin and subcutaneous tissue disorders eczema alopecia, pruritus skin rash Musculoskeletal, connective tissue and bone disorders backache myalgia, arthralgia Renal and urinary disorders renal insufficiency, infection of the urinary tract nycturia 6/7

7 Hepatobiliary disorders liver enzymes increased General disorders and administration site conditions fatigue pain, weakness influenza like symptoms, ague, malaise Following undesirable effects of anagrelide are reported in literature: Pancytopenia, fluid retention, loss of weight, confusion, amnesia, somnolence, loss of coordination, dysarthria, diplopia, cardiomegaly, cardiomyopathy, pericardial effusion, vasodilatation, pleural effusion, pulmonary hypertension, pulmonary infiltrates, allergic alveolitis, anorexia, pancreatitis, gastrointestinal haemorrhage, gastrointestinal disorder, colitis, gingival bleeding, dry skin, increased serum-creatinin, chest pain, fever, asthenia, impotence 4.9 Overdose At higher than recommended dosages anagrelide produces reductions in blood pressure, which may cause hypotension as well as tachycardia. A single dose of 5 mg anagrelide can reduce blood pressure usually accompanied by vertigo. There have been a small number of reports of overdose with anagrelide. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative management. A specific antidote for anagrelide is not identified. In case of overdose close clinical observation of the patient is necessary. This includes monitoring of the platelet count with regard of thrombocytopenia. If required the dose rate should be decreased or administration discontinued until platelet count returns to within the normal range. 7/7