Chemical formula: C₁₀H₇Cl₂N₃O Molecular mass: 256.088 g/mol PubChem compound: 135409400
Anagrelide interacts in the following cases:
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.
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.
CYP1A2 inducers (such as omeprazole) could decrease the exposure of anagrelide increasing its main active metabolite. 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.
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.
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.
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.
Anagrelide may cause intestinal disturbance in some patients and compromise the absorption of hormonal oral contraceptives.
Use of concomitant anagrelide and acetylsalicylic acid has been associated with major haemorrhagic events.
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 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.
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.
There are no adequate data from the use of anagrelide in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Therefore anagrelide 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.
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.
Women of child-bearing potential should use adequate birth-control measures during treatment with anagrelide.
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.
In clinical development, dizziness was commonly reported. Patients are advised not to drive or operate machinery while taking anagrelide if dizziness is experienced.
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.
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.
Common: Anaemia
Uncommon: Pancytopenia, Thrombocytopenia, Haemorrhage, Ecchymosis
Common: Fluid retention
Uncommon: Oedema, Weight loss
Rare: Weight gain
Very common: Headache
Common: Dizziness
Uncommon: Depression, Amnesia, Confusion, Insomnia, Paraesthesia, Hypoaesthesia, Nervousness, Dry mouth
Rare: Migraine, Dysarthria, Somnolence, Abnormal coordination
Rare: Diplopia, Vision abnormal
Rare: Tinnitus
Cardiac disorders
Common: Tachycardia, Palpitations
Uncommon: Ventricular tachycardia, Congestive heart failure, Atrial fibrillation, Supraventricular tachycardia, Arrhythmia, Hypertension, Syncope
Rare: Myocardial infarction, Cardiomyopathy, Cardiomegaly, Pericardial effusion, Angina pectoris, Postural hypotension, Vasodilatation
Not known: Torsade de pointes
Uncommon: Pulmonary hypertension, Pneumonia, Pleural effusion, Dyspnoea, Epistaxis
Rare: Pulmonary infiltrates
Not known: Interstitial lung disease including pneumonitis and allergic alveolitis
Common: Diarrhoea, Vomiting, Abdominal pain, Nausea, Flatulence
Uncommon: Gastrointestinal haemorrhage, Pancreatitis, Anorexia, Dyspepsia, Constipation, Gastrointestinal disorder
Rare: Colitis, Gastritis, Gingival bleeding
Uncommon: Hepatic enzymes increased
Not known: Hepatitis
Common: Rash
Uncommon: Alopecia, Pruritus, Skin discoloration
Rare: Dry skin
Uncommon: Arthralgia, Myalgia, Back pain
Uncommon: Impotence
Rare: Renal failure, Nocturia
Not known: Tubulointerstitial nephritis
Common: Fatigue
Uncommon: Chest pain Fever Chills Malaise Weakness
Rare: Flu-like syndrome, Pain, Asthenia
Rare: Blood creatinine increased
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. 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.
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