Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Shire Pharmaceuticals Ireland Limited, Block 2 & 3 Miesian Plaza, 50 – 58 Baggot Street Lower, Dublin 2, Ireland
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).
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).
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).
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).
The platelet count will 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.
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 recommended for all patients prior to initiating therapy with anagrelide. All patients should be monitored regularly during treatment (e.g. ECG or echocardiography) for evidence of cardiovascular effects that may require further cardiovascular examination and investigation. Hypokalaemia or hypomagnesaemia must be corrected prior to anagrelide administration and should be monitored periodically during therapy.
Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III and because of its positive inotropic and chronotropic effects, anagrelide should be used with caution in patients of any age with known or suspected heart disease. Moreover, serious cardiovascular adverse events have also occurred in patients without suspected heart disease and with normal pre-treatment cardiovascular examination.
Anagrelide should only be used if the potential benefits of therapy outweigh the potential risks.
Cases of pulmonary hypertension have been reported in patients treated with anagrelide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during anagrelide therapy.
Very limited data are available on the use of anagrelide in the paediatric population and anagrelide should be used in this patient group with caution (see sections 4.2, 4.8, 5.1 and 5.2).
As with the adult population, a full blood count and assessment of cardiac, hepatic and renal function should be undertaken before treatment and regularly during treatment. The disease may progress to myelofibrosis or AML. Although the rate of such progression is not known, children have a longer disease course and may, therefore, be at increased risk for malignant transformation, relative to adults. Children should be monitored regularly for disease progression according to standard clinical practices, such as physical examination, assessment of relevant disease markers and bone marrow biopsy.
Any abnormalities should be evaluated promptly and appropriate measures taken, which may also include dose reduction, interruption or discontinuation.
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.
Use of concomitant anagrelide and acetylsalicylic acid has been associated with major haemorrhagic events (see section 4.5).
Xagrid contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Limited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between anagrelide and other medicinal products have been conducted.
Interaction studies have only been performed in adults.
Women of child-bearing potential should use adequate birth-control measures during treatment with anagrelide.
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.
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.
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).
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 (see section 4.2).
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 (see section 5.1). 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 (see section 4.4).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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