ANAGRELIDE TORRENT

Treatment with Anagrelide Torrent should be initiated by a clinician with experience in the management of essential thrombocythaemia. 5 mg/dose). The starting dose should be maintained for at least one week. After one week the dose may be titrated, on an individual basis, to achieve the lowest effective dose required to reduce and/or maintain a platelet count below 600 x 109/l and ideally at levels between 150 x 109/l and 400 x 109/l.

9). During clinical development doses of 10 mg/day have been used. 4). If the starting dose is > 1 mg/day platelet counts should be performed every two days during the first week of treatment and at least weekly thereafter until a stable maintenance dose is reached.

1). 2) do not warrant using a different starting regimen or different dose titration step to achieve an individual patient-optimised anagrelide regimen. During clinical development approximately 50% of the patients treated with anagrelide were over 60 years of age and no age specific alterations in dose were required in these patients.

However, as expected, patients in this age group had twice the incidence of serious adverse events (mainly cardiac). Renal impairment There are limited pharmacokinetic data for this patient population. 3). Hepatic impairment 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.

4). Paediatric population The safety and efficacy of anagrelide in children has not been established. The experience in children and adolescents is very limited; anagrelide should be used in this patient group with caution. In the absence of specific paediatric guidelines, WHO diagnostic criteria for adult diagnosis of ET are considered to be of relevance to the paediatric population.

Diagnostic guidelines for essential thrombocythemia should be followed carefully and diagnosis reassessed periodically in cases of uncertainty, with effort made to distinguish from hereditary or secondary thrombocytosis, which may include genetic analysis and bone marrow biopsy.

Typically cytoreductive therapy is considered in high risk paediatric patients. Anagrelide treatment should only be initiated when the patient shows signs of disease progression or suffers from thrombosis. If treatment is initiated, the benefits and risks of treatment with anagrelide must be monitored regularly and the need for ongoing treatment evaluated periodically.

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). 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.

1). The majority of adverse events observed were among those listed in the SmPC. 4). Reporting of suspected adverse reactions 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.

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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. 3). 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 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. 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).

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.

g. 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.

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.

1. • Patients with moderate or severe hepatic impairment. • Patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min).