Microsoft word - thromboreductin package insert.doc

THROMBOREDUCTIN 0.5 mg PACKAGE INSERT
SCHEDULING STATUS
PROPRIETARY NAME AND DOSAGE FORM
COMPOSITION
Each capsule contains 0.57 mg anagrelide hydrochloride equivalent to 0.5 mg anagrelide base magnesium stearate, titanium dioxide E171, indigo carmine E 132 and gelatin.
PHARMACOLOGICAL CLASSIFICATION
A 8.5 Medicines acting on blood and haemopoietic system – platelet reducing agent PHARMACOLOGICAL ACTION
Anagrelide causes a dose dependent decrease in platelet count; the mechanism of action is unknown. The mechanism of action is species specific for humans; there are no data on a platelet count reducing effect in any experimental animal model. It is therefore hypothesised that anagrelide acts via a metabolite that is generated in man.
Anagrelide exerts its action via reducing the size and ploidy of megakaryocytes in the post Anagrelide does not cause significant changes in white blood cells or coagulation parameters, minor changes in red blood cells were observed.
phosphodiesterase and ADP and collagen induced platelet aggregation.
Anagrelide is rapidly absorbed from the gastro-intestinal tract. The terminal elimination half- life has been reported to be about 3 days, Anagrelide has a high volume of distribution (120 l/kg), the distribution in different compartments is unknown, as is plasma protein binding.
Anagrelide is intensively metabolised before elimination in the urine, less than 1 % of a dose The clinical experience in fasted or non-fasted patients shows that there is no effect on the efficacy of anagrelide. At fasting and a dose of 0.5 mg of anagrelide the plasma half-life is 1.3 Accumulation of anagrelide does not occur upon repeated administration.Upon stopping treatment platelet counts recover to pre-therapy levels within 4 to 8 days.
Limited data are available for elderly patients and patients with renal or liver insufficiency.
When using anagrelide in these patients careful monitoring especially when beginning therapy should be performed (see also special precautions).
INDICATIONS
Thromboreductin 0.5 mg is indicated for treatment of essential thrombocythaemia to reduce the CONTRA-INDICATIONS
Patients with known anaphylactoid reactions to the active ingredient or any of the excipients should not use Thromboreductin 0.5 mg. Lactose intolerance has to be considered in patients.
In clinical studies patients with cardiovascular disease grade 4 or grade 3 (toxicity criteria of the South West Oncology Group, 1992) with a negative benefit/risk ratio, patients with a severe renal disease (creatinine clearance <30 ml/min) or a severe liver disease (AST or ALT > 5 WARNINGS
The concomitant use of aspirin should be done only after careful risk/benefit evaluation for a bleeding tendency as a synergistic effect of Thromboreductin 0.5 mg with aspirin cannot be There is no clinical data to assess the benefit/risk evaluation in patients with cardiovascular, renal or liver diseases, hence use in these patients cannot be recommended.
Careful monitoring of cardiovascular effects is recommended during treatment. When high single doses (5 mg) are administered hypotension and dizziness can occur because of vasodilatation. Following single doses of 2 mg a small and reversible decrease in blood Haematological parameters (in particular haematocrit and leukocyte count) should be controlled in regular intervals during the use of Thromboreductin 0.5 mg.
Patients with renal insufficiency (creatinine > 2 mg/dl) and evidence of hepatic dysfunction (bilirubin AST or measures of liver function > 1.5 times the upper limit of normal) should be monitored closely for signs of renal or hepatic toxicity.
INTERACTIONS
Bioavailability studies evaluating possible interaction between Thromboreductin 0.5 mg and other medicines have not been conducted.
The following medicines were used concomitantly with Thromboreductin 0.5 mg: aspirin, hydroxyurea, allopurinol, furosemide, paracetamol, digoxin and ranitidine. With exception of aspirin, no significant interactions occurred, however, drug-drug interaction studies have not been conducted. There is no clinical evidence to suggest that Thromboreductin 0.5 mg interacts with any of these compounds.
In experimental studies in rabbits Thromboreductin 0.5 mg causes an increase in efficacy of heparin, therefore, this effect should be monitored during treatment.
PREGNANCY AND LACTATION
Thromboreductin 0.5 mg has been shown to be embryotoxic and fetotoxic in animal studies.
Thromboreductin 0.5 mg is contraindicated for use in pregnancy and women of childbearing age should use adequate contraception. It is unknown whether Thromboreductin 0.5 mg is excreted in human milk and should therefore not be administered to breast feeding women.
DOSAGE AND DIRECTIONS FOR USE
Doctors with experience in treatment of patients with essential thrombocythaemia should initiate treatment with Thromboreductin 0.5 mg. Thromboreductin 0.5 mg has to be dosed individually for each patient. Treatment should be started with 0.5 mg per day for at least one
week and then the dose should be increased weekly by 0.5 mg per day until the desired
therapeutic effect is achieved. Normally a therapeutic response is seen within 2 weeks in a dose range of 1 to 3 mg/d. The total daily dose should be administered twice daily (every 12 hours) or three times a day (every 8 hours).
The usual maintenance dose is 1.5 mg to 3mg daily. The total daily dose should not exceed 5 mg per day or as a single-dose 2.5 mg.
The therapeutic response should be controlled regularly.
counts should be measured every 2 days for the first week and thereafter at least weekly until the optimal response is reached (normalisation of platelet count or a reduction to <600.000/l or a decrease by 50 %), afterwards platelet counts should be controlled in regular intervals according to the physicians discretion.
Changing a previous therapy (e.g. hydroxyurea or interferon ) to Thromboreductin 0.5 mg or to a combination therapy with Thromboreductin 0.5 mg should be done in an overlapping Thromboreductin 0.5 mg is indicated for continuous use. Upon stopping a relapse of platelet counts to pre-therapy values will occur within several days.
In case of therapeutic resistance to Thromboreductin 0.5 mg other therapies should be considered. During therapy platelet counts should be measured regularly.
Caution is indicated in patients with cardiovascular diseases (see contra-indications and Limited data are available for patients with renal and liver disease; therefore, Thromboreductin 0.5 mg cannot be recommended for these patients.
Use in elderly: a limited number of elderly patients have been treated with Thromboreductin 0.5 mg. Caution is advised when treating elderly patients with cardiovascular diseases.
Use in children: the safety and efficacy of Thromboreductin 0.5 mg in patients have not been SIDE EFFECTS AND SPECIAL PRECAUTIONS
Adverse reactions reported as more than an isolated case is listed below, by system organ Most adverse events occurred during treatment initiation, were of minor intensity and diminished during ongoing therapy. Adverse events tended to decrease in number and Frequencies are defined as: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (< 1/1000). Depression, somnolence, confusion, insomnia, hypertension, Gastrointestinal system disorders: haemorrage, gastritis, melaena, aphthous stomatitis, eructation.
Haematopoietic and lymphatic system disorders: Anaemia, thrombocytopenia, ecchymosis, lymphadenoma Arrhythmia, haemorrhage, cardiovascular disease, cerebrovascular Heart failure, myocardial infarction, cardiomyopathy, cardio megaly, heart block, atrial fibrillation, cerebrovascular events, pericarditis Elevated liver enzymes were observed in patients during anagrelide Pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension Amblyopia, abnormal vision, visual field abnormality and diplopia.
Pain, fever, chest pain, pharyngitis, malaise, cough, paresthesia, back Flu symptoms, chills, neck pain, photosensitivity Special precautions
Thromboreductin 0.5 mg should be used with caution in patients with cardiovascular disease.
Platelet counts should be monitored closely, especially during the initial stages of treatment.
Liver and kidney function should also be monitored while the platelet count is being lowered.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
There are no data on overdosing of Thromboreductin 0.5 mg.
pharmacological mechanism of action of Thromboreductin 0.5 mg a decrease in platelets has to be anticipated, which might lead to haemorrhage.
system are likely to follow. Because of the peripheral vasodilatory effect of Thromboreductin 0.5 mg, hypotension and tachycardia have to be expected.
cardiovascular and central nervous system, like headache and dizziness have to be expected.
A careful monitoring of the overdosed patient with control of platelet count is recommended.
IDENTIFICATION
Blue/ blue opaque capsule, filled with a white powder.
PRESENTATION
Round, white opaque, high density polyethylene bottles with a white child resistant screw cap STORAGE INSTRUCTIONS
Store at 25C in the original container.
REGISTRATION NUMBER
NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF
REGISTRATION
DATE OF PUBLICATION OF THE PACKAGE INSERT

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