Microsoft word - thromboreductin package insert.doc
THROMBOREDUCTIN 0.5 mg PACKAGE INSERT
PROPRIETARY NAME AND DOSAGE FORM
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.
A 8.5 Medicines acting on blood and haemopoietic system – platelet reducing agent
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).
Thromboreductin 0.5 mg is indicated for treatment of essential thrombocythaemia to reduce the
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
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.
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
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
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.
Blue/ blue opaque capsule, filled with a white powder.
Round, white opaque, high density polyethylene bottles with a white child resistant screw cap
Store at 25C in the original container.
NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF
DATE OF PUBLICATION OF THE PACKAGE INSERT
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