Thromboreductin

Thromboreductin

anagrelide

Manufacturer:

AOP Orphan

Distributor:

Indochina Healthcare
Full Prescribing Info
Contents
Anagrelide HCl.
Description
Thromboreductin also contains the following non-active ingredients: Lactose monohydrate, povidone, crospovidone, microcrystalline cellulose, magnesium stearate, titanium dioxide E171, indigo carmine E132 and gelatine.
Action
Pharmacology: Pharmacodynamics: Anagrelide causes a dose-dependent decrease on 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 hypothesized 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 mitotic phase of maturation.
Anagrelide does not cause significant changes in white blood cells and coagulation parameters, minor changes in red blood cells were observed.
When administered in high, non-therapeutic doses anagrelide inhibits the c-AmP Phosphodiesterase and ADP and collagen-induced thrombocyte aggregation.
Pharmacokinetics: The bioavailability of anagrelide after oral administration is 70%, according to data from a mass balance study. In healthy volunteers the time to maximal plasma (Tmax) level was about 1-2 hrs. The elimination half-life is short (1-2 hrs). 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, at least 4 metabolites emerge. After administration of C14 labelled anagrelide 75% of radioactivity are excreted within 6 days via urine, 10% via faeces.
The clinical experience in fasted or non-fasted patients shows that there is no effect of food on the efficacy of anagrelide.
Accumulation of anagrelide should not occur upon long-term administration because of the short half-life. This assumption is supported by clinical experience: Upon stopping treatment platelet counts recover to pre-therapy levels within 4-8 days.
Toxicology: Preclinical Safety Data: Experimental studies in different species including mice, rats, dogs and monkeys were performed for evaluation of antiaggregatory properties and acute and chronic toxicity. However, since the platelet reducing effect of anagrelide cannot be reproduced in experimental animals because of the lack or insufficient metabolism into the active substance, the results of these studies are of limited value for interpretation of the safety of anagrelide. Anagrelide is used in man for >15 years, there is no single report described on a potential carcinogenicity, in particular no case of leukaemogenicity. A teratogenic effect has not been excluded so far.
Acute Toxicity: The LD50 in mice and rats with a pharmacologically active metabolite is 40.5 mg/kg and 71.4 mg/kg, respectively.
Chronic Toxicity: Published data on long-term exposure with different species (eg, rat, dog and monkey) for up to 1 year were generated, their relevance is unclear. There is no carcinogenicity study available.
Indications/Uses
Treatment of essential thrombocythaemia caused by myeloproliferative disorders after failure with hydroxyurea treatment (2nd-line therapy). The decision for treatment has to be taken individually for each patient depending on the number of platelets, on age, on the clinical symptomatology and anamnesis, on the speed of platelet count increase after diagnosis, on concomitant diseases and risk factors for thromboembolic events, and on current treatment eg, hydroxyurea or interferon α.
Dosage/Direction for Use
Doctors with experience in treatment of patients with essential thrombocythaemia should initiate treatment with anagrelide. Thromboreductin has to be dosed individually for each patient. Treatment should be started with 0.5 mg/day for 1 week and the dose should be increased weekly by 0.5 mg/day, until the desired therapeutic effect is achieved. Normally, a therapeutic response is seen within 2 weeks in a dose range of 1-3 mg/day. The total daily dose should be administered twice daily (every 12 hrs) or thrice daily (every 8 hrs). The total daily dose should not exceed 5 mg.
The therapeutic response should be controlled regularly. Upon treatment initiation, platelet counts should be measured weekly until the optimal response is reached (normalisation of platelet count or a reduction to <600,000/microliter or a decrease by 50%), afterwards platelet counts should be controlled in regular intervals according to the physician's discretion.
Changing a previous therapy (eg, hydroxyurea or interferon α ) to anagrelide or to a combination therapy with anagrelide should be done in an overlapping manner.
Anagrelide is indicated for continuous use. Upon stopping treatment, a relapse of platelet counts to pre-therapy values will occur within several days.
In case of therapeutic resistance to anagrelide, other therapies should be considered. During therapy, platelet counts should be measured regularly.
Overdosage
There are no data on overdosing of anagrelide. According to the pharmacological mechanism of action of anagrelide, a decrease in platelets has to be anticipated, which might lead to haemorrhage. Adverse events affecting the cardiac system are likely to follow. Because of the peripheral vasodilatatory effect of anagrelide, hypotension and tachycardia have to be expected. Adverse events affecting the 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.
Contraindications
Patients with known anaphylactoid reactions to anagrelide or to non-active ingredients of Thromboreductin. Lactose intolerance has to be considered in patients.
In clinical studies, patients with cardiovascular diseases grade 4 or grade 3 (Toxicity criteria of the South West Oncology Group, 1992) with a negative benefit/risk ratio, patients with severe renal disease (creatinine clearance <30 mL/min) or severe liver disease (AST or ALT >5 times normal) were excluded.
Use in pregnancy & lactation: Anagrelide is contraindicated for use in pregnancy. Contraception is indicated during therapy. It is unknown whether anagrelide is excreted in human milk.
Special Precautions
Anagrelide should be used only with caution and after a positive benefit/risk evaluation in patients with cardiovascular, renal or liver diseases.
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 pressure can occur.
Patients should be advised to take anagrelide continuously because missing 1 week of anagrelide administration will rapidly increase the platelet count.
Haematological parameters (in particular haematocrit and leukocyte count), renal and liver parameters should be controlled in regular intervals during the use of anagrelide.
If necessary, anagrelide should be used with close attention of cardiologist in patients with congestive heart failure from coronary heart and pulmonary hypertension.
Caution is indicated in patients with cardiovascular diseases. Limited data are available for patients with renal and liver diseases. Therefore, anagrelide should be used in these patients only under careful risk/benefit analysis.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Anagrelide did not show a mutagenic potential in 3 in vitro and in vivo experiments (Ames test, mouse lymphoma cell test, micronucleus test). The meaning of these results is unclear, because in humans other metabolites might emerge compared to these standard tests with metabolic activation.
Anagrelide does not show any mutagenic activity at the TK locus in L5178Y mouse lymphoma cells. However, in a direct comparison hydroxyurea exhibits potent mutagenic activity both after short- and long-term exposure without metabolic activation. In contrast anagrelide does not show any mutagenic potential after metabolic activation with human S9 microsomes.
There is no long-term carcinogenicity study.
Published data show that anagrelide has potent inotropic and vasodilatory effects in anaesthetised dogs and dogs with heart failure. A dose of 100 mcg/kg reduced the peripheral resistance in healthy dogs and dogs with heart failure by 21% and 51%, respectively, the end-diastolic pressure in the left ventricle by 4 mmHg and 6 mmHg, respectively, the frequency by 19% and 30%, respectively, and contractibility by 51% and 450%, respectively. The mean arterial pressure in healthy dogs was reduced by 23%, however, unchanged in dogs with heart failure, blood flow in the aorta was increased by 200%.
Reproductive Toxicity: Teratogenicity has not been excluded. Since anagrelide exerts a species-specific effect in man, data on the reproductive toxicity in rats are of limited value. Therefore, anagrelide is contraindicated in pregnancy (see Use in pregnancy & lactation under Contraindications).
Use in children: A limited number of children <16 years have been treated with anagrelide. There seem to be no major dosing differences compared to treatment of adults.
Use in the elderly: A limited number of elderly patients have been treated with anagrelide. Caution is advised when treating elderly patients with cardiovascular diseases.
No 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.
Adverse Reactions
The following adverse events occurred during therapy with anagrelide: Headache, palpitations, diarrhoea, weakness, oedema, nausea, abdominal pain, dizziness, pain, dyspnoea, flatulence, vomiting, fever, rash, chest pain, anorexia, tachycardia, pharyngitis, malaise, cough, paresthesia, back pain, pruritus, dyspepsia. Most adverse events occurred during treatment initiation, were of minor intensity and diminished during ongoing therapy. Adverse events tended to decrease in number and intensity with time.
In addition adverse events occurred which involved the following organs: Cardiovascular system, gastrointestinal tract, haematopoietic and lymphatic system, liver, musculoskeletal system, nervous system, respiratory system, dermatological and appendages system, sensory system, urogenital system, flu and flu like symptoms, dehydration.
In case of headache (this occurs mainly upon treatment initiation), a pain medication ie, acetaminophen should be prescribed. In case of diarrhoea, lactase (eg, Laluk) should be prescribed. Lactose intolerance should be considered (see Contraindications).
The following severe adverse events were observed during therapy with anagrelide: Heart failure, myocardial infarction, cardiomyopathy, heart block, atrial fibrillation, cerebrovascular events, pericarditis, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastrointestinal ulcers, seizures.
Drug Interactions
The following drugs were used concomitantly with anagrelide: Acetylsalicylic acid, hydroxyurea, allopurinol, enalapril, ginkgo biloba extract, furosemide, metoprolol, atenolol, hydrochlorothiazide, levothyroxine sodium, paracetamol, pentoxifylline, captopril, interferon α, amoxicillin, isosorbide, lisinopril, ranitidine, atorvastatin, clopidogrel, enoxaparin sodium, molsidomine, omeprazole, thiamine and verapamil. Several other drugs were administered concomitantly with anagrelide. No significant interactions occurred, however, there are no controlled interaction studies.
In experimental studies in rabbits, anagrelide causes an increase in efficacy of heparin, therefore, this effect should be monitored during treatment.
Storage
Store below 25°C.
ATC Classification
L01XX35 - anagrelide ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Cap 0.5 mg x 100's.
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