Thromboreductin

Blue hard capsule in size 4 with dimensions 14.3±0.3 mm filled with a white powder.
Each capsule contains anagrelide hydrochloride monohydrate equivalent to 0.5 mg anagrelide.
Excipient with known effect: Each capsule contains 94 mg lactose monohydrate.
Excipients/Inactive Ingredients: Capsule contents: Lactose monohydrate, Povidone, Crospovidone, Microcrystalline cellulose, Magnesium stearate.
Capsule shell: Titanium dioxide, Indigo carmine, Water, Gelatin.

Pharmacotherapeutic group: Other antineoplastic substances. ATC code: L01XX35.
Pharmacology: Pharmacodynamics: Mechanism of action: Anagrelide causes a dose dependent and selective decrease in platelet count in humans; the specific mechanism of action is not yet fully understood.
Anagrelide is an inhibitor of cyclic AMP PDE III.
In vitro studies on megakaryocytopoiesis in humans have demonstrated that the inhibiting effect on platelet production is caused by a delay in maturation and a reduction of size and ploidy of megakaryocytes. Biopsies of bone marrow of treated patients gave evidence for similar in vivo effects.
Pharmacodynamic effects: Effects on Heart Rate and QTc Interval: The effect of two dose levels of anagrelide (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval was evaluated in a double-blind, randomised, placebo- and active-controlled, cross-over study in healthy adult men and women.
A dose related increase in heart rate was observed during the first 12 hours, with the maximum increase occurring around the time of maximum concentrations. The maximum change in mean heart rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg.
A transient increase in mean QTc was observed for both doses during periods of increasing heart rate and the maximum change in mean QTcF (Fridericia correction) was +5.0 msec occurring at 2 hours for 0.5 mg and +10.0 msec occurring at 1 hour for 2.5 mg.
At therapeutic doses, anagrelide does not cause significant changes in white blood cells and coagulation parameters, but may cause minor changes in red blood cells.
At high, non-therapeutic doses anagrelide inhibits c-AMP phosphodiesterase and ADP- and collagen induced thrombocyte aggregation.
Pharmacokinetics: Absorption: Following oral administration of anagrelide in man, at least 70% is absorbed from the gastrointestinal tract. In fasted subjects, peak plasma levels occur about 1 hour after administration. Pharmacokinetic data from healthy subjects established that food decreases the C_max of anagrelide by 14%, but increases the AUC by 20%. Food also decreased the C_max of the active metabolite, 3-hydroxy anagrelide, by 29%, although it had no effect on the AUC.
Biotransformation: Anagrelide is primarily metabolised by CYP1A2 to form, 3-hydroxy anagrelide, which is further metabolised via CYP1A2 to the inactive metabolite, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline.
The effect of omeprazole, a CYP1A2 inducer, on the pharmacokinetics of anagrelide was investigated in 20 healthy adult subjects following multiple, once daily 40 mg doses. The results showed that in the presence of omeprazole, AUC_(0-∞), AUC_(0-t), and C_max of anagrelide were reduced by 27%, 26%, and 36%, respectively; and the corresponding values for 3-hydroxy anagrelide, an active metabolite of anagrelide, were reduced by 13%, 14%, and 18%, respectively.
Elimination: The plasma half-life of anagrelide is short, approximately 1.3 hours and as expected from its half-life, there is no evidence for anagrelide accumulation in the plasma. Less than 1% is recovered in the urine as anagrelide. The mean recovery of 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in urine is approximately 18-35% of the administered dose.
Paediatric population: Pharmacokinetic data from fasting children and adolescents (age range 7-16 years) with essential thrombocythaemia indicate that dose normalised exposure, C_max and AUC, of anagrelide were higher in children/adolescents as compared to adults. There was also a trend to higher exposure to the active metabolite.
Elderly: Pharmacokinetic data from fasting elderly patients with ET (age range 65 through 75 years) compared to fasting adult patients (age range 22 through 50 years) indicate that the C_max and AUC of anagrelide were 36% and 61% higher respectively in elderly patients, but that the C_max and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the elderly patients. These differences were likely to be caused by lower presystemic metabolism of anagrelide to 3-hydroxy anagrelide in the elderly patients.
Toxicology: Preclinical safety data: Repeated dose toxicity: Following repeated oral administration of anagrelide in dogs, subendocardial haemorrhage and focal myocardial necrosis was observed at 1 mg/kg/day (12 to 16-fold the maximum therapeutic dose) or higher in males and females with males being more sensitive. The no observed effect level (NOEL) for male dogs (0.3 mg/kg/day) corresponds to 0.1, 0.1, and 1.6-fold the AUC in humans for anagrelide at 2 mg/day, and the metabolites BCH24426 and RL603, respectively.
Reproductive toxicity: Fertility: In male rats, anagrelide at oral doses up to 240 mg/kg/day (>1,000 times a 2 mg/day dose, based on body surface area) was found to have no effect on fertility and reproductive performance. In female rats increases in pre- and post-implantation losses and a decrease in the mean number of live embryos was observed at 30 mg/kg/day. The NOEL (10 mg/kg/day) to this effect was 143, 12 and 11-fold higher than the AUC in humans administered a dose of anagrelide 2 mg/day, and the metabolites BCH24426 and RL603, respectively.
Embryofoetal development studies: Maternally toxic doses of anagrelide in rats and rabbits were associated with increased embryo resorption and foetal mortality.
In a pre- and post-natal development study in female rats, anagrelide at oral doses of ≥10 mg/kg produced a non-adverse increase in gestational duration. At the NOEL dose (3 mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and RL603 were 14, 2 and 2-fold higher than the AUC in humans administered an oral dose of anagrelide 2 mg/day.
Anagrelide at ≥60 mg/kg increased parturition time and mortality in the dam and foetus respectively. At the NOEL dose (30 mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and RL603 were 425-, 31- and 13-fold higher than the AUC in humans administered an oral dose of anagrelide 2 mg/day, respectively.
Mutagenic and carcinogenic potential: Studies on the genotoxic potential of anagrelide did not identify any mutagenic or clastogenic effects.
In a two-year rat carcinogenicity study, non-neoplastic findings were observed and related or attributed to an exaggerated pharmacological effect. Among them, the incidence of adrenal phaeochromocytomas was increased relative to the control group in males at all dose levels (≥3 mg/kg/day) and in females receiving 10 mg/kg/day and above. The lowest dose in males (3 mg/kg/day) corresponds to 37 times the human AUC exposure after a 1 mg twice daily dose. Uterine adenocarcinomas of epigenetic origin could be related to an enzyme induction of the CYP1 family. They were observed in females receiving 30 mg/kg/day, corresponding to 572 times the human AUC exposure after a 1 mg twice daily dose.

Thromboreductin is indicated for the reduction of elevated platelet counts and associated clinical symptoms in at high risk essential thrombocythemia patients.
An at high risk essential thrombocythaemia patient is defined by one or more of the following features: Age ≥60 years; Platelet count ≥1.000 x 10⁹/l; A history of thrombo-haemorrhagic events.

Posology: Treatment with Thromboreductin should be initiated by physicians experienced in the treatment of patients with essential thrombocythaemia.
The dosage of Thromboreductin has to be determined individually for each patient and needs to be controlled by the physician.
The recommended starting dose of Thromboreductin is 1.0 mg per day. The starting dose should be maintained for at least one week. After one week, the dose can be adjusted individually to obtain the lowest dose necessary to keep the platelet count <600 x 10⁹/l. The ideal platelet count lies between 150 x 10⁹/l and 400 x 10⁹/l.
An increase of the daily dose should not exceed 0.5 mg per week and the maximum single dose should not exceed 2.5 mg.
The effect of treatment with Thromboreductin should be controlled regularly (see Precautions).
Upon treatment initiation, the platelet count should be measured weekly until the individual optimal response is reached (normalisation of platelet count or a reduction to <600 x 10⁹/l). Afterwards the platelet count should be controlled in regular intervals according to the physicians' discretion.
Normally, a decrease of the platelet count can be seen within 14 to 21 days after treatment initiation. In most patients an adequate therapeutic response can be reached and maintained with a dose between 1 and 3 mg per day.
Thromboreductin is intended for continuous use. Upon discontinuation of Thromboreductin, platelet counts will increase within 4 to 8 days and within 10 to 14 days, pre-therapy values are reached.
Elderly: Age-specific dose changes were not necessary for the treatment of elderly patients with anagrelide.
Renal impairment: There are no specific pharmacokinetic data available for this patient population. Therefore the potential risks and benefits of anagrelide therapy in patients with renal insufficiency should be assessed before treatment is commenced (see Contraindications, Precautions and Pharmacology: Pharmacodynamics under Actions). Treatment with anagrelide in patients with moderate or severe renal insufficiency (creatinine clearance <50 ml/min) is contraindicated (see Contraindications).
Hepatic impairment: There are no specific pharmacokinetic data available for this patient population. Hepatic metabolism represents the most important path for drug clearance and liver function and may therefore be expected to influence this process. Potential risks and advantages of a therapy with anagrelide have to be considered prior to a treatment in patients with mild hepatic impairment (see Contraindications and Precautions). Treatment with anagrelide in patients with moderate or severe hepatic insufficiency is contraindicated (see Contraindications).
Paediatric population: The safety and efficacy of anagrelide in children aged up to 18 years has not been established. Currently available data are described in Pharmacology: Pharmacokinetics under Actions but no recommendation on a posology can be made.
Method of administration: For oral use. Thromboreductin capsules must be swallowed whole with a small amount of liquid.

At higher than recommended dosages anagrelide produces a reduction in blood pressure, which may cause hypotension as well as tachycardia. A single dose of 5 mg anagrelide can reduce blood pressure usually accompanied by vertigo.
There have been a small number of reports of overdose with anagrelide. Reported symptoms include sinus tachycardia and vomiting. Symptoms improved with conservative management.
A specific antidote for anagrelide has not been identified.
In case of overdose close clinical observation of the patient is necessary. This includes monitoring of the platelet count with regard to thrombocytopenia. If required, the dose should be decreased or administration discontinued until the platelet count returns to the normal range.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Cardiovascular disease grade 3 with a negative benefit/risk assessment or grade 4 (South West Oncology Group criteria).
Moderate or severe renal insufficiency (creatinine clearance <50 ml/min).
Moderate or severe hepatic insufficiency.

General: Anagrelide should only be used if the potential benefits of therapy outweigh the potential risks.
The therapy requires close clinical supervision of the patient including a complete blood count (haemoglobin, white blood cell and platelet counts) and tests regarding liver function (e.g. ALT and AST), renal function (serum creatinine and urea) and electrolytes (potassium, magnesium and calcium).
Treatment discontinuation and thrombotic risk: In the event of dosage interruption or treatment withdrawal, the rebound in platelet count is variable, but the platelet count will start to 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 (see Dosage & Administration).
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.
Cardiovascular effects: Serious cardiovascular adverse events, including cases of torsade de pointes, ventricular tachycardia, cardiomyopathy, cardiomegaly and congestive heart failure have been reported (see Adverse Reactions).
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 the QTc interval and hypokalaemia.
Close monitoring for an effect on the QTc interval is advisable.
Care should also be taken in populations that may have a higher maximum plasma concentration (C_max) of anagrelide or its active metabolite, 3-hydroxy-anagrelide, e.g. in case of hepatic impairment or use with CYP1A2 inhibitors (see Interactions).
A pre-treatment cardiovascular examination, including a baseline ECG and an echocardiography is recommended prior to initiating therapy with anagrelide. Patients should be monitored during treatment 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 (PDE 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.
Pulmonary hypertension: 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.
Hepatic impairment (see Dosage & Administration and Contraindications): In patients with hepatic impairment, frequent liver function tests, especially at the beginning of the therapy, are necessary.
Renal impairment (see Dosage & Administration and Contraindications): In patients with renal impairment, frequent kidney function tests especially at the beginning of the therapy are necessary.
Thromboreductin contains lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and operate machinery have been performed. In clinical development, dizziness was a commonly reported side effect.
Patients are advised not to drive or operate machinery while taking Thromboreductin if dizziness is experienced.

Pregnancy: There are no adequate data from the use of anagrelide in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown and therefore, anagrelide 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.
Women of child-bearing potential: Women of child-bearing potential should use adequate birth control measures during treatment with anagrelide.
Breast-feeding: It is unknown whether anagrelide/metabolites transfer to 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.
Fertility: 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 Pharmacology: Toxicology: Preclinical safety data under Actions).

The following undesirable effects are ranked according to system organ class and to their frequency: 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).
Blood and the lymphatic system disorders: Common: anaemia.
Uncommon: pancytopenia, thrombocytopenia, haemorrhage, ecchymosis.
Metabolism and nutrition disorders: Common: fluid retention.
Uncommon: oedema, weight loss.
Rare: weight gain.
Nervous system disorders: Very common: headaches.
Common: dizziness.
Uncommon: depression, amnesia, confusion, insomnia, paraesthesia, hypoaesthesia, nervousness, dry mouth.
Unknown: cerebral infarction*.
Eye disorders: Rare: diplopia, vision abnormal.
Ear and labyrinth disorders: 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, Prinzmetal angina.
Not known: Torsade de pointes.
Respiratory, thoracic and mediastinal disorders: Uncommon: pulmonary hypertension, pneumonia, pleural effusion, dyspnoea, epistaxis.
Rare: pulmonary infiltrates.
Not known: interstitial lung disease including pneumonitis and allergic alveolitis.
Gastrointestinal disorders: Common: diarrhoea, vomiting, abdominal pain, nausea, flatulence.
Uncommon: gastrointestinal haemorrhage, pancreatitis, anorexia, dyspepsia, constipation, gastrointestinal disorder.
Rare: colitis, gastritis, gingival bleeding.
Hepatobiliary disorders: Uncommon: hepatic enzymes increased.
Not known: hepatitis.
Skin and subcutaneous tissue disorders: Common: rash.
Uncommon: alopecia, pruritus, skin discoloration.
Rare: dry skin.
Musculoskeletal, connective tissue and bone disorders: Uncommon: arthralgia, myalgia, back pain.
Renal and urinary disorders: Uncommon: impotence.
Rare: renal failure, nocturia.
Not known: tubulointerstitial nephritis.
General disorders and administration site conditions: Common: fatigue.
Uncommon: chest pain, fever, chills, malaise, weakness.
Rare: flu-like syndrome, pain, asthenia.
Investigations: Rare: blood creatinine increased.
*Cerebral infarction - see Treatment discontinuation and thrombotic risk under Precautions.

Limited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between anagrelide and other medicinal products have been conducted.
Effects of other substances on anagrelide: Anagrelide is primarily metabolised by CYP1A2. CYP1A2 is inhibited by several medicinal products, including fluvoxamine and enoxacin, and such medicinal products could theoretically adversely influence the clearance of anagrelide. CYP1A2 inducers (such as omeprazole) could decrease the exposure of anagrelide (see Pharmacology: Pharmacokinetics under Actions).
In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the pharmacokinetic properties of anagrelide.
Caution should be taken when using anagrelide with medicinal products that can prolong the QTc interval and hypokalaemia.
Effects of anagrelide on other substances: Anagrelide demonstrates a somewhat limited inhibitory activity towards CYP1A2, which may present a potential for interaction with other co-administered medicinal products sharing this clearance mechanism e.g. theophylline.
Anagrelide is an inhibitor of PDE III. The effects of medicinal products with similar properties such as the inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by anagrelide.
At the doses recommended for use in the treatment of essential thrombocythaemia, anagrelide may theoretically potentiate the effects of other medicinal products that inhibit or modify platelet function, e.g. acetylsalicylic acid.
Co-administration of repeat-dose anagrelide and acetylsalicylic acid may enhance the anti-platelet aggregation effects of each drug compared with administration of acetylsalicylic acid alone. In some ET patients concomitantly treated with acetylsalicylic acid and anagrelide formulations, major haemorrhages occurred. Therefore, due to the lack of data in ET patients, the potential risks of the simultaneous use of anagrelide with acetylsalicylic acid should be assessed before treatment is initiated, particularly in patients with a high risk profile for haemorrhage.
Anagrelide may cause intestinal disturbance in some patients and compromise the absorption of hormonal oral contraceptives.
Food interactions: Food delays the absorption of anagrelide but does not significantly alter systemic exposure. The effects of food on bioavailability are not considered clinically relevant to the use of anagrelide.

Incompatibilities: Not applicable.
Special precautions for disposal and other handlings: No special requirements.

Shelf life: The expiration date is indicated on the packaging.
Special precautions for storage: Do not store above 30°C. Store in the original package in order to protect from light.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

L01XX35 - anagrelide ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.

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