ANATOR 0.5

Indications

• Essential thrombocythaemia
• Idiopathic thrombocytopenic purpura (not licensed for use in children)

Dosage

Children: null

Adults: 1–3 mg daily in divided doses (max. per dose 2.5 mg); maximum 10 mg per day.

Mechanism of action

Anagrelide works by inhibiting the enzyme phosphodiesterase III, leading to an increase in cyclic AMP levels, which subsequently reduces megakaryocyte proliferation and platelet production in the bone marrow.

Pharmacodynamics

The pharmacodynamic effect of anagrelide is characterized by its ability to decrease platelet counts in patients with essential thrombocythaemia, consequently reducing the risk of thrombo-haemorrhagic events.

Pharmacokinetics

Anagrelide is absorbed from the gastrointestinal tract, with peak plasma concentrations occurring about 1 to 2 hours after oral administration. It undergoes hepatic metabolism and has a half-life of approximately 1.3 to 2.5 hours. The drug is primarily excreted in urine as metabolites.

Contra-indications

• Severe cardiovascular disease
• Concurrent use of drugs that prolong QT-interval
• Hypersensitivity to anagrelide or any of its excipients

Adverse effects

• Anaemia
• Arrhythmias
• Asthenia
• Palpitations
• Skin reactions
• Vomiting
• Alopecia
• Decreased appetite
• Chest pain
• Confusion
• Congestive heart failure
• Insomnia
• Malaiase
• Memory loss
• Myalgia
• Nervousness
• Oedema
• Pancreatitis
• Pneumonia
• Pancytopenia

Interactions

• Mexiletine - increases exposure
• Osilodrostat - increases exposure
• Rucaparib - increases exposure
• SSRIs - increases exposure
• Vemurafenib - increases exposure
• Ciprofloxacin - increases exposure
• Fluvoxamine - increases exposure

Precautions

• Assess cardiac function before and regularly during treatment
• Monitor for risk factors for QT-interval prolongation
• Use with caution in patients with idiopathic thrombocytopenic purpura

Pregnancy

Use only if the potential benefit justifies the potential risk to the fetus; limited data available.

Breast-feeding

Not recommended; excreted in breast milk.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Powder and solvent for solution for injection

Mechanism of action

The exact mechanism by which anagrelide lowers platelet count is unclear. Evidence from human trials suggests a dose-related suppression of megakaryocyte maturation, the cells responsible for platelet production - blood drawn from patients receiving anagrelide showed a disruption to the post-mitotic phase of megakaryocyte development and a subsequent reduction in their size and ploidy. This may be achieved via indirect suppression of certain transcription factors required for megakaryocytopoeisis, including GATA-1 and FOG-1. Anagrelide is a known inhibitor of phosphodiesterase 3A (PDE3A), although its platelet-lowering effects appear unrelated to this inhibition. While PDE3 inhibitors, as a class, can inhibit platelet aggregation, this effect is only seen at higher anagrelide doses (i.e. greater than those required to reduce platelet count). Modulation of PDE3A has been implicated in causing cell cycle arrest and apoptosis in cancer cells expressing both PDE3A and SLFN12, and may be of value in the treatment of gastrointestinal stromal tumours. The mechanism by which anagrelide reduces blood platelet count is under investigation. Studies support a hypothesis of dose-related reduction in platelet production resulting from a decrease in megakaryocyte hypermaturation. In blood withdrawn from healthy volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide dose not produce significant changes in white cell counts or coagulation parameters and may have a small but clinically insignificant effect on red cell parameters. Platelet aggregation is inhibited in people at doses higher than those required to reduce platelet count. Anagrelide inhibits cyclic AMP phosphodiesterase and ADP- and collagen-induced platelet aggregation.

Pharmacodynamics

Anagrelide decreases platelet counts by suppressing transcription factors necessary for the synthesis and maturation of platelet-producing cells. The drug itself appears to have a relatively short residence time in the body necessitating twice or four times daily dosing. However, given that the pharmacological effect of anagrelide therapy is reliant on a gradual suppression of platelet-producing cells, it may take 7 to 14 days for its administration to be reflected in reduced platelet counts - for this reason any changes to anagrelide doses should not exceed 0.5 mg/day in any one week. Evidence from animal studies suggests anagrelide may impair female fertility. Female patients of reproductive age should be advised of the potential for adverse effects on fertility prior to initiating therapy.