Anagrelide

Anagrelide lowers the platelet count in essential thrombocythaemia. The precise mechanism is unknown, but it slows the maturation of megakaryocytes, the bone marrow cells that produce platelets. Its efficacy as a platelet-lowering agent was evaluated in four open-label, non-controlled trials including more than 4,000 patients with myeloproliferative neoplasms. In essential thrombocythaemia, the time to complete response (platelets down to 600 × 10⁹/L or a 50% fall from baseline, held for at least 4 weeks) ranged from 4 to 12 weeks. Clinical benefit in terms of thrombo-haemorrhagic events has not been convincingly demonstrated.

Mechanism of Action

• Megakaryocyte maturation: in studies of human megakaryocyte development, anagrelide reduced platelet formation by retarding megakaryocyte maturation and reducing their size and ploidy. Similar effects were seen in bone marrow biopsies from treated patients.
• Transcription factors: in cell culture it suppressed expression of GATA-1 and FOG-1, which megakaryocyte development requires, leading to lower platelet production.
• Phosphodiesterase III: anagrelide inhibits cyclic AMP phosphodiesterase III. Its platelet-lowering effect seems unrelated to this; the effect on platelet aggregation is seen only at doses higher than those that lower the platelet count. The SmPC attributes the most common side effects (headache, palpitations, fluid retention, nausea, diarrhoea) to this PDE III inhibition, and its positive inotropic and chronotropic effects call for caution in patients with heart disease.
• Active metabolite: 3-hydroxy anagrelide has a similar platelet-lowering potency and inhibits PDE III about 40 times more strongly than the parent drug.
• Onset: the platelet count typically starts to fall within 14 to 21 days.

Pharmacokinetics

• Absorption: at least 70% is absorbed from the gut, with peak plasma levels about 1 hour after a dose in fasted subjects. Food lowers the Cmax of anagrelide by 14% and raises its AUC by 20%, and lowers the Cmax of 3-hydroxy anagrelide by 29% with no effect on its AUC. These effects are not considered clinically relevant. Exposure is proportional to dose between 0.5 and 2 mg.
• Metabolism: mainly by CYP1A2 to 3-hydroxy anagrelide, which is further metabolised by CYP1A2 to the inactive 2-amino-5,6-dichloro-3,4-dihydroquinazoline. Omeprazole, a CYP1A2 inducer, lowered the AUC of anagrelide by 27% and its Cmax by 36% (13% and 18% for 3-hydroxy anagrelide).
• Elimination: the plasma half-life is short, about 1.3 hours, with no accumulation and no sign of auto-induction of clearance; the active metabolite has a half-life of about 2.5 hours. Less than 1% is recovered in urine as anagrelide, and the quinazoline metabolite accounts for about 18 to 35% of the dose in urine.
• Children and adolescents (7 to 16 years): dose-normalised exposure (Cmax and AUC) tended to be higher than in adults, with a trend to higher exposure to the active metabolite.
• Elderly (65 to 75 years, compared with 22 to 50 years): Cmax and AUC of anagrelide were 36% and 61% higher, while those of 3-hydroxy anagrelide were 42% and 37% lower.
• Hepatic and renal impairment: pharmacokinetic data are limited; hepatic metabolism is the main route of clearance.

• Essential thrombocythaemia (ET): reduction of elevated platelet counts in at-risk ET patients who are intolerant to their current therapy or whose elevated platelet counts are not reduced to an acceptable level by their current therapy.
• At-risk patient: an at-risk ET patient has one or more of the following: age over 60 years; a platelet count above 1,000 × 10⁹/L; a history of thrombo-haemorrhagic events.

• Hypersensitivity to anagrelide or to any of the excipients.
• Moderate or severe hepatic impairment.
• Moderate or severe renal impairment (creatinine clearance below 50 mL/min).

Safety was assessed in four open-label studies: 942 patients in three of them and 3,660 patients in a later one, at a mean dose of about 2 mg a day. The most commonly reported reactions were headache (about 14%), palpitations (about 9%), fluid retention and nausea (each about 6%) and diarrhoea (5%). These are expected from the pharmacology of anagrelide (PDE III inhibition), and gradual dose titration may help reduce them.

Very common (≥1/10): headache.

Common (≥1/100 to <1/10): anaemia; fluid retention; dizziness; tachycardia, palpitations; diarrhoea, vomiting, abdominal pain, nausea, flatulence; rash; fatigue.

Uncommon (≥1/1,000 to <1/100): pancytopenia, thrombocytopenia, haemorrhage, ecchymosis; oedema, weight loss; depression, amnesia, confusion, insomnia, paraesthesia, hypoaesthesia, nervousness, dry mouth; ventricular tachycardia, congestive heart failure, atrial fibrillation, supraventricular tachycardia, arrhythmia, hypertension, syncope; pulmonary hypertension, pneumonia, pleural effusion, dyspnoea, epistaxis; gastrointestinal haemorrhage, pancreatitis, anorexia, dyspepsia, constipation, gastrointestinal disorder; raised liver enzymes; alopecia, pruritus, skin discolouration; arthralgia, myalgia, back pain; impotence; chest pain, fever, chills, malaise, weakness.

Rare (≥1/10,000 to <1/1,000): weight gain; migraine, dysarthria, somnolence, abnormal coordination; diplopia, abnormal vision; tinnitus; myocardial infarction, cardiomyopathy, cardiomegaly, pericardial effusion, angina pectoris, postural hypotension, vasodilatation, Prinzmetal angina; pulmonary infiltrates; colitis, gastritis, gingival bleeding; dry skin; renal failure, nocturia; flu-like syndrome, pain, asthenia; raised blood creatinine.

Not known: cerebral infarction (see Special Instructions), torsade de pointes; interstitial lung disease including pneumonitis and allergic alveolitis; hepatitis; tubulointerstitial nephritis.

Serious cardiovascular events (torsade de pointes, ventricular tachycardia, cardiomyopathy, cardiomegaly, congestive heart failure), pulmonary hypertension and major bleeding when combined with acetylsalicylic acid are the important serious reactions. In children, 48 patients aged 6 to 17 years received anagrelide for up to 6.5 years; most events were among those listed, but the data are too limited to compare with adults.

• CYP1A2 inhibitors (fluvoxamine, enoxacin): anagrelide is mainly metabolised by CYP1A2, so inhibitors could in theory reduce its clearance and raise exposure.
• CYP1A2 inducers (omeprazole): may lower anagrelide exposure. The effect on safety and efficacy is not established, so clinical and laboratory monitoring is recommended and the dose can be adjusted if needed.
• Effect on CYP1A2 substrates: anagrelide has limited CYP1A2 inhibitory activity, so there is a theoretical interaction with medicines cleared the same way, such as theophylline.
• Other PDE III inhibitors (milrinone, amrinone, enoximone, olprinone, cilostazol): their effects may be exacerbated, and concomitant use is not recommended.
• Acetylsalicylic acid and other antiplatelet medicines: anagrelide may potentiate their effects. With acetylsalicylic acid 75 mg daily and anagrelide 1 mg daily, the anti-platelet effect of each increased, and major haemorrhages occurred in some ET patients. The risk of the combination should be assessed before starting, especially in patients at high risk of bleeding.
• Digoxin and warfarin: no pharmacokinetic interaction in either direction.
• Hormonal oral contraceptives: anagrelide may cause intestinal disturbance in some patients and impair their absorption.
• QT-prolonging medicines: caution is needed (see Special Instructions).
• Food: food delays absorption of anagrelide but does not significantly change exposure; the effect is not clinically relevant. It can be taken with or without food.

Treatment should be started by a clinician experienced in managing essential thrombocythaemia. The capsules are swallowed whole; the contents must not be crushed or dissolved in a liquid.

Recommended Dose

• Starting dose: 1 mg a day, in two divided doses of 0.5 mg, kept for at least one week.
• Titration: after one week the dose may be adjusted individually to the lowest effective dose that reduces or maintains the platelet count below 600 × 10⁹/L and ideally between 150 and 400 × 10⁹/L. The increase must not exceed 0.5 mg a day in any one week, and the recommended maximum single dose is 2.5 mg. Doses of 10 mg a day have been used in clinical development.
• Maintenance: a fall in platelet count is typically seen within 14 to 21 days, and in most patients an adequate response is reached and kept at 1 to 3 mg a day.
• Monitoring: effects are monitored regularly. If the starting dose is above 1 mg a day, platelet counts are done every two days in the first week and at least weekly until a stable maintenance dose is reached.

Special Populations

• Elderly: no different starting regimen or titration step is needed. About half of the patients treated in development were over 60 and needed no age-specific dose change, but this age group had twice the incidence of serious adverse events, mainly cardiac.
• Renal impairment: pharmacokinetic data are limited. Risks and benefits are assessed before treatment; moderate or severe impairment (creatinine clearance below 50 mL/min) is a contraindication.
• Hepatic impairment: data are limited, and as hepatic metabolism is the major route of clearance, patients with moderate or severe impairment should not be treated. In mild impairment, risks and benefits are assessed first; use is not recommended with transaminases more than 5 times the upper limit of normal.
• Children and adolescents: safety and efficacy have not been established, experience is very limited and anagrelide should be used with caution. WHO adult diagnostic criteria for ET are considered relevant, and the diagnosis should be reassessed periodically. Anagrelide is started only when there are signs of disease progression or thrombosis; benefits and risks are monitored regularly, and stopping should be considered if the response is unsatisfactory after about 3 months. No recommendation on dose can be made.

Thrombotic Risk and Stopping Treatment

Abrupt discontinuation should be avoided, because platelet counts can rise suddenly and cause potentially fatal thrombotic complications such as cerebral infarction. Patients should be told how to recognise the early signs of thrombosis, such as those of cerebral infarction, and to seek medical help if they occur. After an interruption or withdrawal the platelet count starts to rise within 4 days and returns to pre-treatment levels within 10 to 14 days, possibly rebounding above baseline, so platelets are monitored frequently.

Monitoring

Therapy needs close clinical supervision: a full blood count (haemoglobin, white cells, platelets), liver function (ALT, AST), renal function (serum creatinine, urea) and electrolytes (potassium, magnesium, calcium). A cardiovascular examination with a baseline ECG and echocardiography is recommended for every patient before treatment, with regular monitoring (for example ECG or echocardiography) during treatment. Hypokalaemia or hypomagnesaemia must be corrected before the first dose and monitored periodically.

Cardiovascular Effects

Serious cardiovascular events, including torsade de pointes, ventricular tachycardia, cardiomyopathy, cardiomegaly and congestive heart failure, have been reported, also in patients with no suspected heart disease and a normal examination before treatment. Because of its positive inotropic and chronotropic effects, caution is needed in patients of any age with known or suspected heart disease. Caution is also needed with risk factors for QT prolongation (congenital long QT syndrome, a history of acquired QTc prolongation, medicines that prolong the QTc interval, hypokalaemia) and where exposure to anagrelide or 3-hydroxy anagrelide may be higher (hepatic impairment, CYP1A2 inhibitors); close monitoring of the QTc interval is advisable. Anagrelide should be used only if the expected benefit outweighs the risk.

Pulmonary Hypertension

Cases of pulmonary hypertension have been reported. Patients should be evaluated for signs of underlying heart or lung disease before and during treatment.

Bleeding Risk

Use of anagrelide with acetylsalicylic acid has been associated with major haemorrhagic events. Combination with other PDE III inhibitors is not recommended.

Liver and Kidney Impairment

The risks and benefits are assessed before treatment in mild hepatic impairment or any renal impairment, and treatment is not recommended with transaminases more than 5 times the upper limit of normal.

Children and Adolescents

Data are very limited. A full blood count and cardiac, hepatic and renal function are assessed before and regularly during treatment. The disease may progress to myelofibrosis or acute myeloid leukaemia, and children, with a longer disease course, may be at higher risk of malignant transformation. They should be monitored regularly for progression (physical examination, relevant disease markers, bone marrow biopsy). Any abnormality is evaluated promptly, and measures may include dose reduction, interruption or discontinuation.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use adequate birth control during treatment.
• Pregnancy: there are no adequate data. Animal studies showed reproductive toxicity and the risk to humans is unknown, so Xagrid is not recommended in pregnancy. A patient who is or becomes pregnant should be told of the potential risk to the foetus.
• Breastfeeding: it is unknown whether anagrelide or its metabolites pass into human milk, but animal data show excretion in milk. A risk to the infant cannot be excluded, and breastfeeding should be stopped during treatment.
• Fertility: no human data. In male rats fertility and reproductive performance were unaffected; in female rats, at doses above the therapeutic range, implantation was disrupted.

Lactose

Each capsule contains lactose (53.7 mg monohydrate and 65.8 mg anhydrous). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effect on Driving

Dizziness was commonly reported in clinical development. Patients who feel dizzy should not drive or operate machinery.

Xagrid capsules need no special storage conditions. They are supplied in high-density polyethylene bottles of 100 capsules with child-resistant closures and a desiccant. Keep out of the sight and reach of children.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B), with treatment started by a clinician experienced in the management of essential thrombocythaemia. Anagrelide capsules are taken at home, so they are supplied to the patient or to the treating clinic on prescription.