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Drug Details

XAGRID 0.5mg Hard Capsule

• Drug Class Description
  L 01 X (Other Antineoplastic Agents)
• Generic Name
  Anagrelide
• Presentation
  Xagrid 0.5mg hard capsule - Each capsule contains 0.5 mg anagrelide (as 0.61 mg anagrelide hydrochloride)
• Description
  Capsule, hard An opaque white hard capsule imprinted with S 063
• Indications
  

  Xagrid is indicated for the reduction of elevated platelet counts in at risk essential thrombocythaemia (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.

  An at risk patient An at risk essential thrombocythaemia patient is defined by one or more of the following features: >60 years of age or A platelet count>1000 x 109/l or A history of thrombo-haemorrhagic events.

• Adult Dosage
  

  Treatment with Xagrid capsules should be initiated by a clinician with experience in the management of essential thrombocythaemia.

  The recommended starting dosage of anagrelide is 1mg/day, which should be administered orally in two divided doses (0.5mg/dose).

  The starting dose should be maintained for at least one week. After one week the dosage may be titrated, on an individual basis, to achieve the lowest effective dosage required to reduce and/or maintain a platelet count below 600 x 10⁹/l and ideally at levels between 150 x 10⁹/l and 400 x 10⁹/l.

  The dosage increment must not exceed more than 0.5mg/day in any one-week and the recommended maximum single dose should not exceed 2.5mg. During clinical development dosages of 10mg/day have been used.

  The effects of treatment with anagrelide must be monitored on a regular basis. If the starting dose is>1mg/day platelet counts should be performed every two days during the first week of treatment and at least weekly thereafter until a stable maintenance dose is reached. Typically, a fall in the platelet count will be observed within 14 to 21 days of starting treatment and in most patients an adequate therapeutic response will be observed and maintained at a dosage of 1 to 3mg/day.

  Renal impairment

  Currently, there are no specific pharmacokinetic data for this patient population and the potential risks and benefits of anagrelide therapy in a patient with impairment of renal function should be assessed before treatment is commenced.

  Hepatic impairment

  Currently, there are no specific pharmacokinetic data for this patient population. However, hepatic metabolism represents the major route of drug clearance and liver function may therefore be expected to influence this process. Therefore it is recommended that patients with moderate or severe hepatic impairment are not treated with anagrelide. The potential risks and benefits of anagrelide therapy in a patient with mild impairment of hepatic function should be assessed before treatment is commenced

• Child Dosage
  

  The experience in children is limited.

• Elderly Dosage
  

  No specific pharmacokinetic studies have been conducted in this patient population. However, during the clinical development approximately 50% of the patients treated with anagrelide were over 60 years of age and no age specific alterations in dosage were required in these patients. However, as expected, patients in this age group had twice the incidence of serious adverse events (mainly cardiac). Doses are titrated on an individual patient basis.

• Contra Indications
  

  Hypersensitivity to anagrelide or to any of the excipients of the medicinal product.

  Patients with moderate or severe hepatic impairment. Patients with moderate or severe renal impairment (creatinine clearance <50ml/min).

• Special Precautions
  

  Hepatic impairment: the potential risks and benefits of anagrelide therapy in a patient with mild impairment of hepatic function should be assessed before treatment is commenced. It is not recommended in patients with elevated transaminases (>5 times the upper limit of normal).

  Renal impairment: the potential risks and benefits of anagrelide therapy in a patient with impairment of renal function should be assessed before treatment is commenced.

  General: therapy requires close clinical supervision of the patient which will include a full blood count (haemoglobin and white blood cell and platelet counts), and assessment of liver function (ALT and AST) and renal function (serum creatinine and urea) tests.

  Platelets: the platelet count will increase within 4 days of stopping treatment with Xagrid capsules and will return to pre-treatment levels within 10 to 14 days.

  Cardiovascular: Cases of cardiomegaly and congestive heart failure have been reported. Anagrelide should be used with caution in patients of any age with known or suspected heart disease, and only if the potential benefits of therapy outweigh the potential risks.Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III and because of its positive inotropic effects, a pre-treatment cardiovascular examination (including further investigation such as echocardiography, electrocardiogram) is recommended. Patients should be monitored during treatment for evidence of cardiovascular effects that may require further cardiovascular examination and investigation.

  Paediatric patients: limited data are available on the use of anagrelide in the paediatric population and anagrelide should be used in this patient group with caution.

  Clinically relevant interactions: anagrelide is an inhibitor of cyclic AMP phosphodiesterase III (PDE III). Concomitant use of anagrelide with other PDE III inhibitors such as milrinone, amrinone, enoximone, olprinone and cilostazol is not recommended.

  Excipients: This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

• Interactions
  

  Limited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between anagrelide and other medicinal products have been conducted.

   

  Drug interactions: effects of other substances on anagrelide

  • Anagrelide is primarily metabolised by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine and omeprazole, and such medicinal products could theoretically adversely influence the clearance of anagrelide.

  • In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the pharmacokinetic properties of anagrelide.

   

  Drug interactions: effects of anagrelide on other substances

  • Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other co-administered medicinal products sharing that 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.

  • In vivo interaction studies in humans have demonstrated that anagrelide does not affect the pharmacokinetic properties of digoxin or warfarin.

  • At the doses recommended for use in the treatment of essential thrombocythaemia, anagrelide may potentiate the effects of other medicinal products that inhibit or modify platelet function e.g. acetylsalicylic acid.

  • A clinical interaction study performed in healthy subjects showed that co-administration of repeat-dose anagrelide 1 mg once daily and acetylsalicylic acid 75 mg once daily may enhance the anti-platelet aggregation effects of each drug compared with administration of acetylsalicylic acid alone. In some ET patients concomitantly treated by acetylsalicylic acid and anagrelide, major haemorrhages occurred. Therefore, the potential risks of the concomitant use of anagrelide with acetylsalicylic acid should be assessed, particularly in patients with a high risk profile for haemorrhage before treatment is initiated.

  • 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.
• Adverse Drug Reactions
  

  The safety of anagrelide has been examined in 4 open label clinical studies. In 3 of the studies 942 patients who received anagrelide at a mean dose of approximately 2mg/day were assessed for safety. In these studies 22 patients received anagrelide for up to 4 years.

  In the later study 3660 patients who received anagrelide at a mean dose of approximately 2mg/day were assessed for safety. In this study 34 patients received anagrelide for up to 5 years.

  The most commonly reported drug related adverse reactions were headache occurring at approximately 14%, palpitations occurring at approximately 9%, fluid retention and nausea both occurring at approximately 6%, and diarrhoea occurring at 5%. These adverse drug reactions are expected based on the pharmacology of anagrelide (inhibition of PDE III). Gradual dose titration may help diminish these effects.

  The following convention was used for frequency of adverse drug reactions: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); not known (cannot be estimated from the available data).

  Blood and lymphatic system disorders

  Common: Anaemia

  Uncommon: Thrombocytopenia, pancytopenia, ecchymosis, haemorrhage

  Metabolism and nutrition disorders

  Common: Fluid retention

  Uncommon: Oedema, weight loss

  Rare: Weight gain

  Nervous system disorders

  Very common: Headache

  Common: Dizziness

  Uncommon: Paraesthesia, insomnia, depression, confusion, hypoaesthesia, nervousness, dry mouth, amnesia

  Rare: Somnolence, abnormal coordination, dysarthria, migraine

  Special senses

  Rare: Vision abnormal, tinnitus, diplopia

  Cardiac disorders

  Common: Palpitations, tachycardia

  Uncommon: Congestive heart failure, hypertension, arrhythmia, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, syncope

  Rare: Angina pectoris, myocardial infarction, cardiomegaly, cardiomyopathy, pericardial effusion, vasodilatation, postural hypotension

  Respiratory and thoracic disorders

  Uncommon: Dyspnoea, epistaxis, pleural effusion, pneumonia

  Rare: Pulmonary hypertension, pulmonary infiltrates

  Not known: Allergic alveolitis

  Gastrointestinal disorders

  Common: Nausea, diarrhoea, abdominal pain, flatulence, vomiting

  Uncommon: Dyspepsia, anorexia, pancreatitis, constipation, gastrointestinal haemorrhage, gastrointestinal disorder

  Rare: Colitis, gastritis, gingival bleeding

  Hepatobiliary disorders

  Uncommon: Hepatic enzymes increased

  Skin and subcutaneous tissue

  Common: Rash

  Uncommon: Alopecia, skin discoloration, pruritus

  Rare: Dry skin

  Musculoskeletal and connective tissue disorders

  Uncommon: Myalgia, arthralgia, back pain

  Urogenital

  Uncommon: Impotence

  Rare: Nocturia, renal failure

  Investigations

  Rare: Blood creatinine increased

  General disorders and administration site conditions

  Common: Fatigue

  Uncommon: Chest pain, weakness, chills, malaise, fever

  Rare: Asthenia, pain, flu-like syndrome