Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands
Treatment of B-cell chronic lymphocytic leukaemia (CLL) in adult patients with sufficient bone marrow reserves.
First line treatment with Fludara oral should only be initiated in adult patients with advanced disease, Rai stages III/IV (Binet stage C) or Rai stages I/II (Binet stage A/B) where the patient has disease related symptoms or evidence of progressive disease.
The recommended dose is 40 mg fludarabine phosphate/m² body surface given daily for 5 consecutive days every 28 days by oral route. This dose corresponds to 1.6 times the recommended intravenous dose of fludarabine phosphate (25 mg/m² body surface per day).
The following table provides guidance for determining the number of tablets of Fludara oral to be administered:
| Body Surface Area (BSA) [m²] | Calculated total daily dose based on BSA (rounded up or down to whole number) [mg/day] | Number of tablets per day (total daily dose) |
|---|---|---|
| 0.75-0.88 | 30–35 | 3 (30 mg) |
| 0.89-1.13 | 36–45 | 4 (40 mg) |
| 1.14-1.38 | 46–55 | 5 (50 mg) |
| 1.39-1.63 | 56–65 | 6 (60 mg) |
| 1.64-1.88 | 66–75 | 7 (70 mg) |
| 1.89-2.13 | 76–85 | 8 (80 mg) |
| 2.14-2.38 | 86–95 | 9 (90 mg) |
| 2.39-2.50 | 96–100 | 10 (100 mg) |
The duration of treatment depends on the success of treatment and the tolerability of the drug. Fludara oral should be administered until best response is achieved (complete or partial remission, usually 6 cycles) and then the drug should be discontinued.
Dose adjustments for the first treatment cycle (start of therapy with Fludara) are not recommended (except in patients with impairment of renal function, see ‘Patients with renal impairment’).
Patients undergoing treatment with Fludara should be closely monitored for response and toxicity.
Individual dosing should be carefully adjusted according to the observed haematological toxicity.
If at the start of a subsequent cycle cell numbers are too low to administer the recommended dosage and there is evidence of treatment associated myelosuppression, the planned treatment cycle should be postponed until granulocyte count is above 1.0 × 109/L and platelet count is above 100 × 109/L. Treatment should only be postponed up to a maximum of two weeks. If granulocyte and platelet counts have not recovered after two weeks of postponement, the dose should be reduced according to the suggested dose adjustments in the table below.
| Granulocytes and/or Platelets [109/L] | Fludarabine phosphate dose | |
|---|---|---|
| 0.5-1.0 | 50-100 | 30 mg/m²/day |
| <0.5 | ><50 | 20 mg/m²/day |
Dose should not be reduced if thrombocytopenia is disease related.
If a patient does not respond to treatment after two cycles and shows no or little haematological toxicity a careful dose adjustment towards higher fludarabine phosphate doses in subsequent treatment cycles could be considered.
Doses should be adjusted for patients with reduced kidney function. If creatinine clearance is between 30 and 70 ml/min, the dose should be reduced by up to 50% and close haematological monitoring should be used to assess toxicity (see section 4.4).
Fludara oral treatment is contraindicated if creatinine clearance is <30 ml/min (see section 4.3).
No data are available concerning the use of Fludara in patients with hepatic impairment. In this group of patients, Fludara should be used with caution.
The safety and efficacy of Fludara oral in children below the age of 18 years have not been established. Therefore, Fludara is not recommended for use in children.
Since there are limited data for the use of Fludara in older people (>75 years), caution should be exercised with the administration of Fludara in these patients.
In patients over the age of 65 years, creatinine clearance should be measured (see “Patients with renal impairment” and section 4.4).
Fludara oral should be prescribed by a qualified physician experienced in the use of antineoplastic therapy.
Fludara oral can be taken either on an empty stomach or together with food. The tablets have to be swallowed whole with water, they should not be chewed or broken.
Precautions to be taken before handling the medicinal product
For instructions on handling of the medicinal product, see section 6.6.
High doses of Fludara given intravenously have been associated with leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome (RPLS). Symptoms may include headache, nausea and vomiting, seizures, visual disturbances such as vision loss, altered sensorium, and focal neurological deficits. Additional effects may include optic neuritis, and papillitis, confusion, somnolence, agitation, paraparesis/quadriparesis, muscle spasticity, incontinence, irreversible central nervous system toxicity characterised by delayed blindness, coma, and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression.
There is no known specific antidote for Fludara overdosage. Treatment consists of drug discontinuation and supportive therapy.
Shelf life: 3 years.
Store in the original package to protect from moisture.
This medicinal product does not require any special temperature storage conditions.
Blisters of 5 tablets each, comprising polyamide/aluminium/polypropylene thermoformable foil with a lidding foil of aluminium. The blisters are packed in a polyethylene tablet container with a child-resistant polypropylene screw cap.
Pack sizes: 15 or 20 film-coated tablets per tablet container.
Not all pack sizes may be marketed.
Fludara should not be handled by pregnant staff.
Procedures for proper handling should be followed according to local requirements for cytotoxic drugs. Waste material may be disposed of by incineration.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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