FLUDARA

Posology The recommended dose is 40 mg fludarabine phosphate/m² body surface given daily for 5 consecutive days every 28 days by oral route. 6 times the recommended intravenous dose of fludarabine phosphate (25 mg/m2 body surface per day).

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. 0 x 109/L and platelet count is above 100 x 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.

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.

Patients with renal impairment Doses should be adjusted for patients with reduced kidney function. 4). 3). Patients with hepatic impairment 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.

Paediatric population 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. Older people 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.

4). Method of administration 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.

6.

Summary of safety profile Based on the experience with the use of Fludara, the most common adverse events include myelosuppression (neutropenia, thrombocytopenia and anaemia), infection including pneumonia, cough, fever, fatigue, weakness, nausea, vomiting and diarrhoea.

Other commonly reported events include chills, oedema, malaise, peripheral neuropathy, visual disturbance, anorexia, mucositis, stomatitis and skin rash. Serious opportunistic infections have occurred in patients treated with Fludara.

Fatalities as a consequence of serious adverse events have been reported. Tabulated list of adverse reactions The table below reports adverse events by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data regardless of the causal relationship with Fludara.

The rare adverse reactions were mainly identified from the post-marketing experience. g. progressive multifocal leukoencephalopat hy, Herpes zoster virus Esptein-Barr- virus), pneumonia Lympho- proliferative disorder (EBV- associated) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myelodysplastic syndrome and Acute Myeloid Leukaemia (mainly associated with prior, concomitant or subsequent treatment with alkylating agents, topoisomerase inhibitors or irradiation) Blood and lymphatic system disorders Neutropenia, anaemia, thrombocytopenia Myelosuppression Immune system disorders Autoimmune disorder (including autoimmune haemolytic anaemia, Evan’s syndrome, thrombocytopen ic purpura, acquired haemophilia, pemphigus Metabolism and nutrition disorders Anorexia Tumour lysis syndrome (including renal failure, metabolic acidosis, hyperkalaemia, hypocalcaemia, hyperuricaemia, haematuria, urate crystalluria, hyperphosphata emia) Nervous system disorders Peripheral neuropathy Confusion Coma, seizures, agitation Eye disorders Visual disturbances Blindness, optic neuritis, optic neuropathy Cardiac disorders Heart failure, arryhthmia Respiratory, thoracic and mediastinal disorders Cough Pulmonary toxicity (including pulmonary fibrosis, pneumonitis, dyspnoea) Gastro- intestinal disorders Vomiting, diarrhoea, nausea Stomatitis Gastrointestinal haemorrhage, pancreatic enzymes abnormal Hepatobiliary disorders Hepatic enzymes abnormal Skin and subcutaneous tissue disorders Rash Skin cancer, necrolysis epidermal toxic (Lyell type) Stevens-Johnson syndrome General disorders and administration site conditions Fever, fatigue, weakness Oedema, mucositis, chills, malaise The most appropriate MedDRA term to describe a certain adverse event is listed.

Synonyms or related conditions are not listed, but should be taken into account as well. 0. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 4) • Respiratory, thoracic and mediastinal disorders o Pulmonary haemorrhage • Renal and urinary disorder o Haemorrhagic cystitis Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard

Myelosuppression Severe bone marrow suppression, notably anaemia, thrombocytopenia and neutropenia, has been reported in patients treated with Fludara. In a Phase I intravenous study in adult solid tumour patients, the median time to nadir counts was 13 days (range 3 – 25 days) for granulocytes and 16 days (range 2 - 32 days) for platelets.

Most patients had haematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of fludarabine phosphate requires careful haematologic monitoring.

Fludarabine phosphate is a potent antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed for signs of haematologic and non-haematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect the development of anaemia, neutropenia and thrombocytopenia.

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in adult patients. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year.

These episodes have occurred both in previously treated or untreated patients. As with other cytotoxics, caution should be exercised with fludarabine phosphate, when further haematopoietic stem cell sampling is considered. 8) have been reported to occur during or after treatment with Fludara.

The majority of patients experiencing haemolytic anaemia developed a recurrence in the haemolytic process after rechallenge with Fludara. Patients treated with Fludara oral should be closely monitored for signs of haemolysis. Discontinuation of therapy with Fludara is recommended in case of haemolysis.

Blood transfusion (irradiated, see below) and adrenocorticoid preparations are the most common treatment measures for autoimmune haemolytic anaemia. Neurotoxicity The effect of chronic administration of Fludara on the central nervous system is unknown.

However, patients tolerated the recommended intravenous dose, in some studies for relatively long treatment times (for up to 26 courses of therapy). Patients should be closely observed for signs of neurologic effects. When used at high doses in dose-ranging studies in patients with acute leukaemia, intravenous Fludara was associated with severe neurological effects, including blindness, coma and death.

Symptoms appeared from 21 to 60 days from last dose. This severe central nervous system toxicity occurred in 36 % of patients treated intravenously with doses approximately four times greater (96 mg/m²/day for 5 - 7 days) than the recommended dose.

8) In post-marketing experience neurotoxicity has been reported to occur earlier or later than in clinical trials. Administration of Fludara can be associated with leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL) or reversible posterior leukoencephalopathy syndrome (RPLS).

These may occur: • at the recommended dose o when Fludara is given following, or in combination with, medications known to be associated with LE, ATL or RPLS, o or when Fludara is given in patients with other risk factors such as cranial or total body irradiation, Hematopoietic Cell Transplantation, Graft versus Host Disease, renal impairment, or hepatic encephalopathy.

• at doses higher than the recommended dose LE, ATL or 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 and incontinence.

LE/ ATL/ RPLS may be irreversible, life-threatening, or fatal. Whenever LE, ATL or RPLS is suspected, fludarabine treatment should be stopped. Patients should be monitored and should undergo brain imaging, preferably utilizing MRI. If the diagnosis is confirmed, fludarabine therapy should be permanently discontinued.

Tumour lysis syndrome Tumour lysis syndrome has been reported in CLL patients with large tumour burdens. Since Fludara can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication, and hospitalisation may be recommended for these patients during the first course of treatment.

Transfusion-associated graft-versus-host disease Transfusion-associated graft-versus-host disease (reaction by the transfused immunocompetent lymphocytes to the host) has been observed after transfusion of non- irradiated blood in Fludara treated patients.

Fatal outcome as a consequence of this disease has been reported with a high frequency. Therefore, to minimise the risk of transfusion- associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received treatment with Fludara should receive irradiated blood only.

Skin cancer The worsening or flare up of pre-existing skin cancer lesions as well as new onset of skin cancer has been reported in some patients during or after Fludara therapy. Impaired state of health In patients with impaired state of health, Fludara should be given with caution and after careful risk/benefit consideration.

This applies especially for patients with severe impairment of bone marrow function (thrombocytopenia, anaemia, and/or granulocytopenia), immunodeficiency or with a history […]

1. - Renal impairment with creatinine clearance <30 ml/min. - Decompensated haemolytic anaemia. - Lactation.