FLUDARABINE PHOSPHATE

Posology Adults The recommended dose is 25 mg fludarabine phosphate/m² body surface given daily for 5 consecutive days every 28 days by the intravenous route. The required dose (calculated on the basis of the patient's body surface) of the concentrate is drawn up into a syringe.

9 % sodium chloride. 9 % sodium chloride and infused over approximately 30 minutes. The duration of treatment depends on the treatment success and the tolerability of the drug. In CLL patients, Fludarabine Phosphate should be administered up to the achievement of best response (complete or partial remission, usually 6 cycles) and then the drug should be discontinued.

Patients with renal impairment Doses should be adjusted for patients with reduced renal 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.

For further information see section

Summary of safety profile Based on the experience with the use of Fludarabine Phosphate, 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 rashes. Serious opportunistic infections have occurred in patients treated with fludarabine phosphate.

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 fludarabine.

The rare adverse reactions were mainly identified from the post-marketing experience. g. progressive multifocal leukoencephalo pathy, Herpes zoster virus, Epstein-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 sub-sequent treatment with alkylating agents, topo-isomerase inhibitors or irradiation) Blood and lymphatic system disorders Neutropenia, anaemia, thrombocytope nia Myelosuppressio n System Organ Class MedDRA Very Common ≥1/10 Common ≥ 1/100 to <1/10 Uncommon ≥ 1/1000 to <1/100 Rare ≥1/10,000 to <1/1000 Immune system disorders Autoimmune disorder (including autoimmune haemolytic anaemia, Evans syndrome, thrombocytope nic purpura, acquired haemophilia, pemphigus) Metabolism and nutrition disorders Anorexia Tumour lysis syndrome (including renal failure, metabolic acidosis, hyperkalaemia hypocalcaemia, hyperuricemia, haematuria, urate crystalluria, hyperphosphat aemia) Nervous system disorders Neuropathy peripheral Confusion Coma, seizures, agitation Eye disorders Visual disturbance Blindness, optic neuritis, optic neuropathy Cardiac disorders Heart failure, arrhythmia Respiratory, thoracic and mediastinal disorders Cough Pulmonary toxicity (including pulmonary fibrosis, pneumonitis, dyspnoea) System Organ Class MedDRA Very Common ≥1/10 Common ≥ 1/100 to <1/10 Uncommon ≥ 1/1000 to <1/100 Rare ≥1/10,000 to <1/1000 Gastro- intestinal disorders Vomiting, diarrhoea, nausea Stomatitis Gastro- intestinal haemorrhage, pancreatic enzymes abnormal Hepatobiliary disorders Hepatic enzyme 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. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 4) • Respiratory, thoracic and mediastinal disorders • Pulmonary haemorrhage • Renal and urinary disorder • 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4. 3). Patients with hepatic impairment No data are available concerning the use of fludarabine phosphate in patients with hepatic impairment. In this group of patients, Fludarabine should be used with caution. Paediatric population Fludarabine is not recommended for use in children and adolescents below age 18, due to a lack of data on safety and efficacy.

Elderly population Since there are limited data for the use of fludarabine in elderly persons (>75 years), caution should be exercised with the administration of fludarabine in these patients. 4). Method of administration Fludarabine Phosphate should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

It is strongly recommended that Fludarabine Phosphate should only be administered intravenously. No cases have been reported in which paravenously administered Fludarabine Phosphate led to severe local adverse reactions. However, unintentional paravenous administration must be avoided.

6. 1 - Renal impairment with creatinine clearance < 30 ml/min. - Decompensated haemolytic anaemia. 4 Special warnings and precautions for use Myelosuppression Severe bone marrow suppression, notably anaemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate.

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 haematological 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 haematological monitoring. Fludarabine Phosphate is a potent antineoplastic agent with potentially significant toxic side effects.

Patients undergoing therapy should be closely observed for signs of haematological and non-haematological 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 fludarabine phosphate.

The majority of patients experiencing haemolytic anaemia developed a recurrence in the haemolytic process after rechallenge with fludarabine phosphate. Patients treated with Fludarabine Phosphate should be closely monitored for signs of haemolysis.

Discontinuation of therapy with Fludarabine Phosphate is recommended in case of haemolysis. Blood transfusion (irradiated, see above) and adrenocorticoid preparations are the most common treatment measures for autoimmune haemolytic anaemia.

Neurotoxicity The effect of chronic administration of Fludarabine Phosphate on the central nervous system is unknown. However, patients tolerated the recommended 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 fludarabine phosphate 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 Fludarabine Phosphate 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 Fludarabine Phosphate is given following, or in combination with, medications known to be associated with LE, ATL or RPLS, o or when Fludarabine Phosphate 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, […]

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