Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands
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.
Irrespective of any previous history of autoimmune processes or Coombs test status, life-threatening and sometimes fatal autoimmune phenomena (see section 4.8) 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 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.
The effect of chronic administration of Fludara 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 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. In patients treated at doses in the range of the dose recommended for CLL, severe central nervous system toxicity occurred rarely (coma, seizures and agitation) or uncommonly (confusion) (see section 4.8).
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:
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 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 (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.
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.
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 of opportunistic infection.
The total body clearance of the principle plasma metabolite 2-F-ara-A shows a correlation with creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the compound. Patients with reduced renal function demonstrated an increased total body exposure (AUC of 2F-ara-A). There are limited clinical data available in patients with impairment of renal function (creatinine clearance <70 ml/min).
Fludara must be administered cautiously in patients with renal insufficiency. In patients with moderate impairment of renal function (creatinine clearance between 30 and 70 ml/min), the dose should be reduced by up to 50% and the patient should be monitored closely (see section 4.2). Fludara treatment is contraindicated if creatinine clearance is <30ml/min (see section 4.3).
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 (see also section 4.2).
In patients aged 65 years or older, creatinine clearance should be measured before start of treatment, see “Renal impairment” and section 4.2.
Fludara should not be used during pregnancy unless clearly necessary (e.g. life-threatening situation, no alternative safer treatment available without compromising the therapeutic benefit, treatment cannot be avoided). It has the potential to cause foetal harm (see sections 4.6 and 5.3). Prescribers may only consider the use of Fludara, if the potential benefits justify the potential risks to the foetus.
Women should avoid becoming pregnant while on Fludara therapy.
Women of childbearing potential must be apprised of the potential hazard to the foetus.
Women of child-bearing potential or fertile males must take effective contraceptive measures during and at least for 6 months after cessation of therapy (see section 4.6).
During and after treatment with Fludara vaccination with live vaccines should be avoided.
A crossover from initial treatment with Fludara to chlorambucil for non responders to Fludara should be avoided because most patients who have been resistant to Fludara have shown resistance to chlorambucil.
Each vial Fludara 50 mg powder for solution for injection/infusion contains less than 1 mmol sodium (23 mg), i.e. essentially ‘sodium-free’.
In a clinical investigation using intravenous Fludara in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukaemia (CLL), there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludara in combination with pentostatin is not recommended.
Dipyridamole and other inhibitors of adenosine uptake may reduce the therapeutic efficacy of Fludara.
Clinical studies and in vitro experiments showed that during use of Fludara in combination with cytarabine the intracellular peak concentration and intracellular exposure of Ara-CTP (active metabolite of cytarabine) increased in leukaemic cells. Plasma concentrations of Ara-C and the elimination rate of Ara-CTP were not affected.
Women of childbearing potential must be apprised of the potential hazard to the foetus.
Both sexually active men and women of childbearing potential must take effective contraceptive measures during and at least for 6 months after cessation of therapy (see section 4.4).
Pre-clinical data in rats demonstrated a transfer of Fludara and/or metabolites through the placenta. The results from intravenous embryotoxicity studies in rats and rabbits indicated an embryolethal and teratogenic potential at the therapeutic doses (see section 5.3).
There are very limited data of Fludara use in pregnant women in the first trimester.
Fludara should not be used during pregnancy unless clearly necessary (e.g. life-threatening situation, no alternative safer treatment available without compromising the therapeutic benefit, treatment cannot be avoided). Fludara has the potential to cause foetal harm. Prescribers may only consider the use of Fludara if the potential benefits justify the potential risks to the foetus.
It is not known whether this drug or its metabolites are excreted in human milk.
However, there is evidence from preclinical data that fludarabine phosphate and/or metabolites transfer from maternal blood to milk.
Because of the potential for serious adverse reactions to Fludara in breast-fed infants, Fludara is contraindicated in nursing mothers (see section 4.3).
Fludara may reduce the ability to drive and use machines, since e.g. fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.
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.
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.
Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000)
Very Common: Infections/Opportunistic infections (like latent viral reactivation, e.g. progressive multifocal leukoencephalopathy, Herpes zoster virus Esptein-Barr-virus), pneumonia
Rare: Lympho-proliferative disorder (EBV-associated)
Common: Myelodysplastic syndrome and Acute Myeloid Leukaemia (mainly associated with prior, concomitant or subsequent treatment with alkylating agents, topoisomerase inhibitors or irradiation)
Very Common: Neutropenia, anaemia, thrombocytopenia
Common: Myelosuppression
Uncommon: Autoimmune disorder (including autoimmune haemolytic anaemia, Evan’s syndrome, thrombocytopenic purpura, acquired haemophilia, pemphigus
Common: Anorexia
Uncommon: Tumour lysis syndrome (including renal failure, metabolic acidosis, hyperkalaemia, hypocalcaemia, hyperuricaemia, haematuria, urate crystalluria, hyperphosphataemia)
Common: Peripheral neuropathy
Uncommon: Confusion
Rare: Coma, seizures, agitation
Common: Visual disturbances
Rare: Blindness, optic neuritis, optic neuropathy
Rare: Heart failure, arryhthmia
Very Common: Cough
Uncommon: Pulmonary toxicity (including pulmonary fibrosis, pneumonitis, dyspnoea)
Very Common: Vomiting, diarrhoea, nausea
Common: Stomatitis
Uncommon: Gastrointestinal haemorrhage, pancreatic enzymes abnormal
Uncommon: Hepatic enzymes abnormal
Common: Rash
Rare: Skin cancer, necrolysis epidermal toxic (Lyell type) Stevens-Johnson syndrome
Very Common: Fever, fatigue, weakness
Common: 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. Adverse event term representation is based on MedDRA version 12.0.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Nervous system disorders: Cerebral haemorrhage, Leukoencephalopathy (see section 4.4), Acute toxic leukoencephalopathy (see section 4.4), Reversible posterior leukoencephalopathy syndrome (RPLS) (see section 4.4)
Respiratory, thoracic and mediastinal disorders: Pulmonary haemorrhage
Renal and urinary disorder: Haemorrhagic cystitis
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. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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