Lactation
4.4 Special warnings and special precautions for use
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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) 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 haematological monitoring.
Fludarabine Phosphate Powder for Solution for Injection or Infusion 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 sampling is considered.
Irrespective of any previous history of autoimmune processes or Coombs test status, life-threatening and sometimes fatal autoimmune phenomena 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 Powder for Solution for Injection or Infusion should be closely monitored for haemolysis.
Discontinuation of therapy with Fludarabine Phosphate Powder for Solution for Injection or Infusion is recommended in case of haemolysis. Blood transfusion (irradiated, see above) and adrenocorticoid preparations are the most common treatment measures for autoimmune haemolytic anaemia.
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. In patients treated at doses in the range of the dose recommended for CLL, severe central nervous system toxicity has occurred rarely (coma, seizures and agitation) or uncommonly (confusion).
The effect of chronic administration of Fludarabine Phosphate Powder for Solution for Injection or Infusion on the central nervous system is unknown. However, patients tolerated the recommended dose, in some studies for relatively long term treatment times, (for up to 26 courses of therapy). Patients should be closely observed for signs of neurological side effects.
In postmarketing experience neurotoxicity has been reported to occur earlier or later than in clinical trials.
Tumour lysis syndrome associated with fludarabine phosphate treatment has been reported in CLL patients with large tumour burdens. Since Fludarabine Phosphate Powder for Solution for Injection or Infusion 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.
- 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 fludarabine phosphate 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 have received, treatment with Fludarabine Phosphate Powder for Solution for Injection or Infusion 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 to occur during or after fludarabine phosphate therapy.
In patients with impaired state of health, Fludarabine Phosphate Powder for Solution for Injection or Infusion 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 metabolite 2-F-ara-A shows a correlation with creatinine, 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).
Fludarabine Phosphate Powder for Solution for Injection or Infusion 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). Fludarabine Phosphate Powder for Solution for Injection or Infusion treatment is contraindicated if creatinine clearance is < 30 ml/min (see section 4.3).
Since there are limited data for the use of Fludarabine Phosphate Powder for Solution for Injection or Infusion in elderly persons (> 75 years), caution should be exercised with the administration in these patients.
In patients aged 65 years or older, creatinine clearance should be measured before start of treatment, see ‘Renal Impairment’ and section 4.2.
Fludarabine phosphate 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 fetal harm (see sections 4.6 and 5.3). Prescribers may only consider the use of fludarabine phosphate, if the potential benefits justify the potential risks to the foetus.
Women should avoid becoming pregnant while on fludarabine phosphate 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 contraceptive measures during and for at least 6 months after cessation of therapy (see section 4.6).
During and after treatment with Fludarabine Phosphate Powder for Solution for Injection or Infusion, vaccination with live vaccines should be avoided.
- Retreatment options after initial fludarabine phosphate treatment
A crossover from initial treatment with Fludarabine Phosphate Powder for Solution for Injection or Infusion to chlorambucil for non responders to Fludarabine Phosphate Powder for Solution for Injection or Infusion should be avoided because most patients who have been resistant to fludarabine phosphate have shown resistance to chlorambucil.
4.5 Interaction with other medicinal products and other forms of interaction
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In a clinical investigation using intravenous (WORD ADDED) fludarabine phosphate 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 Fludarabine Phosphate Powder for Solution for Injection or Infusion in combination with pentostatin is not recommended.
Dipyridamole and other inhibitors of adenosine uptake may reduce the therapeutic efficacy of Fludarabine Phosphate Powder for Solution for Injection or Infusion.
Clinical studies and in vitro experiments showed that during use of fludarabine in combination with cytarabine the 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.
4.6 Pregnancy and lactation
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Preclinical data in rats demonstrated a transfer of fludarabine and/or metabolites through the placenta. The results from intravenous embryotoxicity studies in rats and rabbits indicated an embyrolethal and teratogenic potential at the therapeutic doses (see section 5.3).
There are very limited data of fludarabine use in pregnant women in the first trimester.
Fludarabine 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). Fludarabine has the potential to cause fetal harm. Prescribers may only consider the use of fludarabine, if the potential benefits justify the potential risks to the foetus.
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).
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 fludarabine in breast-fed infants. Fludarabine is contraindicated in nursing mothers (see section 4.3).
4.7 Effects on ability to drive and use machines
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Fludarabine may reduce the ability to drive and use machines, since e.g. fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.
4.8 Undesirable effects
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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 Powder for Solution for Injection or Infusion. 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 fludarabine. The rare adverse reactions were mainly identified from the post-marketing experience.
|
System Organ Class
MedDRA
|
Very Common
³1/10
|
Common
≥ 1/100 to <1/10
|
Uncommon
≥ 1/1000 to <1/100
|
Rare
³1/10,000 to <1/1000
|
Not known
|
|
Infections and infestations
|
Infections / Opportunistic infections
(like latent viral reactivation,
e.g. Progressive multifocal leucoencephalopathy, Herpes zoster virus
Epstein-Barr-virus),
Pneumonia
|
|
|
Lymphoproliferative 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,
Evans syndrome,
Thrombocytopenic purpura, Acquired haemophilia, Pemphigus)
|
|
|
|
Metabolism and nutrition disorders
|
|
Anorexia
|
Tumour lysis syndrome
(including
Renal failure, Metabolic acidosis, Hyperkalaemia,
Hypocalcemia, Hyperuricemia,
Haematuria,
Urate crystalluria, Hyperphosphatemia)
|
|
|
|
Nervous system
disorders
|
|
Neuropathy peripheral
|
Confusion
|
Coma,
Seizures,
Agitation
|
Cerebral haemorrhage
|
|
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)
|
|
Pulmonary haemorrhage
|
|
Gastrointestinal disorders
|
Vomiting,
Diarrhoea, Nausea
|
Stomatitis
|
Gastrointestinal 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
|
|
|
Renal and urinary disorder
|
|
|
|
|
Haemorrhagic cystitis
|
|
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. Adverse event term representation is based on MedDRA version 12.0.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
4.9 Overdose
High doses of fludarabine phosphate have been associated with an irreversible central nervous system toxicity characterized 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 (WORD ADDED) antidote for Fludarabine Phosphate Powder for Solution for Injection or Infusion overdose. Treatment consists of drug discontinuation and supportive therapy.
10. DATE OF REVISION OF THE TEXT
DATE CHANGE
April 2011
