Drugs List

Therapeutic Indications

Uses

Treatment of patients with B-cell chronic lymphocytic leukaemia (CLL) with sufficient bone marrow reserves.

The use of oral fludarabine as a first line treatment, should only be commenced in 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.

Unlicensed Uses

In children poor prognosis or relapsed acute myeloid leukaemia, relapsed acute lymphoblastic leukaemia and conditioning before bone marrow transplantation.

Administration

For oral administration

The tablets must be swallowed whole, not chewed or broken, with water on an empty stomach or with food.

Handling

Standard guidelines on handling cytotoxic drugs should be followed:
1. Trained personnel should reconstitute cytotoxics;
2. Protective clothing (including gloves) should be worn;
3. The eyes should be protected and means of first aid should be specified;
4. Pregnant staff should not handle cytotoxics;
5. Adequate care should be taken for the disposal of waste material, including syringes, containers and absorbent material.

Contraindications

Renal impairment - creatinine clearance below 30ml/minute - see Dosage - Renal impairment
Decompensated haemolytic anaemia
Breastfeeding - see Lactation section
Pregnancy - see Pregnancy section
Galactosaemia

Precautions and Warnings

Fludarabine should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

Whilst the doses stated are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

Observe patients carefully for signs of neurological toxicity. Fludarabine has been associated with severe central nervous system toxicity at doses within the dose range for CLL (Chronic Lymphocytic Leukaemia). Side effects include coma, blindness, seizures and agitation (rare) and confusion (uncommon).

Renal impairment requires dose adjustment. Creatinine clearance should be measured if renal impairment is clinically suspected or in patients over the age of 65 years. A dose reduction by up to 50% is suggested for creatinine clearance between 30 and 70ml/minute and close haematological monitoring should be used to assess toxicity - see Dosage - Renal impairment.

At present, there are insufficient data available in patients with hepatic impairment. Use with caution in these patients.

Use with caution in patients with impaired health. This applies particularly to patients with severe impairment of bone marrow function (thrombocytopenia, anaemia and/or granulocytopenia), immunodeficiency or with a history of opportunistic infection.

Severe bone marrow depression, notably anaemia, thrombocytopenia and neutropenia has been reported in patients receiving fludarabine. In a Phase I intravenous study in patients with solid tumours, the median time to nadir counts was 13 days (range 3 to 25 days) for granulocytes and 16 days (range 2 to 32) for platelets. Most patients had haematological impairment at baseline either as a result of their disease, or previous myelosuppressive therapy.

Administration of fludarabine requires careful haematological monitoring as cumulative myelosuppression may be seen. Chemotherapy-induced myelosuppression is often reversible. Periodic assessment of peripheral blood counts is recommended to monitor for 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.

Evolution of Epstein-Barr Virus (EBV) infection/reactivation into EBV-associated lymphoproliferative disorders has been observed in immunocompromised patients.

Caution when further haematopoietic stem sampling is required.

Transfusion-associated graft-versus-host disease (reaction by the transfused immunocompetent lymphocytes to the host) has been observed after infusion of non-irradiated blood in patients treated with intravenous fludarabine and has a fatal outcome in a high proportion of patients. Patients requiring blood transfusion should receive irradiated blood only.

Reversible worsening or flare-up of pre-existing skin cancer lesions has been reported during or after intravenous fludarabine treatment. New onset skin cancer has also been reported.

Tumour lysis syndrome has uncommonly been associated with fludarabine treatment in patients with a high tumour burden. This response may be induced as early as the first week of treatment. Use with caution in patients at risk of developing tumour lysis syndrome.

Life-threatening and sometimes fatal autoimmune phenomena have been reported during or after intravenous fludarabine, irrespective of any previous history of autoimmune process or Coombs' test status. The majority of patients experiencing haemolytic anaemia developed a recurrence after rechallenge with fludarabine. Monitor patients for signs of autoimmune haemolytic anaemia. If haemolysis occurs, discontinue treatment. Blood transfusion (with irradiated blood) and adrenocorticoid preparations are the most common treatment for autoimmune haemolytic anaemia.

A crossover from initial treatment with fludarabine to chlorambucil for non-responders to fludarabine should be avoided. Most patients who have been resistant to fludarabine have shown resistance to chlorambucil.

Use with caution in patients over 75 years of age as there are limited data for use in elderly patients and decline in renal function with age may require dose adjustment - see Dosage - Renal impairment.

The safety and effectiveness of fludarabine in children under 18 years has not been established by the manufacturer. Therefore, treatment with fludarabine in children is not recommended - see Dosage - Children.

Women of child-bearing age and men must take contraceptive precautions during and for 6 months after treatment with fludarabine. If pregnancy occurs, they should inform their physician immediately.

Avoid vaccination with live vaccines during treatment.

Central nervous system side effects may impair ability to drive or operate machinery. Patients experiencing such events should not drive or operate machinery.

Some brands contain lactose. Patients with rare hereditary problems of galactose intolerance or glucose-galactose malabsorption should not take this medicine.

Pregnancy and Lactation

Pregnancy

Fludarabine is contraindicated during pregnancy, and it has the potential to cause foetal harm.

Very limited human experience supports the findings of embryotoxicity studies in animals demonstrating an embryotoxic and/or teratogenic potential at the therapeutic dose. Pre-clinical studies in rats demonstrated a transfer of fludarabine and/or metabolites across the placenta.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Licensed in pregnancy? - No

Known human teratogen? - Unknown but animal data suggests likely

Lactation

Fludarabine is contraindicated during breastfeeding.

Breastfeeding should be discontinued for the duration of fludarabine treatment.

It is not known if the drug is excreted into human milk, but there is evidence from preclinical data that fludarabine or its metabolites are excreted in milk.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Drug substance licensed in infants? - No

Side Effects

Infections
Fever
Fatigue
Weakness
Malaise
Chills
Neutropenia
Thrombocytopenia
Anaemia
Myelosuppression
Reactivation of herpes zoster
Reactivation of Epstein Barr virus
Progressive multifocal leukoencephalopathy (PML)
Lymphoproliferative disorders
Myelodysplastic syndrome
Autoimmune disorders
Haemolytic anaemia
Thrombocytopenic purpura
Pemphigus
Evans' syndrome
Tumour lysis syndrome
Hyperuricaemia
Hyperphosphataemia
Hypocalcaemia
Metabolic acidosis
Hyperkalaemia
Haematuria
Crystalluria
Renal failure
Oedema
Alterations in hepatic enzymes
Alterations in pancreatic enzymes
Peripheral neuropathy
Confusion
Coma
Agitation
Seizures
Visual disturbances
Optic neuritis
Optic neuropathy
Blindness
Pneumonia
Interstitial pulmonary infiltrate
Pneumonitis
Dyspnoea
Cough
Nausea
Vomiting
Diarrhoea
Stomatitis
Anorexia
Gastro-intestinal haemorrhage
Cardiac failure
Arrhythmias
Haemorrhagic cystitis
Rash
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Flare up of pre-existing skin cancer lesions
Mucositis
Skin carcinoma
Acute myeloid leukaemia
Acquired haemophilia
Cerebral haemorrhage
Pulmonary fibrosis
Pulmonary haemorrhage
Pulmonary toxicity
Bone marrow hypoplasia
Bone marrow aplasia
Pancytopenia

Presentation

Film coated tablets containing 10mg fludarabine phosphate

Drugs List

Therapeutic Indications

Uses

Treatment of patients with B-cell chronic lymphocytic leukaemia (CLL) with sufficient bone marrow reserves.

The use of oral fludarabine as a first line treatment, should only be commenced in 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.

Unlicensed Uses

In children poor prognosis or relapsed acute myeloid leukaemia, relapsed acute lymphoblastic leukaemia and conditioning before bone marrow transplantation.

Dosage

Fludarabine should only be prescribed by a qualified physician experienced in the use of antineoplastic therapy.

Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

Adults

Elderly

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Administration

For oral administration

The tablets must be swallowed whole, not chewed or broken, with water on an empty stomach or with food.

Handling

Standard guidelines on handling cytotoxic drugs should be followed:
1. Trained personnel should reconstitute cytotoxics;
2. Protective clothing (including gloves) should be worn;
3. The eyes should be protected and means of first aid should be specified;
4. Pregnant staff should not handle cytotoxics;
5. Adequate care should be taken for the disposal of waste material, including syringes, containers and absorbent material.

Contraindications

Renal impairment - creatinine clearance below 30ml/minute - see Dosage - Renal impairment
Decompensated haemolytic anaemia
Breastfeeding - see Lactation section
Pregnancy - see Pregnancy section
Galactosaemia

Precautions and Warnings

Fludarabine should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

Whilst the doses stated are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

Observe patients carefully for signs of neurological toxicity. Fludarabine has been associated with severe central nervous system toxicity at doses within the dose range for CLL (Chronic Lymphocytic Leukaemia). Side effects include coma, blindness, seizures and agitation (rare) and confusion (uncommon).

Renal impairment requires dose adjustment. Creatinine clearance should be measured if renal impairment is clinically suspected or in patients over the age of 65 years. A dose reduction by up to 50% is suggested for creatinine clearance between 30 and 70ml/minute and close haematological monitoring should be used to assess toxicity - see Dosage - Renal impairment.

At present, there are insufficient data available in patients with hepatic impairment. Use with caution in these patients.

Use with caution in patients with impaired health. This applies particularly to patients with severe impairment of bone marrow function (thrombocytopenia, anaemia and/or granulocytopenia), immunodeficiency or with a history of opportunistic infection.

Severe bone marrow depression, notably anaemia, thrombocytopenia and neutropenia has been reported in patients receiving fludarabine. In a Phase I intravenous study in patients with solid tumours, the median time to nadir counts was 13 days (range 3 to 25 days) for granulocytes and 16 days (range 2 to 32) for platelets. Most patients had haematological impairment at baseline either as a result of their disease, or previous myelosuppressive therapy.

Administration of fludarabine requires careful haematological monitoring as cumulative myelosuppression may be seen. Chemotherapy-induced myelosuppression is often reversible. Periodic assessment of peripheral blood counts is recommended to monitor for 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.

Evolution of Epstein-Barr Virus (EBV) infection/reactivation into EBV-associated lymphoproliferative disorders has been observed in immunocompromised patients.

Caution when further haematopoietic stem sampling is required.

Transfusion-associated graft-versus-host disease (reaction by the transfused immunocompetent lymphocytes to the host) has been observed after infusion of non-irradiated blood in patients treated with intravenous fludarabine and has a fatal outcome in a high proportion of patients. Patients requiring blood transfusion should receive irradiated blood only.

Reversible worsening or flare-up of pre-existing skin cancer lesions has been reported during or after intravenous fludarabine treatment. New onset skin cancer has also been reported.

Tumour lysis syndrome has uncommonly been associated with fludarabine treatment in patients with a high tumour burden. This response may be induced as early as the first week of treatment. Use with caution in patients at risk of developing tumour lysis syndrome.

Life-threatening and sometimes fatal autoimmune phenomena have been reported during or after intravenous fludarabine, irrespective of any previous history of autoimmune process or Coombs' test status. The majority of patients experiencing haemolytic anaemia developed a recurrence after rechallenge with fludarabine. Monitor patients for signs of autoimmune haemolytic anaemia. If haemolysis occurs, discontinue treatment. Blood transfusion (with irradiated blood) and adrenocorticoid preparations are the most common treatment for autoimmune haemolytic anaemia.

A crossover from initial treatment with fludarabine to chlorambucil for non-responders to fludarabine should be avoided. Most patients who have been resistant to fludarabine have shown resistance to chlorambucil.

Use with caution in patients over 75 years of age as there are limited data for use in elderly patients and decline in renal function with age may require dose adjustment - see Dosage - Renal impairment.

The safety and effectiveness of fludarabine in children under 18 years has not been established by the manufacturer. Therefore, treatment with fludarabine in children is not recommended - see Dosage - Children.

Women of child-bearing age and men must take contraceptive precautions during and for 6 months after treatment with fludarabine. If pregnancy occurs, they should inform their physician immediately.

Avoid vaccination with live vaccines during treatment.

Central nervous system side effects may impair ability to drive or operate machinery. Patients experiencing such events should not drive or operate machinery.

Some brands contain lactose. Patients with rare hereditary problems of galactose intolerance or glucose-galactose malabsorption should not take this medicine.

Pregnancy and Lactation

Pregnancy

Fludarabine is contraindicated during pregnancy, and it has the potential to cause foetal harm.

Very limited human experience supports the findings of embryotoxicity studies in animals demonstrating an embryotoxic and/or teratogenic potential at the therapeutic dose. Pre-clinical studies in rats demonstrated a transfer of fludarabine and/or metabolites across the placenta.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Licensed in pregnancy? - No

Known human teratogen? - Unknown but animal data suggests likely

Lactation

Fludarabine is contraindicated during breastfeeding.

Breastfeeding should be discontinued for the duration of fludarabine treatment.

It is not known if the drug is excreted into human milk, but there is evidence from preclinical data that fludarabine or its metabolites are excreted in milk.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Drug substance licensed in infants? - No

Effects on Ability to Drive and Operate Machinery

Central nervous system side effects may impair ability to drive or operate machinery. Patients experiencing such events should not drive or operate machinery.

Counselling

Advise women of child-bearing age and men to take contraceptive precautions during and for 6 months after treatment with fludarabine. If pregnancy occurs, they should inform their physician immediately.

Central nervous system side effects may impair ability to drive or operate machinery. Advise patients experiencing such events not to drive or operate machinery.

Side Effects

Infections
Fever
Fatigue
Weakness
Malaise
Chills
Neutropenia
Thrombocytopenia
Anaemia
Myelosuppression
Reactivation of herpes zoster
Reactivation of Epstein Barr virus
Progressive multifocal leukoencephalopathy (PML)
Lymphoproliferative disorders
Myelodysplastic syndrome
Autoimmune disorders
Haemolytic anaemia
Thrombocytopenic purpura
Pemphigus
Evans' syndrome
Tumour lysis syndrome
Hyperuricaemia
Hyperphosphataemia
Hypocalcaemia
Metabolic acidosis
Hyperkalaemia
Haematuria
Crystalluria
Renal failure
Oedema
Alterations in hepatic enzymes
Alterations in pancreatic enzymes
Peripheral neuropathy
Confusion
Coma
Agitation
Seizures
Visual disturbances
Optic neuritis
Optic neuropathy
Blindness
Pneumonia
Interstitial pulmonary infiltrate
Pneumonitis
Dyspnoea
Cough
Nausea
Vomiting
Diarrhoea
Stomatitis
Anorexia
Gastro-intestinal haemorrhage
Cardiac failure
Arrhythmias
Haemorrhagic cystitis
Rash
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Flare up of pre-existing skin cancer lesions
Mucositis
Skin carcinoma
Acute myeloid leukaemia
Acquired haemophilia
Cerebral haemorrhage
Pulmonary fibrosis
Pulmonary haemorrhage
Pulmonary toxicity
Bone marrow hypoplasia
Bone marrow aplasia
Pancytopenia

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Shelf Life and Storage

Store in original packaging. This medicinal product does not require any special temperature storage conditions.

Further Information

Last Full Review Date: June 2012

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.

Summary of Product Characteristics: Fludara oral 10mg film-coated tablet. Genzyme. Revised March 2011.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 17 August 2017