Drugs List

Therapeutic Indications

Uses

B cell chronic lymphocytic leukaemia

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

Fludarabine should only be initiated as first line treatment in cases of 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

Conditioning prior to haematopoietic progenitor cell transplantation
Leukaemia - acute lymphoblastic
Leukaemia - acute myeloid

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

Administration

For intravenous injection or infusion after dilution.

Contraindications

Breastfeeding
Haemolytic anaemia
Pregnancy
Renal impairment - creatinine clearance below 30 ml/minute

Precautions and Warnings

Children under 18 years
Patients over 65 years
Hepatic impairment
Immunodeficiency syndromes
Myelosuppression
Renal impairment - creatinine clearance below 70ml/min
Skin cancer

Administration of live vaccines is not recommended
Reduce dose in patients with creatinine clearance below 70ml/min
Advise patient CNS effects may affect ability to drive or operate machinery
Consult local policy on the safe use of anti-cancer drugs
Must be diluted before use
Patients who require blood transfusion should only receive irradiated blood
Staff: Not to be handled by pregnant staff
Treatment to be administered by or under supervision of specialist
Elderly: Monitor renal function and consider dose modification
Monitor for signs of neurological toxicity
Monitor haematological parameters regularly throughout treatment
Monitor patient closely for haemolysis
Monitor patients for signs of tumour lysis syndrome
Advise patient to report headaches, seizures, confusion, visual disturbance
Discontinue treatment if haemolysis occurs
Flare of pre-existing skin cancer lesions may occur during/after treatment
Male & female: Contraception required during & for 6 months after treatment
Advise patient to inform physician of any skin changes immediately

Progressive Multifocal Leukoencephalopathy Syndrome (PML)
Progressive multifocal leukoencephalopathy syndrome (PML) has been reported in some patients treated with this agent. If patients present with symptoms indicating PML such as worsening neurological, cognitive or behavioural signs or symptoms, an MRI should be performed. If PML is diagnosed with other agents it is normally recommended that treatment should be permanently discontinued.

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.

Pregnancy and Lactation

Pregnancy

Fludarabine is contraindicated in pregnancy.

Insufficient data exists to support the safety of fludarabine in human pregnancy. Given the low molecular weights of the parent drug and active metabolite (365 and 269 respectively), the low plasma protein binding and the elimination half life, it is expected both compounds will cross the placenta.

In animal studies placental transfer has been demonstrated and significant adverse effects were reported in the offspring such as cleft palate, exencephaly and vertebrae deformities.

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 to 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 ).

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 the properties of the drug and drug processing by the body suggest fludarabine will be excreted into the milk of breastfeeding mothers. Given the systemic toxicity of fludarabine across multiple body systems it would be wise to avoid use in breastfeeding.

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

Side Effects

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

Presentation

Powder or concentrate for solution for injection or infusion containing fludarabine

Drugs List

Therapeutic Indications

Uses

B cell chronic lymphocytic leukaemia

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

Fludarabine should only be initiated as first line treatment in cases of 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

Conditioning prior to haematopoietic progenitor cell transplantation
Leukaemia - acute lymphoblastic
Leukaemia - acute myeloid

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

Dosage

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

Fludarabine is usually given for 6 cycles.

Adults

Elderly

Patients with Renal Impairment

Administration

For intravenous injection or infusion after dilution.

Contraindications

Breastfeeding
Haemolytic anaemia
Pregnancy
Renal impairment - creatinine clearance below 30 ml/minute

Precautions and Warnings

Children under 18 years
Patients over 65 years
Hepatic impairment
Immunodeficiency syndromes
Myelosuppression
Renal impairment - creatinine clearance below 70ml/min
Skin cancer

Administration of live vaccines is not recommended
Reduce dose in patients with creatinine clearance below 70ml/min
Advise patient CNS effects may affect ability to drive or operate machinery
Consult local policy on the safe use of anti-cancer drugs
Must be diluted before use
Patients who require blood transfusion should only receive irradiated blood
Staff: Not to be handled by pregnant staff
Treatment to be administered by or under supervision of specialist
Elderly: Monitor renal function and consider dose modification
Monitor for signs of neurological toxicity
Monitor haematological parameters regularly throughout treatment
Monitor patient closely for haemolysis
Monitor patients for signs of tumour lysis syndrome
Advise patient to report headaches, seizures, confusion, visual disturbance
Discontinue treatment if haemolysis occurs
Flare of pre-existing skin cancer lesions may occur during/after treatment
Male & female: Contraception required during & for 6 months after treatment
Advise patient to inform physician of any skin changes immediately

Progressive Multifocal Leukoencephalopathy Syndrome (PML)
Progressive multifocal leukoencephalopathy syndrome (PML) has been reported in some patients treated with this agent. If patients present with symptoms indicating PML such as worsening neurological, cognitive or behavioural signs or symptoms, an MRI should be performed. If PML is diagnosed with other agents it is normally recommended that treatment should be permanently discontinued.

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.

Pregnancy and Lactation

Pregnancy

Fludarabine is contraindicated in pregnancy.

Insufficient data exists to support the safety of fludarabine in human pregnancy. Given the low molecular weights of the parent drug and active metabolite (365 and 269 respectively), the low plasma protein binding and the elimination half life, it is expected both compounds will cross the placenta.

In animal studies placental transfer has been demonstrated and significant adverse effects were reported in the offspring such as cleft palate, exencephaly and vertebrae deformities.

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 to 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 ).

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 the properties of the drug and drug processing by the body suggest fludarabine will be excreted into the milk of breastfeeding mothers. Given the systemic toxicity of fludarabine across multiple body systems it would be wise to avoid use in breastfeeding.

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

Side Effects

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

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 ).

Further Information

Last Full Review Date: March 2014

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 50 mg powder for solution for injection or infusion. Sanofi. Revised March 2011.

Summary of Product Characteristics: Fludarabine 50 mg lyophilisate for solution for injection or infusion. Actavis UK Ltd. Revised November 2010.

Summary of Product Characteristics: Fludarabine Phosphate 25 mg/ml Concentrate for solution for injection or infusion. Actavis UK Ltd. Revised June 2013.

Summary of Product Characteristics: Fludarabine phosphate 50 mg powder for solution for injection or infusion. Hospira. Revised April 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