Drugs List

Therapeutic Indications

Uses

Fluorouracil may be used alone or in combination for its action in the management of common malignancies, particularly cancer of the colon and breast.

Administration

To be given as an intravenous or intra-arterial infusion or as an intravenous injection.

Handling

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

Reconstitution

Fluorouracil injection may be given undiluted or diluted with glucose 5% injection, sodium chloride 0.9% injection or water for injections immediately before parenteral use. See individual manufacturer's advice.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2-8 degrees C, unless opening and dilution has taken place in controlled and validated aseptic conditions.

Different manufacturers quote different chemical and physical in use stability of fluorouracil solutions. See specialist literature and individual product SPCs for further information.

Incompatibilities

Fluorouracil injection solutions are alkaline. Admixture with acidic drugs or preparations should be avoided.

Fluorouracil Injection is incompatible with calcium folinate, carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, droperidol, filgrastim, gallium nitrate, methotrexate, metoclopramide, morphine, ondansetron, parenteral nutrition, vinorelbine or other anthracyclines.

Contraindications

Children under 18 years old
Pregnancy
Breastfeeding
Severe debilitation
Bone marrow suppression after radiotherapy or treatment with other anti-neoplastic agents
Serious infections e.g. herpes zoster and chicken pox

Precautions and Warnings

Fluorouracil should be given only under the strict supervision of a physician conversant with the use of potent antimetabolites. Facilities for regular monitoring of clinical, biochemical and haematological effects during and after administration should also be available.

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

Reduction of dose is advisable in patients with cachexia, reduced bone marrow function or impaired renal or hepatic function or within 30 days of major surgery.

It is customary to calculate the dose in accordance with the patient's actual weight unless there is obesity, oedema or some other form of abnormal fluid retention such as ascites. In these cases, use the patient's ideal weight as the basis for the dose calculation.

All patients should be admitted to hospital for initial treatment because of the possibility of severe toxic reactions.

Adequate treatment with fluorouracil is usually followed by leucopenia, the lowest white blood cell count commonly being observed between the 7th and 14th day of the first course, but occasionally being delayed for as long as 20 days. The count usually returns to normal by the 30th day. Daily monitoring of platelet and white blood cell count is recommended and treatment should be stopped if platelets fall below 100,000/cubic millimetre or the white blood cell count below 3,500/cubic millimetre. If the total WBC count is less than 2000/cubic millimetre, and especially if there is granulocytopenia, place the patient in protective isolation in the hospital and treat with appropriate measures to prevent systemic infection.

Discontinue treatment at the first sign of oral ulceration or if there is evidence of gastrointestinal side effects such as stomatitis, diarrhoea, bleeding from the gastrointestinal tract or haemorrhage at any site. The ratio between effective dose and toxic dose is small and therapeutic response is unlikely without some degree of toxicity. Take care in the selection of patients and adjustment of dose.

Use with caution in patients with reduced renal or liver function or jaundice.

Isolated cases of angina, ECG abnormalities and rarely myocardial infarction have been reported. Care should be exercised in treating patients who experience chest pain during courses of treatment or patients with a history of heart disease.

Increased toxicity has been reported in patients who have dihydropyrimidine dehydrogenase (DPD) deficiency. If applicable, determination of DPD enzyme activity is indicated prior to the treatment with fluorouracil.

Vaccination with live vaccines should be avoided in patients receiving fluorouracil due to the potential for serious or fatal infections. Contact should be avoided with people who have recently been treated with polio virus vaccine.

Risk of photosensitivity. Avoid prolonged exposure to sunlight.

Use with caution in patients who have had high-dose pelvic radiation.

Patients of both sexes should use adequate contraception during and for up to 6 months after treatment.
Fluorouracil could induce chromosomal damage in human spermatozoa. Male patients should be advised to seek information regarding sperm conservation due to the possibility of infertility.
Female patients should be advised not to become pregnant during treatment. Patients desiring to have children should be advised to obtain genetic counselling if appropriate and available.

Fluorouracil is an irritant; contact with eyes and mucous membranes should be avoided.

Ability to drive and operate machinery may be affected by side effects.

The use of an anti-emetic should be considered if required during treatment.

Pregnancy and Lactation

Pregnancy

Contraindicated during pregnancy.

No adequate data, at the time of writing, on the use of fluorouracil in pregnant women, however, fatal defects and miscarriages have been reported.

Animal studies have shown fluorouracil to be embryotoxic and teratogenic in mice, rats and hamsters given parenteral doses equivalent to the human dose. Although not teratogenic in monkeys, divided doses above 40mg/kg resulted in abortions.

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 ).

Lactation

Contraindicated in breastfeeding.

No adequate data, at the time of writing, on the use of fluorouracil during breastfeeding.

The low molecular weight suggests fluorouracil would be excreted into breast milk. Women should not breastfeed during treatment due to the potential of severe adverse reactions in nursing infants.

Schaefer suggests women receiving injections of fluorouracil should withhold breastfeeding for a minimum of 8 hours.

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

Infections
Sepsis
Leucopenia
Myelosuppression
Neutropenia
Granulocytopenia
Thrombocytopenia
Anaemia
Pancytopenia
Agranulocytosis
Immunosuppression
Hyperuricaemia
Altered thyroid hormone levels
Reversible confusional states
Ataxia
Extrapyramidal effects
Cerebellar syndrome (reversible)
Nystagmus
Headache
Vertigo
Parkinson-like symptoms
Euphoria
Leukoencephalopathy
Speech disturbances
Aphasia
Convulsions
Coma
Optic neuritis
Peripheral neuropathy
Conjunctivitis
Lachrymation
Dacryostenosis
Visual disturbances
Photophobia
Diplopia
Blepharitis
Ectropion
Ocular changes
Chest pain
Tachycardia
ECG changes
Angina
Arrhythmias
Myocardial infarction
Myocarditis
Cardiac failure
Sudden cardiac death
Cardiomyopathy
Vasculitis
Raynaud's phenomenon
Ischaemia
Thromboembolism
Epistaxis
Bronchospasm
Diarrhoea
Nausea
Vomiting
Mucositis
Stomatitis
Gastro-intestinal ulceration and bleeding
Haemorrhage
Hepatic damage
Hepatic necrosis
Alopecia
Palmar-Plantar Erythrodysesthesia syndrome
Dermatitis
Skin pigmentation changes
Nail disorders
Exanthema
Dry skin
Urticaria
Photosensitivity
Fever
Fatigue
Thrombophlebitis (localised)
Vein tracking
Dehydration
Cardiogenic shock
Dyspnoea
Anaphylactic shock
Cardiotoxicity
Dizziness
Somnolence
Dysarthria
Disorientation
Myasthenia
Blurred vision
Proctitis
Anorexia
Pharyngitis
Oesophagitis
Dysaesthesia
Hypotension
Allergic reaction
Anaphylaxis
Interference with spermatogenesis
Dysfunctional ovulation
Renal failure
Weakness
Cholecystitis

Presentation

Solution for injection containing 25mg/ml fluorouracil per vial.

Solution for injection containing 50mg/ml fluorouracil per vial.

Drugs List

Therapeutic Indications

Uses

Fluorouracil may be used alone or in combination for its action in the management of common malignancies, particularly cancer of the colon and breast.

Dosage

Selection of an appropriate dose and treatment regime will depend upon the condition of the patient, the type of carcinoma being treated and whether fluorouracil is to be administered alone or in combination with other therapy.

Initial treatment should be given in hospital. Fluorouracil should be given only under the strict supervision of a physician conversant with the use of potent antimetabolites. Facilities for regular monitoring of clinical, biochemical and haematological effects during and after administration should also be available.

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

Administration

To be given as an intravenous or intra-arterial infusion or as an intravenous injection.

Handling

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

Reconstitution

Fluorouracil injection may be given undiluted or diluted with glucose 5% injection, sodium chloride 0.9% injection or water for injections immediately before parenteral use. See individual manufacturer's advice.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2-8 degrees C, unless opening and dilution has taken place in controlled and validated aseptic conditions.

Different manufacturers quote different chemical and physical in use stability of fluorouracil solutions. See specialist literature and individual product SPCs for further information.

Incompatibilities

Fluorouracil injection solutions are alkaline. Admixture with acidic drugs or preparations should be avoided.

Fluorouracil Injection is incompatible with calcium folinate, carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, droperidol, filgrastim, gallium nitrate, methotrexate, metoclopramide, morphine, ondansetron, parenteral nutrition, vinorelbine or other anthracyclines.

Contraindications

Children under 18 years old
Pregnancy
Breastfeeding
Severe debilitation
Bone marrow suppression after radiotherapy or treatment with other anti-neoplastic agents
Serious infections e.g. herpes zoster and chicken pox

Precautions and Warnings

Fluorouracil should be given only under the strict supervision of a physician conversant with the use of potent antimetabolites. Facilities for regular monitoring of clinical, biochemical and haematological effects during and after administration should also be available.

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

Reduction of dose is advisable in patients with cachexia, reduced bone marrow function or impaired renal or hepatic function or within 30 days of major surgery.

It is customary to calculate the dose in accordance with the patient's actual weight unless there is obesity, oedema or some other form of abnormal fluid retention such as ascites. In these cases, use the patient's ideal weight as the basis for the dose calculation.

All patients should be admitted to hospital for initial treatment because of the possibility of severe toxic reactions.

Adequate treatment with fluorouracil is usually followed by leucopenia, the lowest white blood cell count commonly being observed between the 7th and 14th day of the first course, but occasionally being delayed for as long as 20 days. The count usually returns to normal by the 30th day. Daily monitoring of platelet and white blood cell count is recommended and treatment should be stopped if platelets fall below 100,000/cubic millimetre or the white blood cell count below 3,500/cubic millimetre. If the total WBC count is less than 2000/cubic millimetre, and especially if there is granulocytopenia, place the patient in protective isolation in the hospital and treat with appropriate measures to prevent systemic infection.

Discontinue treatment at the first sign of oral ulceration or if there is evidence of gastrointestinal side effects such as stomatitis, diarrhoea, bleeding from the gastrointestinal tract or haemorrhage at any site. The ratio between effective dose and toxic dose is small and therapeutic response is unlikely without some degree of toxicity. Take care in the selection of patients and adjustment of dose.

Use with caution in patients with reduced renal or liver function or jaundice.

Isolated cases of angina, ECG abnormalities and rarely myocardial infarction have been reported. Care should be exercised in treating patients who experience chest pain during courses of treatment or patients with a history of heart disease.

Increased toxicity has been reported in patients who have dihydropyrimidine dehydrogenase (DPD) deficiency. If applicable, determination of DPD enzyme activity is indicated prior to the treatment with fluorouracil.

Vaccination with live vaccines should be avoided in patients receiving fluorouracil due to the potential for serious or fatal infections. Contact should be avoided with people who have recently been treated with polio virus vaccine.

Risk of photosensitivity. Avoid prolonged exposure to sunlight.

Use with caution in patients who have had high-dose pelvic radiation.

Patients of both sexes should use adequate contraception during and for up to 6 months after treatment.
Fluorouracil could induce chromosomal damage in human spermatozoa. Male patients should be advised to seek information regarding sperm conservation due to the possibility of infertility.
Female patients should be advised not to become pregnant during treatment. Patients desiring to have children should be advised to obtain genetic counselling if appropriate and available.

Fluorouracil is an irritant; contact with eyes and mucous membranes should be avoided.

Ability to drive and operate machinery may be affected by side effects.

The use of an anti-emetic should be considered if required during treatment.

Pregnancy and Lactation

Pregnancy

Contraindicated during pregnancy.

No adequate data, at the time of writing, on the use of fluorouracil in pregnant women, however, fatal defects and miscarriages have been reported.

Animal studies have shown fluorouracil to be embryotoxic and teratogenic in mice, rats and hamsters given parenteral doses equivalent to the human dose. Although not teratogenic in monkeys, divided doses above 40mg/kg resulted in abortions.

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 ).

Lactation

Contraindicated in breastfeeding.

No adequate data, at the time of writing, on the use of fluorouracil during breastfeeding.

The low molecular weight suggests fluorouracil would be excreted into breast milk. Women should not breastfeed during treatment due to the potential of severe adverse reactions in nursing infants.

Schaefer suggests women receiving injections of fluorouracil should withhold breastfeeding for a minimum of 8 hours.

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

Effects on Ability to Drive and Operate Machinery

Side effects such as nausea and vomiting may affect patients' ability to drive or operate machinery.

Counselling

Advise patients to avoid prolonged exposure to sunlight.

Advise male patients regarding sperm conservation due to the possibility of infertility. Advised female patients not to become pregnant during treatment.

Patients of both sexes should use adequate contraception during and for 6 months after treatment.

Patients desiring to have children after therapy completion should be advised to obtain genetic counselling if appropriate and available.

Ability to drive and operate machinery may be affected by side effects.

Side Effects

Infections
Sepsis
Leucopenia
Myelosuppression
Neutropenia
Granulocytopenia
Thrombocytopenia
Anaemia
Pancytopenia
Agranulocytosis
Immunosuppression
Hyperuricaemia
Altered thyroid hormone levels
Reversible confusional states
Ataxia
Extrapyramidal effects
Cerebellar syndrome (reversible)
Nystagmus
Headache
Vertigo
Parkinson-like symptoms
Euphoria
Leukoencephalopathy
Speech disturbances
Aphasia
Convulsions
Coma
Optic neuritis
Peripheral neuropathy
Conjunctivitis
Lachrymation
Dacryostenosis
Visual disturbances
Photophobia
Diplopia
Blepharitis
Ectropion
Ocular changes
Chest pain
Tachycardia
ECG changes
Angina
Arrhythmias
Myocardial infarction
Myocarditis
Cardiac failure
Sudden cardiac death
Cardiomyopathy
Vasculitis
Raynaud's phenomenon
Ischaemia
Thromboembolism
Epistaxis
Bronchospasm
Diarrhoea
Nausea
Vomiting
Mucositis
Stomatitis
Gastro-intestinal ulceration and bleeding
Haemorrhage
Hepatic damage
Hepatic necrosis
Alopecia
Palmar-Plantar Erythrodysesthesia syndrome
Dermatitis
Skin pigmentation changes
Nail disorders
Exanthema
Dry skin
Urticaria
Photosensitivity
Fever
Fatigue
Thrombophlebitis (localised)
Vein tracking
Dehydration
Cardiogenic shock
Dyspnoea
Anaphylactic shock
Cardiotoxicity
Dizziness
Somnolence
Dysarthria
Disorientation
Myasthenia
Blurred vision
Proctitis
Anorexia
Pharyngitis
Oesophagitis
Dysaesthesia
Hypotension
Allergic reaction
Anaphylaxis
Interference with spermatogenesis
Dysfunctional ovulation
Renal failure
Weakness
Cholecystitis

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

Do not store above 25 degrees C
Do not refrigerate or freeze
Keep container in outer carton to protect from light

Further Information

Last Full review Date: March 2012

Reference Sources

British National Formulary, 63rd Edition (2012) Pharmaceutical Press, London.

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

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.

HPRA Safety Notice - 5-Fluorouracil (i.v.), capecitabine and tegafur containing products: Pre-treatment testing to identify DPD-deficient patients at increased risk of severe toxicity Available at: https://www.hpra.ie/homepage/medicines/safety-notices/item?t=/important-safety-information-from-marketing-authorisation-holders-of-products-containing-5-fluorouracil-(i.v.)-capecitabine-and-tegafur-as-approved-by-the-hpra&id=809e0d26-9782-6eee-9b55-ff00008c97d0
Last accessed: 26 October 2020

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

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

The Cytotoxics Handbook Fourth Edition (2002), ed. Allwood, Stanley, Wright. Radcliffe Medical Press, Abingdon.

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

Summary of Product Characteristics: Fluorouracil 25mg/ml. Medac GmbH. Revised June 2009
Summary of Product Characteristics: Fluorouracil 50mg/ml. Medac GmbH. Revised November 2007
Summary of Product Characteristics: Fluorouracil 50mg/ml Injection. Hospira UK Ltd. Revised August 2011
Summary of Product Characteristics: Fluorouracil 25mg/ml Injection. Hospira UK Ltd. Revised August 2011
Summary of Product Characteristics: Fluorouracil 50mg/ml Injection. Accord Healthcare Ltd. Revised July 2011

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Azithromycin. Last revised: March 01, 2012
Last accessed: March 26, 2012