FLUOROURACIL

What it is

Fluorouracil Accord is an injection solution containing fluorouracil as the active ingredient, available in five strengths: 250 mg/5 mL, 500 mg/10 mL, 1 g/20 mL, 2.5 g/50 mL and 5 g/100 mL. The solution is a clear, colourless to slightly pale yellow preparation.

Approved indications

Fluorouracil Accord is indicated, alone or in combination, for the palliative treatment of malignant tumours, particularly of the breast, colon or rectum; and in the treatment of gastric, primary hepatic, pancreatic, uterine (cervical particularly), ovarian and bladder carcinomas. Fluorouracil should only be used when other proven measures have failed or are considered impractical.

Dosing overview

The total daily dose of fluorouracil should not exceed 1 g. For intravenous infusion, the recommended dose is 15 mg/kg bodyweight (to a maximum of 1 g) daily diluted in 300 to 500 mL of 5% glucose given over a period of four hours. For intravenous injection, 12 mg/kg bodyweight is given daily for three consecutive days. If toxic effects do not appear, the patient may then receive 6 mg/kg intravenously on the 5th, 7th and 9th days. Maintenance therapy is 5 to 10 mg/kg bodyweight by intravenous injection once a week. Initial recommended doses should be reduced by one-third to one-half if poor nutritional state, major surgery within 30 days, inadequate bone marrow function, or impaired hepatic and/or renal function are present.

Key safety warnings

Fluorouracil has a narrow margin of safety and is a highly toxic drug. The most pronounced and dose-limiting toxic effects are on the normal, rapidly proliferating tissues of the bone marrow and the lining of the gastrointestinal tract. Fluorouracil therapy should be discontinued promptly whenever signs of toxicity appear, including leucopenia, thrombocytopenia, stomatitis, oesophagopharyngitis, intractable vomiting, diarrhoea, melaena, haemorrhage, oral ulceration, or evidence of gastrointestinal ulceration or bleeding. Fluorouracil administration has been associated with myocardial ischaemia, cardiomyopathy and, very rarely, sudden death. Angina, tachycardia, breathlessness, arrhythmia, electrocardiogram abnormalities, myocardial infarction and stress cardiomyopathy have been reported after administration of fluorouracil. Fluorouracil should not be re-administered after a documented cardiovascular reaction (arrhythmia, angina, ST segment changes) as there is a risk of sudden death. Severe toxicity (such as stomatitis, diarrhoea, neutropenia, and neurotoxicity) associated with fluorouracil has been attributed to deficiency of dihydropyrimidine dehydrogenase (DPD) activity. DPD-deficiency related toxicity usually occurs during the first cycle of treatment or after dose increase, and fatal outcome has been reported in some cases. Special attention should be given to DPD status before therapy through laboratory testing. Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity, and a reduced starting dose should be considered to limit this toxicity. Fluorouracil should be used with caution in elderly patients. An age of 70 years or older and the female gender are statistically significant risk factors for severe toxicity from fluorouracil based chemotherapy, and these effects may be additive in older women.

Contraindications

Fluorouracil is contraindicated in patients who have any known hypersensitivity to fluorouracil or its excipients, who are debilitated, who are suffering a poor nutritional state, who are suffering from bone marrow depression following radiotherapy or therapy with other antineoplastic agents (leucocyte count less than 5,000/mm³, platelet count less than 100,000/mm³), who are suffering from a potentially serious infection, who are pregnant, or with known complete dihydropyrimidine dehydrogenase (DPD) deficiency. Fluorouracil must not be taken within 4 weeks of treatment with brivudine, sorivudine or their chemically related analogues.

Regulatory history

Fluorouracil Accord was first registered on the Australian Register of Therapeutic Goods on 8 June 2018, with registrations for multiple strengths including 250 mg/5 mL, 500 mg/10 mL, 1 g/20 mL, 2.5 g/50 mL and 5 g/100 mL injection vials.