DBL Fluorouracil Special Precautions

It is recommended that fluorouracil be given only by or under strict supervision of a qualified physician who is well acquainted with the use of potent antimetabolites. Because of the possibility of severe toxic reactions, all patients should be hospitalised, at least during the initial course of therapy.
Fluorouracil should not be re-administered after a documented cardiovascular reaction (arrhythmia, angina, ST segment changes) as there is a risk of sudden death.
Patients taking phenytoin concomitantly with fluorouracil should undergo regular testing because of the possibility of an elevated plasma level of phenytoin (see Interactions).
Toxicity: Fluorouracil has a narrow margin of safety and is a highly toxic drug. The most pronounced and dose-limiting toxic effects of fluorouracil 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 one of the following signs of toxicity appears: leucopenia, thrombocytopenia, stomatitis, oesophagopharyngitis, intractable vomiting, diarrhoea, melena, haemorrhage, oral ulceration, evidence of gastrointestinal ulceration or bleeding.
Any form of therapy that adds to the stress of the patient, interferes with nutritional uptake or depresses bone marrow function, will increase the toxicity of fluorouracil.
The ratio between effective and toxic dose is small and therapeutic response is unlikely without some degree of toxicity. Care must be taken, therefore, in the selection of patients and adjustment of dosage.
Myelosuppression: Cytotoxic agents, including fluorouracil, may produce myelosuppression (including, but not limited to, leucopenia, granulocytopenia, pancytopenia and thrombocytopenia). Leucopenia and thrombocytopenia commonly follow treatment with fluorouracil.
The initial dose should be reduced, or treatment should not be started in the presence of diminished leucocytes and/or platelets (see Contraindications and Dosage & Administration).
Leucopenia occurs after nearly every treatment period with an effective dose. The nadir for white blood cell count usually occurs from the 9^th to the 14^th day after initiation of therapy, but may occur as late as the 20^th day. The count usually returns to normal by the 30^th day. Thrombocytopenia may also occur, with the lowest platelet counts occurring from the 7^th to the 17^th day of therapy.
Daily monitoring of platelet and white blood cell counts is recommended. Treatment with fluorouracil should be discontinued if the leucocyte count falls rapidly or if it falls below 3,500/mm³, or if there is a fall in the platelet count below 100,000/mm³. If the leucocyte count falls below 2,000/mm³ the patients should be placed in an isolation unit and given an appropriate preventative treatment for systemic infection.
Clinical consequences of severe myelosuppression include infections. Viral, bacterial, fungal and/or parasitic infections, either localized or systemic, may be associated with the use of fluorouracil alone or in combination with other immunosuppressive agents. These infections may be mild, but can be severe and at times fatal.
Cardiotoxicity: Fluorouracil administration has been associated with myocardial ischaemia, cardiomyopathy and, very rarely, sudden death. Angina, tachycardia, breathlessness, arrhythmia, ECG abnormalities and myocardial infarction have been reported after administration of fluorouracil. Attention should therefore be paid to patients who experience chest pain during treatment, and patients with a history of heart disease. There is an increased risk of death associated with readministration of fluorouracil in patients with a documented cardiovascular reaction (see Adverse Reactions).
Combination chemotherapy/radiotherapy: May depress bone marrow function and increase the toxicity of fluorouracil. Extreme caution is necessary when administering fluorouracil to patients who have had high dose pelvic irradiation, or have been previously treated with alkylating agents and in those who have a widespread involvement of bone marrow by metastatic tumours. Radiation therapy on the bone marrow, especially to the area of the chest and mediastinum, may potentiate the bone marrow effects of fluorouracil. Fluorouracil treatment may potentiate necrosis caused by radiation. Concomitant use of other chemotherapeutic agents may depress bone marrow function and increase the toxicity of fluorouracil.
Combination with phenytoin: Patients taking phenytoin concomitantly with fluorouracil should undergo regular testing because of the possibility of an elevated plasma level of phenytoin (see Interactions).
Dihydropyrimidine dehydrogenase deficiency: Rarely, severe toxicity (e.g., 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. Fatal outcome has been reported in some cases. Absence of this catabolic enzyme appears to result in prolonged clearance of fluorouracil. Special attention should be given to DPD status before therapy through laboratory testing for the detection of total or partial DPD-deficiency, or when evaluating patients experiencing fluorouracil-related toxicities.
Gastrointestinal effects: Loss of appetite, nausea and vomiting are common adverse effects, which generally occur during the first week of therapy. These adverse effects may be treated symptomatically and can often be alleviated by antiemetics. Stomatitis is usually an early sign of impending severe toxicity which may become evident as early as the fourth day, but more commonly appears after 5-8 days of therapy. Symptoms include soreness, erythema or ulceration of the oral cavity or dysphagia. Other reported gastrointestinal symptoms are diarrhoea, proctitis and oesophagitis, therefore, the dose may require adjustment or therapy may need to be discontinued. Diarrhoea is usually mild and occurs later in treatment. Severe diarrhoea may also be accompanied by dehydration and melaena. Gastrointestinal side effects may be exacerbated if fluorouracil is given with folinic acid
Photosensitivity reactions: Some patients may experience photosensitivity reactions following administration of fluorouracil, it is recommended that patients are warned to avoid prolonged exposure to sunlight (see Adverse Reactions).
Immunosuppressant effects/increased susceptibility to infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including fluorouracil, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving fluorouracil. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Hand-foot syndrome: The administration of fluorouracil has been associated with the occurrence of palmar-plantar erythrodysesthesia syndrome, also known as hand-foot syndrome. Continuous-infusion fluorouracil may increase the incidence and severity of palmar-plantar erythrodysesthesia. This syndrome has been characterized as a tingling sensation of hands and feet, which may progress over the next few days to pain when holding objects or walking. The palms and soles become symmetrically swollen and erythematous with tenderness of the distal phalanges, possibly accompanied by desquamation. Interruption of therapy is followed by gradual resolution over 5 to 7 days. Supplementation of chemotherapy with oral pyridoxine has been reported to prevent or resolve such symptoms.
Multifocal inflammatory leucoencephalopathy (MILE): Combination therapy with 5-fluorouracil and levamisole has been associated with multifocal inflammatory leucoencephalopathy (MILE). Symptoms may include memory loss, confusion, paraesthesia, lethargy, muscle weakness, speech disturbances, coma and seizures. The cerebrospinal fluid may show mild pleiocytosis, and computed tomography and magnetic resonance scans may show lesions in the white matter suggestive of demyelination. If this syndrome occurs, treatment should be discontinued immediately. The condition is at least partially reversible if 5-fluorouracil and levamisole are discontinued and corticosteroids given.
Effects on laboratory tests: Fluorouracil could interfere with diagnostic tests of thyroid function by causing rises in total thyroxine and liothyronine due to increased globulin binding. Plasma albumin may be decreased because of drug-induced protein malabsorption.
Effects on ability to drive and use machines: The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
Renal and hepatic impairment: Fluorouracil should be used with caution in patients with reduced renal or liver function, jaundice or heart disease.
Use in Children: No data available.
Use in the Elderly: 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. These effects may be additive in older women. While advanced age does not contraindicate the use of this type of chemotherapy, close monitoring for multiple organ toxicities and vigorous supportive care of those with toxicity are necessary.