Fluorouracil
(British Approved Name, US Adopted Name, rINN)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Pharmacopoeias. In China, Europe, International, Japan, and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Fluorouracil). A white or almost white, crystalline powder. Sparingly soluble in water; slightly soluble in alcohol. A 1% solution in water has apH of 4.5 to 5.0. Protect from light.
The United States Pharmacopeia 31, 2008 (Fluorouracil). A white to practically white, practically odourless, crystalline powder. Sparingly soluble in water; slightly soluble in alcohol; practically insoluble in chloroform and in ether. Store in airtight containers. Protect from light.
Incompatibility. Preparations of fluorouracil are alkaline, and compatibility problems may be expected with acidic drugs and preparations, or those which are unstable in the presence of alkali. Fluorouracil is reported to be incompatible with cytarabine, diazepam, doxorubicin (and presumably other anthracyclines that are unstable at alkaline pH), and calcium folinate. Although fluorouracil has been stated to be incompatible with methotrexate a study of the long-term stability of an admixture of the 2 drugs in sodium chloride 0.9% injection suggests otherwise.
Stability. Despite one report that fluorouracil had limited stability when dissolved in glucose 5% at room temperature (10% loss from solution in 43 hours when stored in PVC and in only 7 hours when stored in glass), others found such a solution to be stable for at least 16 weeks when stored in PVC at 5°. When stored at room temperature in PVC, solutions of fluorouracil may lose water by evaporation, which slowly increases their concentration. Results of a study of fluorouracil and methotrexate admixtures in sodium chloride 0.9% suggest that extended stability (up to 13 weeks) is possible in this diluent at 5° in PVC bags. Commercial solutions of fluorouracil for injection have been reported to be stable for 7 days at 37° in a portable infusion pump, although at 25° one brand showed evidence of precipitation. Fluorouracil solutions may be incompatible with synthetic elastomers: microscopic precipitation has been reported as soon as 4 hours after placement into poly isoprene reservoirs of elastomeric infusers and in polypropylene syringes with an elastomeric joint. Some have questioned the validity of this finding.
Adverse Effects and Treatment
For general discussions see Antineoplastics.
The main adverse effects of fluorouracil are on the bone marrow and the gastrointestinal tract, and may be dose-limiting. Toxicity is schedule dependent: reducing the rate of injection to a slow infusion is associated with less haematological toxicity but does not decrease gastrointestinal toxicity. With protracted continuous infusion in particular, the palmar-plantar erythrodysesthesia syndrome (erythema and painful desquama-tion of the hands and feet) may occur. Gastrointestinal toxicity may be exacerbated if fluorouracil is given with folinic acid.
Leucopenia, thrombocytopenia, stomatitis, gastrointestinal ulceration and bleeding, diarrhoea, or haemorrhage from any site, are signs that treatment should be stopped. The nadir of the white cell count may occur from 7 to 20 days after a dose, and counts usually return to normal after about 30 days. Thrombocytopenia is usually at a maximum 7 to 17 days after a dose. Anaemia may also occur. Nausea and vomiting, rashes, and alopecia are common. Ocular irritation, central neurotoxicity (notably cerebellar ataxia), and myocardial ischaemia have occurred.
Local inflammatory and photo sensitivity reactions have occurred after topical use. Dermatitis and, rarely, erythema multiforme have been reported.
Effects on the eyes. Systemic fluorouracil therapy has been associated with various types of ocular toxicity including several cases of excessive lachrymation and watering of the eyes. In one patient this was associated with symptoms suggesting fibrosis of the tear duct, and possibly representing local irritation due to the presence of fluorouracil in tear fluid, although symptoms have not always resolved on stopping the drug. More seriously a case of bilateral total corneal epithelial erosion has been described. Optic neuropathy, culminating in near blindness, has also occurred in a patient given fluorouracil as part of a combination regimen. Severe ulceration and corneal abscess with hyopyon has followed local injection of fluorouracil into the eye in a diabetic patient with idiopathic band keratopathy.
Effects on the heart. Life-threatening cardiotoxicity (arrhythmias, ventricular tachycardia, and cardiac arrest, secondary to transmural ischaemia) has been reported to occur in 0.55% of patients given fluorouracil, although the incidence of angina and less severe cardiotoxicity associated with coronary artery spasm may be higher. Possible risk factors include pre-existing heart disease or mediastinal radiotherapy, and prolonged infusion of the drug, but symptoms can also occur in patients without these risk factors. Therefore, at present, it is not possible to reliably predict patients at risk. Some suggest that the use of a trometa-mol buffer in the fluorouracil formulation may contribute to the formation of cardiotoxic degradation products.
Effects on the nervous system. Central neurotoxicity, including cerebellar ataxia, confusion, disorientation, and emotional lability is reported to occur rarely in patients receiving fluorouracil, although the incidence may be increased with high-dose or intensive regimens. Patients with disorders of pyrimidine metabolism may be at increased risk of neurotoxicity. It has also been suggested that fluorouracil may produce neurotoxicity by causing thiamine deficiency, and that thiamine may be used to treat it.
Effects on the skin. In addition to reports of fluorouracil-associated dermatitis and photosensitivity a syndrome of erythema, pain, and desquamation of the skin of palms and soles has been reported (the palmar-plantar erythrodysesthesia syndrome). Although particularly associated with continuous infusion the syndrome can also occur after bolus doses. Symptoms generally respond to stopping the drug, but addition of oral pyridoxine to chemotherapy regimens has been reported to prevent or resolve symptoms, as has application of a nicotine patch in one patient.
Rash and confusion developing in an elderly man with malab-sorption and poor nutritional intake who received fluorouracil for a biliary-tract tumour were diagnosed as pellagra. Symptoms responded to nicotinic acid therapy.
Hypersensitivity. Although local hyper sensitivity reactions are included in licensed product information as potential adverse effects of topical fluorouracil, hypersensitivity reactions to systemic fluorouracil have been reported very rarely. For a report of the successful use of fluorouracil in a patient allergic to capecitabine, suggesting that cross-sensitivity does not occur between the two.
Precautions
For general discussions see Antineoplastics. Fluorouracil should be given with care to weak or malnourished patients, to those with a history of heart disease, or to those with hepatic or renal insufficiency. Patients with a history of high-dose pelvic irradiation or treatment with alkylating agents, and those with widespread metastases to the bone marrow should also be treated with extreme caution. Blood cell counts should be determined frequently during therapy. Fluorouracil should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency as this can lead to increased toxicity.
Topical fluorouracil should not be used on mucous membranes. There is a possibility of increased absorption if used excessively or on ulcerated or inflamed skin. Occlusive dressings may increase inflammatory actions. Exposure to UV light during treatment should be avoided. Creams are preferably applied using a non-metal applicator or gloved hand; if bare fingertips are used the hands must be washed immediately afterwards.
Handling and disposal. Fluorouracil is irritant; avoid contact with skin and mucous membranes.
Urine and faeces produced for up to 48 hours and 5 days respectively after an oral dose of fluorouracil should be handled wearing protective clothing.
Metabolic disorders. For reference to increased risk of neurotoxicity in patients with a defect of pyrimidine metabolism given fluorouracil, see under Effects on the Nervous System, above.
Interactions
For a general discussion of antineoplastic drug interactions. The actions of fluorouracil may be modified by other drugs including allopurinol, cimetidine, folinic acid, methotrexate, and metronidazole (see also under Administration, below).
Antineoplastics. Oxaliplatin, which is given with fluorouracil and folinic acid in the treatment of colorectal cancer, reduced fluorouracil clearance in a study of 29 patients with colorectal cancer. The effect was delayed and prolonged, lasting about 15 days, and an increase in toxicity correlated with raised fluorouracil concentrations. The mechanism of this interaction is unclear. In contrast, however, another study found no effect of oxaliplatin on fluorouracil pharmacokinetics; the study was not designed to investigate a delayed effect and the dose of oxaliplatin was lower than that used in the first study.
Sorafenib has been reported to have variable effects on fluorouracil exposure.
For reference to the effect of fluorouracil on the action ofpaclitaxel, see Antineoplastics. For the increased risk of haemolytic-uraemic syndrome that may be seen if fluorouracil is used with mitomycin, see Effects on the Kidneys.
Antiprotozoals. Metroradazole increased the toxicity of fluorouracil in patients with colorectal cancer, apparently by reducing the clearance of the antineoplastic. No enhanced antineoplastic effect was seen with the combination in vitro.
Antivirals. Giving interferon alfa-2b with fluorouracil has produced a marked increase in the initial plasma concentration of fluorouracil and a decrease in fluorouracil clearance. Severe leucopenia, fatal in some cases, has been reported in patients given fluorouracil or fluorouracil prodrugs (such as tegafur) with sorivudine A metabolite of sorivudine appears to inhibit dihydropyrimidine dehydrogenase, the primary enzyme responsible for the inactivation of fluorouracil.
Gastrointestinal drugs. Pretreatment with cimetidine for 4 weeks increased plasma concentrations of fluorouracil after intravenous and oral doses in 6 patients. The effect was probably due to a combination of hepatic enzyme inhibition and reduced hepatic blood flow. No such effect was seen after single doses of cimetidine in 5 patients or pretreatment for just 1 week in 6. Care is required in patients given both drugs together.
Pharmacokinetics
Absorption of fluorouracil from the gastrointestinal tract is unpredictable and fluorouracil is usually given intravenously. Little is absorbed when fluorouracil is applied to healthy skin.
After intravenous injection fluorouracil is cleared rapidly from plasma with a mean half-life of about 16 minutes. It is distributed throughout body tissues and fluids (including crossing the blood-brain barrier to appear in the CSF), and disappears from the plasma within about 3 hours. Within the target cell fluorouracil is converted to 5-fluorouridine monophosphate and floxuridine monophosphate (5-fluorodeoxyuridine monophosphate), the former undergoing conversion to the triphosphate which can be incorporated into RNA while the latter inhibits thymidylate synthetase. About 15% of an intravenous dose is excreted unchanged in the urine within 6 hours. The remainder is inactivated primarily in the liver and is catabolised via dihydropyrimidine dehydrogenase (DPD) similarly to endogenous uracil. A large amount is excreted as respiratory carbon dioxide; urea and other metabolites are also produced.
Chronopharmacology. Plasma concentrations of fluorouracil during continuous intravenous infusion are reported to undergo circadian variations of as much as 50% of the mean, peak concentrations occurring in the middle of the night. The variation may be due to a circadian variation in the activity of the enzyme dihydropyrimidine dehydrogenase in blood, but striking inter-patient variations in peak concentrations of fluorouracil and peak enzyme activity suggest that any adjustment of infusion times would need to be individualised. It has been suggested that pharmacokinetic monitoring should be investigated as a means of individualising fluorouracil doses with the aim of improving efficacy and reducing toxicity.
Uses and Administration
Fluorouracil, an analogue of the pyrimidine uracil, is an antineoplastic that acts as an antimetabolite. After intracellular conversion to the active deoxynucleotide it interferes with the synthesis of DNA by blocking the conversion of deoxyuridylic acid to thymidylic acid by the cellular enzyme thymidylate synthetase. It can also interfere with RNA synthesis.
Fluorouracil is used alone or in combination in the adjuvant and palliative treatment of gastrointestinal cancer. In this setting it may be combined with folinic acid (see Administration, below). Fluorouracil is often given with cyclophosphamide and methotrexate or doxo-rubicin in the adjuvant treatment of breast cancer. It may also be used in the palliation of other malignant neoplasms such as those of the head and neck, liver, and pancreas. In addition, it may be used topically for treating malignant or premalignant lesions of the skin. Its use in these malignancies is further discussed under Choice of Antineoplastic as indicated by the cross-references given below.
Many dosage regimens have been used. Although it is most often given in combination regimens for the treatment of malignancy, many of the licensed dosage regimens relate to single-agent use. Such licensed regimens include:
• by intravenous injection, usual doses of 12 mg/kg daily (to a maximum of 0.8 to 1 g daily) for 3 or 4 days. If there is no evidence of toxicity, this may be followed after 1 day by 6 mg/kg on alternate days for 3 or 4 further doses. An alternative schedule is to give 15 mg/kg intravenously once a week throughout the course. The course may be repeated after 4 to 6 weeks or maintenance doses of 5 to 15 mg/kg to a maximum of 1 g may be given weekly.
• by intravenous infusion, usual doses of 15 mg/kg daily (to a maximum of 1 g daily) being infused in 500 mL of sodium chloride 0.9% or glucose 5% over 4 hours and repeated on successive days until toxicity occurs or a total of 12 to 15 g has been given. Continuous infusion may also be used. The course may be repeated after 4 to 6 weeks.
• by continuous intra-arterial infusion, in doses of 5 to 7.5 mg/kg daily (regional perfusion).
• by mouth, although the parenteral route is generally preferred, a dose of 15 mg/kg, to a maximum of 1 g in one day, has been given once weekly for maintenance.
Suggested regimens with folinic acid include:
• 200 mg/m of folinic acid (as calcium folinate) by slow intravenous injection followed immediately by an intravenous bolus of fluorouracil 370 mg/m; the treatment is given daily for 5 consecutive days, and may be repeated every 4 to 5 weeks
• lower doses of folinic acid (20 mg/m) followed by fluorouracil 425 mg/m for 5 consecutive days, repeated every 4 to 5 weeks (the Mayo regimen)
• an initial dose of 200 mg/m of folinic acid, followed by fluorouracil 400 mg/m as an initial intravenous bolus injection and then 600 mg/m by continuous intravenous infusion. This dosage is given for 2 consecutive days every 2 weeks (the de Gramont regimen)
The white cell count should be determined frequently during treatment with fluorouracil and therapy stopped immediately if the count falls rapidly or if the white cell or platelet count falls below acceptable levels (see also Bonemarrow Depression) or if severe adverse effects occur. Doses should be reduced by up to half in patients with poor nutritional status, impaired bone-marrow, hepatic, or renal function, and within 30 days of major surgery.
Fluorouracil is used topically in the treatment of solar (actinic) keratoses and other superficial tumours and premalignant conditions of the skin including Bowen’s disease and superficial basal cell carcinomas. For actinic keratosis it is usually applied as a 0.5 to 5% cream or as a 1 to 5% solution in propylene glycol once or twice daily for 2 to 4 weeks; the higher strength may be applied for at least 3 to 6 weeks for superficial basal cell carcinomas.
Administration. Modulation of fluorouracil by other drugs has been tried in an effort to enhance its effects, particularly in the treatment of colorectal cancer.
Folinic acidhas been extensively used to modulate the effects of fluorouracil, and has become the agent of choice. Various regimens have been used, modifying the fluorouracil schedule (continuous infusion versus bolus), folinic acid dose (low-dose versus high-dose) and the regimen frequency (monthly, bimonthly, or weekly). Despite numerous studies, the optimum regimen in terms of efficacy and tolerability has yet to be determined.
In the adjuvant setting, a large-scale randomised trial found no difference in efficacy between low-dose and high-dose folinic acid when added to fluorouracil given either once weekly for 30 doses, or for 5 consecutive days per month over 6 months. Fluorouracil and low-dose folinic acid may therefore become the preferred regimen in the adjuvant setting.
In the palliation of advanced disease, meta-analyses have revealed the value of the addition of folinic acid to fluorouracil, and the use of infusions rather than bolus fluorouracil, in terms of response rates. An updated meta-analysis confirmed the benefit of addition of folinic acid to fluorouracil in terms of response rate, and found a small but statistically significant advantage in terms of overall survival. Survival benefit was restricted to trials using the same dose of fluorouracil in the treatment arms (fluorouracil alone versus fluorouracil and folinic acid), suggesting that the benefit of modulation with folinic acid could be compensated by an increase of fluorouracil dose in the fluorouracil alone arm. However, increased toxicity from high-dose fluorouracil might occur. The data for low-dose folinic acid versus high-dose are less clear. In 1 randomised trial, a bimonthly infusion regimen of fluorouracil plus high-dose folinic acid (the de Gramont regimen) was more effective than a monthly bolus regimen of fluorouracil plus low-dose folinic acid. Further studies comparing the effect of high- and low-dose folinic acid added to the same schedule of continuous infusion fluorouracil are required.
Interferon alfa also appears to modify the actions of fluorouracil (see also under Interactions, above), and has been investigated in combination with fluorouracil and folinic acid. Although some early results were promising, later randomised controlled trials failed to show any benefit for the addition of interferon alfa to fluorouracil or fluorouracil plus folinic acid. It is not clear whether interferon beta will prove of any greater benefit.
Based on the results of early adjuvant studies, levamisole was used as standard therapy to modulate fluorouracil, particularly in the USA. However, more recent trials indicate that levamisole is no more effective than placebo when added to fluorouracil, or to fluorouracil plus folinic acid.
Methotrexate has also been used to modulate fluorouracil. Meta-analysis of several studies of fluorouracil preceded by methotrexate found that the combination doubled the response rate to fluorouracil in metastatic colorectal cancer and produced some survival benefits. (Combination in the reverse order, i.e. methotrexate preceded by fluorouracil, may reduce methotrexate toxicity — see under Treatment of Adverse Effects.)
Darier’s disease. Two patients with resistant Darier’s disease receiving long-term oral retinoid therapy responded to treatment with topical fluorouracil applied as a 1% cream once daily. There was complete clearance of skin lesions after 3 weeks of treatment.
Eye disorders. Aside from its use in glaucoma surgery (below), fluorouracil has been used adjunctively in other ocular surgery. It has also shown promising results in the treatment of ocular surface malignancies.
Glaucoma. A regimen of subconjunctival injections of fluorouracil is effective in improving the outcome of glaucoma filtering surgery in selected patients when used as an adjunct to prevent the formation of scar tissue. However, in view of the increased risk of late-onset conjunctival wound leaks caution has been suggested in its use in eyes with a good prognosis. Although one study found that fluorouracil improved the success rate of combined glaucoma filtering surgery and cataract surgery earlier studies had failed to demonstrate any advantage. A systematic review of these and 2 other studies concluded that fluorouracil reduced the risk of surgical failure of trabeculectomy in eyes at high risk of failure, and in those undergoing surgery for the first time, but noted that the methodological quality of the studies was not high, and that this practice has largely been superseded by the use of intra-operative mitomycin. However, a later survey in the UK found that the use of antime-tabolites in glaucoma surgery was much less common than in the USA or Japan, and that fluorouracil was strongly preferred to mitomycin.
Intra-operative topical application of fluorouracil has been tried as an alternative to subconjunctival injection with conflicting results.
Malignant neoplasms. Fluorouracil plays an important role in the adjuvant treatment of gastrointestinal cancer, as discussed, and has been widely used in adjuvant regimens for early breast cancer. It may also be employed in the management of a wide variety of other malignancies including pancreatic endocrine tumours, cancers of the cervix and head and neck, liver metastases, and tumours of the exocrine pancreas. It is reported to have only modest activity in neoplasms of the kidney. In addition, it is sometimes applied topically as part of the management of malignant or pre-malignant lesions of the skin (see Basal Cell and Sq-uamous Cell Carcinoma, or surface neoplasia of the eye.
The role of fluorouracil in chemoradiotherapy of various malignancies has been reviewed.
Toxoplasmosis. For mention of the use of fluorouracil with clindamycin to treat cerebral toxoplasmosis.
Warts. Fluorouracil has been used, as a 1% or, more usually, a 5% cream or solution in the treatment of genital warts (condylomata acuminata). It has been tried as an adjuvant to laser therapy in severe papillomavirus-associated vulvar disease, with variable results, and in men with subclinical or clinically apparent penile lesions. A preparation of fluorouracil 3% in a collagen gel basis, together with adrenaline as a local vasoconstrictor, has been tried by injection into genital warts. A combination of fluorouracil 0.5% and salicylic acid 10% has also been stated to be effective in the topical treatment of common and plantar warts. For a discussion of the various agents, including cytotox-ics such as fluorouracil, employed to produce destruction of warts.
Preparations
British Pharmacopoeia 2008: Fluorouracil Cream; Fluorouracil Injection
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Fluorouracil Cream; Fluorouracil Injection; Fluorouracil Topical Solution.
Single-ingredient Preparations
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
Argentina: Cinco-Fu¤; Efudix; Ifocid¤; Oncofu; Triosules; Australia: Efudix; Fluoroplex¤; Fluroblastin¤; Belgium: Efudix¤; Fluroblastine; Brazil: Killit; Utoral¤; Canada: Adrucil¤; Efudex; Fluoroplex¤; Chile: Efudix; Fluoracilo; Czech Republic: La-Fu; Denmark: Flurablastin; Finland: Flurablastin; France: Efudix; Germany: Actino-Hermal¤; Cytosafe¤; Effluderm¤; Efudix; Fluroblastin¤; Neofluor; O-fluor¤; Onkofluor; Ribofluor; Hong Kong: Efudix¤; Hungary: Efudix; India: Fivefluro; Florac; Fluracil; Ireland: Efudix; Israel: Efudix; Fluracedyl¤; Italy: Efudix; Malaysia: Fluracedyl; Mexico: Efudix; Fiverocil¤; Flurox; Ifacil¤; Rhonuracil¤; Tecflu; Netherlands: Efudix; Fluracedyl; Norway: Flurablastin; Fluracedyl¤; New Zealand: Efudix; Portugal: Cinkef-U; Russia: Flurox (Флурокс); South Africa: Efudix; Fluroblastin; Singapore: Efudix; Spain: Efudix; Sweden: Flurablastin; Fluracedyl; Switzerland: Efudix; Fluroblastine¤; Thailand: Efudix¤; Fivoflu; Fluracedyl¤; Flurox; United Kingdom: AccuSite¤; Efudix; United States: Adrucil; Carac; Efudex; Fluoroplex; Venezuela: Fivoflu
Multi-ingredient Preparations
Austria: Verrumal; Brazil: Efurix; Czech Republic: Verrumal; Germany: Verrumal; Greece: Verruca Hermal; Hong Kong: Verrumal; Hungary: Verrumal; Israel: Verrumal; Verucid; Malaysia: Verrumal; Portugal: Verrucare; Verrumal; Singapore: Verrumal; Switzerland: Verrumal; Thailand: Verrumal
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