Fluorouracil

(BAN, USAN, rINN)
Fluorouracil Chemical formula
Synonyms: 5-Fluorouracil; Fluorouracilas; Fluorouracile; Fluorouracilo; Fluorouracilum; Fluorouracyl; Fluorourasiili; Fluorourasil; 5-Fluorourasil; Fluoruracil; 5-FU; NSC19893; Ro-2-9757; WR-69596. 5Fluoropyrimidine-2,4(1H,3H)-dione.
Cyrillic synonym: Флуороурацил.

💊 Chemical information

Chemical formula: C4H3FN2O2 = 130.1.
CAS — 51-21-8.
ATC — L01BC02.
ATC Vet — QL01BC02.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, and US.

Ph. Eur. 6.2

(Fluorouracil). A white or almost white, crystalline powder. Sparingly soluble in water; slightly soluble in alcohol. A 1% solution in water has a pH of 4.5 to 5.0. Protect from light.

USP 31

(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, 1 diazepam, 2 doxorubicin 2 (and presumably other anthracyclines that are unstable at alkaline pH), and calcium folinate. 3 Although fluorouracil has been stated to be incompatible with methotrexate 1 a study of the long-term stability of an admixture of the 2 drugs in sodium chloride 0.9% injection suggests otherwise. 4 1. McRae MP, King JC. Compatibility of antineoplastic, antibiotic and corticosteroid drugs in intravenous admixtures. Am J Hosp Pharm 1976; 33: 1010–13. 2. Dorr RT. Incompatibilities with parenteral anticancer drugs. Am J Intravenous Ther 1979; 6: 42–52. 3. Trissel LA, et al. Incompatibility of fluorouracil with leucovorin calcium or levoleucovorin calcium. Am J Health-Syst Pharm 1995; 52: 710–15. 4. Vincké BJ, et al. Extended stability of 5-fluorouracil and methotrexate solutions in PVC containers. Int J Pharmaceutics 1989; 54: 181–9.

Stability.

Despite one report 1 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 2 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. 2,3 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. 3 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. 4 Fluorouracil solutions may be incompatible with synthetic elastomers: microscopic precipitation has been reported as soon as 4 hours after placement into polyisoprene reservoirs of elastomeric infusers and in polypropylene syringes with an elastomeric joint. 5 Some have questioned the validity of this finding. 6,7 1. Benvenuto JA, et al. Stability and compatibility of antitumor agents in glass and plastic containers. Am J Hosp Pharm 1981; 38: 1914–18. 2. Quebbeman EJ, et al. Stability of fluorouracil in plastic containers used for continuous infusion at home. Am J Hosp Pharm 1984; 41: 1153–6. 3. Vincké B, et al. Extended stability of 5-fluorouracil and methotrexate solutions in PVC containers. Int J Pharmaceutics 1989; 54: 181–9. 4. Stiles ML, et al. Stability of fluorouracil administered through four portable infusion pumps. Am J Hosp Pharm 1989; 46: 2036–40. 5. Corbrion V, et al. Precipitation of fluorouracil in elastomeric infusers with a polyisoprene reservoir and in polypropylene syringes with an elastomeric joint. Am J Health-Syst Pharm 1997; 54: 1845–8. 6. Trissel LA. Fluorouracil precipitate. Am J Health-Syst Pharm 1998; 55: 1314–15. 7. Allwood MC. Fluorouracil precipitate. Am J Health-Syst Pharm 1998; 55; 1315–16.

💊 Adverse Effects and Treatment

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 desquamation 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 photosensitivity 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.1 In one patient this was associated with symptoms suggesting fibrosis of the tear duct,1 and possibly representing local irritation due to the presence of fluorouracil in tear fluid,2 although symptoms have not always resolved on stopping the drug.1 More seriously a case of bilateral total corneal epithelial erosion has been described.3Optic neuropathy, culminating in near blindness, has also occurred in a patient given fluorouracil as part of a combination regimen.4 Severe ulceration and corneal abscess with hyopyon has followed local injection of fluorouracil into the eye in a diabetic patient with idiopathic band keratopathy.5
1. Haidak DJ, et al. Tear-duct fibrosis (dacryostenosis) due to 5fluorouracil. Ann Intern Med 1978; 88: 657
2. Christophidis N, et al. Lacrimation and 5-fluorouracil. Ann Intern Med 1978; 89: 574
3. Hirsh A, et al. Bilateral total corneal epithelial erosion as a side effect of cytotoxic therapy. Br J Ophthalmol 1990; 74: 638
4. Adams JW, et al. Recurrent acute toxic optic neuropathy secondary to 5-FU. Cancer Treat Rep 1984; 68: 565–6
5. Hickey-Dwyer M, Wishart PK. Serious corneal complication of 5-fluorouracil. Br J Ophthalmol 1993; 77: 250–1.

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,1 although the incidence of angina and less severe cardiotoxicity associated with coronary artery spasm may be higher.1-3 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.2-4 Therefore, at present, it is not possible to reliably predict patients at risk.5 Some suggest that the use of a trometamol buffer in the fluorouracil formulation may contribute to the formation of cardiotoxic degradation products.6
1. Keefe DL, et al. Clinical cardiotoxicity of 5-fluorouracil. J Clin Pharmacol 1993; 33: 1060–70
2. McLachlan SA, et al. The spectrum of 5-fluorouracil cardiotoxicity. Med J Aust 1994; 161: 207–9
3. Anand AJ. Fluorouracil cardiotoxicity. Ann Pharmacother 1994; 28: 374–8.
4. Hannaford R. Sudden death associated with 5-fluorouracil. Med J Aust 1994; 161: 225
5. Becker K, et al. Cardiotoxicity of the antiproliferative compound fluorouracil. Drugs 1999; 57: 475–84
6. Lukaschek J, et al. Cardiotoxicity and neurotoxicity of high-dose continuous fluorouracil as a result of degradation compounds in the drug vials. J Clin Oncol 2004; 22: 5022–5.

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 highdose or intensive regimens. Patients with disorders of pyrimidine metabolism may be at increased risk of neurotoxicity.1-3 It has also been suggested that fluorouracil may produce neurotoxicity by causing thiamine deficiency, and that thiamine may be used to treat it.4
1. Tuchman M, et al. Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity. N Engl J Med 1985; 313: 245–9
2. Stéphan F, et al. Depressed hepatic dihydropyrimidine dehydrogenase activity and fluorouracil-related toxicities. Am J Med 1995; 99: 685–8
3. Takimoto C, et al. Reversible 5-fluorouracil-associated encephalopathy in a dihydropyrimidine dehydrogenase (DPD) deficient patient. Clin Pharmacol Ther 1996; 59: 161
4. Pirzada NA, et al. Fluorouracil-induced neurotoxicity. Ann Pharmacother 2000; 34: 35–8.

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 reported1-4. Although particularly associated with continuous infusion1,2 the syndrome can also occur after bolus doses.3,4Symptoms generally respond to stopping the drug, but addition of oral pyridoxine to chemotherapy regimens has been reported to prevent or resolve symptoms,5 as has application of a nicotine patch in one patient.6 Rash and confusion developing in an elderly man with malabsorption and poor nutritional intake who received fluorouracil for a biliary-tract tumour were diagnosed as pellagra.7 Symptoms responded to nicotinic acid therapy.
1. Lokich JJ, Moore C. Chemotherapy-associated palmar-plantar erythrodysesthesia syndrome. Ann Intern Med 1984; 101: 798–800
2. Feldman LD, Ajani JA. Fluorouracil-associated dermatitis of the hands and feet. JAMA 1985; 254: 3479
3. Atkins JN. Fluorouracil and the palmar-plantar erythrodysesthesia syndrome. Ann Intern Med 1985; 102: 419
4. Curran CF, Luce JK. Fluorouracil and palmar-plantar erythrodysesthesia. Ann Intern Med 1989; 111: 858
5. Vukelja SJ, et al. Pyridoxine for the palmar-plantar erythrodysesthesia syndrome. Ann Intern Med 1989; 111: 688–9
6. Kingsley EC. 5-Fluorouracil dermatitis prophylaxis with a nicotine patch. Ann Intern Med 1994; 120: 813
7. Stevens HP, et al. Pellagra secondary to 5-fluorouracil. Br J Dermatol 1993; 128: 578–80.

Hypersensitivity.

Although local hypersensitivity reactions are included in licensed product information as potential adverse effects of topical fluorouracil, hypersensitivity reactions to systemic fluorouracil have been reported very rarely.1-6 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.
1. Reed WP, Morris DM. Maculopapular eruption resulting from systemic administration of 5-fluorouracil. Cutis 1984; 33: 381–2
2. Sridhar KS. Allergic reaction to 5-fluorouracil infusion. Cancer 1986; 58: 862–4
3. Milla Santos A, Sanchiz Medina F. Anaphylactic reaction following iv administration of 5-fluorouracil. Cancer Treat Rep 1986; 70: 1346
4. Duley JA, Nethersell AB. Delayed hypersensitivity to 5-fluorouracil associated with reduced dihydropyrimidine dehydrogenase (DPD) activity. Adv Exp Med Biol 1998; 431: 147–50
5. Eppinger T, Sperber K. Desensitization to 5-fluorouracil. Allergy 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, or surface neoplasia of the eye. The role of fluorouracil in chemoradiotherapy of various malignancies has been reviewed.1
1. Rich TA, et al. Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy. J Clin Oncol 2004; 22: 2214–32.
To x o p l a s m o s i s . 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).1-3 It has been tried as an adjuvant to laser therapy in severe papillomavirus-associated vulvar disease,4 with variable results, and in men with subclinical or clinically apparent penile lesions.5 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.6 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.7 For a discussion of the various agents, including cytotoxics such as fluorouracil, employed to produce destruction of warts.
1. Kling AR. Genital warts—therapy. Semin Dermatol 1992; 11: 247–55
2. Stone KM. Human papillomavirus infection and genital warts: update on epidemiology and treatment. Clin Infect Dis 1995; 20 (suppl 1): S91–7
3. Beutner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med 1997; 102: 28–37
4. Reid R, et al. Superficial laser vulvectomy IV: extended laser vaporization and adjunctive 5-fluorouracil therapy of human papillomavirus-associated vulvar disease. Obstet Gynecol 1990; 76: 439–48
5. Bergman A, Nalick R. Genital human papillomavirus infection in men: diagnosis and treatment with a laser and 5-fluorouracil. J Reprod Med 1991; 36: 363–6
6. Swinehart JM, et al. Intralesional fluorouracil/epinephrine injectable gel for treatment of condylomata acuminata: a phase 3 clinical study. Arch Dermatol 1997; 133: 67–73
7. Zschocke I, et al. Wirksamkeit und Nutzen eines 5-FU-/Salicylsäure-haltigen Präparates in der Therapie vulgärer und plantarer Warzen—systematische Literaturübersicht und Metaanalyse. J Dtsch Dermatol Ges 2004; 2: 187–93.

💊 Preparations

BP 2008: Fluorouracil Cream; Fluorouracil Injection; USP 31: Fluorouracil Cream; Fluorouracil Injection; Fluorouracil Topical Solution.

Proprietary Preparations

Arg.: Cinco-Fu†; Efudix; Ifocid†; Oncofu†; Triosules; Austral.: Efudix; Belg.: Efudix; Fluracedyl; Fluroblastine; Braz.: Killit†; Utoral†; Canad.: Adrucil†; Efudex; Chile: Efudix; Fluoracilo; Cz.: La-Fu; Denm.: Flurablastin; Fin.: Flurablastin; Fr.: Efudix; Ger.: Efudix; Neofluor; O-fluor†; Onkofluor; Ribofluor; Gr.: Uraciflor; Hong Kong: Efudix†; Hung.: Efudix; India: Fivefluro; Florac; Fluracil; Indon.: Curacil; Fluracedyl; Irl.: Efudix; Israel: Efudix; Ital.: Efudix; Malaysia: Fluracedyl; Mex.: Efudix; Flurox; Ifacil†; Tecflu; Neth.: Efudix; Fluracedyl; Norw.: Flurablastin; NZ: Efudix; Philipp.: Fivoflu; Fluoxan; Fluracedyl; Fluroblastin; Uflahex; Utoral; Pol.: Efudix; Port.: Cinkef-U; Rus.: Flurox (Флурокс)†; S.Afr.: Efudix; Fluroblastin; Singapore: Efudix; Spain: Efudix†; Swed.: Flurablastin; Fluracedyl†; Switz.: Efudix; Thai.: Fivoflu; Fluracedyl†; Flurox; UK: Efudix; USA: Adrucil; Carac; Efudex; Fluoroplex; Venez.: Fivoflu; Fluroblastin. Multi-ingredient: Austria: Verrumal; Braz.: Efurix; Cz.: Verrumal; Ger.: Verrumal; Gr.: Verruca Hermal; Hong Kong: Verrumal; Hung.: Verrumal; Israel: Verrumal; Verucid†; Malaysia: Verrumal; Pol.: Verrumal; Port.: Verrucare; Verrumal; Singapore: Verrumal; Switz.: Verrumal; Thai.: Verrumal; Turk.: Verrutol.
Published January 08, 2019.