Chemical formula: C₄H₃FN₂O₂ Molecular mass: 130.077 g/mol PubChem compound: 3385
Fluorouracil interacts in the following cases:
Vaccination with live vaccines should be avoided in immunocompromised patients.
Caution is advised and the dose might need to be reduced in patients with renal impairment.
Caution is advised and the dose might need to be reduced in patients with hepatic impairment.
In patients receiving cyclophosphamide, Methotrexate and 5-fluorouracil, addition of thiazide diuretics resulted in a more pronounced decrease of the number of granulocytes when compared to patients not receiving thiazides.
Both the efficacy and toxicity of 5-fluorouracil may be increased when 5-fluorouracil is used in combination with folinic acid. Side effects may be more pronounced and severe diarrhoea may occur. Life-threatening diarrhoeas have been observed if 600 mg/m² of fluorouracil (i.v. bolus once weekly) is given together with folinic acid.
The toxicity profile of 5-fluorouracil may be enhanced or shifted by folinic acid The most common manifestations are leucopenia, mucositis, stomatitis and/or diarrhoea which may be dose limiting. When 5-fluorouracil and folinic acid are used in combination, the fluorouracil dosage must be reduced more in cases of toxicity than when fluorouracil is used alone. Toxicities observed in patients treated with the combination are qualitatively similar to those observed in patients treated with 5-fluorouracil alone.
Gastrointestinal toxicities are observed more commonly and may be more severe or even life threatening (particularly stomatitis and diarrhoea). In severe cases, 5-fluorouracil and folinic acid must be withdrawn, and supportive intravenous therapy initiated. Patients should be instructed to consult their treating physician immediately if stomatitis (mild to moderate ulcers) and/or diarrhoea (watery stools or bowel movements) two times per day occur.
Men treated with fluorouracil are advised not to father a child during and for up to 6 months following cessation of treatment. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with fluorouracil.
No clinical data in humans are available on the effects of topical fluorouracil on fertility.
Experiments in various species revealed an impairment of the fertility and reproductive performance of systemic 5-fluorouracil. The reduced systemic exposure to 5-FU following its topical administration will reduce the potential toxicity. The use of topical 5-fluorouracil may impair female and male fertility. Topical fluorouracil is not recommended in men attempting to father a child.
Increased incidence of cerebral infarction has been reported in oropharyngeal cancer patients treated with fluorouracil and cisplatin.
Fluorouracil should be avoided in combination with clozapine due to increased risk of agranulocytosis.
In patients with breast cancer, combination therapy with cyclophosphamide, methotrexate, 5-fluorouracil and tamoxifen has been reported to increase the risk of thromboembolic events.
Hepatotoxicity (increase in alkaline phosphatases, transaminases or bilirubin) has been observed commonly in patients receiving 5-fluorouracil in combination with levamisol.
Cimetidine, metronidazole and interferone may increase the plasma level of 5-fluorouracil, thereby increasing the toxicity of 5-fluorouracil.
In patients receiving phenytoin and fluorouracil concomitantly, an increase of phenytoin plasma concentration has been reported resulting in symptoms of phenytoin toxicity.
Serious, potentially life-threatening mucositis may occur following co-administration of vinorelbine and 5-fluorouracil/folinic acid.
Marked elevations of prothrombin time and INR have been reported in a few patients stabilised on warfarin therapy following initiation of fluorouracil regimes.
Cases of encephalopathies (including hyperammonaemic encephalopathy, leukoencephalopathy) associated with 5-fluorouracil treatment have been reported from post-marketing sources. Signs or symptoms of encephalopathy are altered mental status, confusion, disorientation, coma or ataxia. If a patient develops any of these symptoms withhold treatment and test serum ammonia levels immediately. In case of elevated serum ammonia levels initiate ammonia-lowering therapy.
Caution is necessary when administering fluorouracil to patients with renal and/or hepatic impairment. Patients with impaired renal and/or hepatic function may have an increased risk for hyperammonaemia and hyperammonaemic encephalopathy.
Treatment should also be stopped at the first sign of oral ulceration or if there is evidence of gastrointestinal side effects such as stomatitis, diarrhoea, bleeding from the G.I. tract or haemorrhage at any site. 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. Treatment should be stopped in case of severe toxicity.
Adequate treatment with fluorouracil is usually followed by leucopenia, the lowest white blood cell (W.B.C.) 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 W.B.C. count is recommended and treatment should be stopped if platelets fall below 100,000 per mm³ or the W.B.C. count falls below 3,500 per mm³. If the total count is less than 2,000 per mm³, and especially if there is granulocytopenia, it is recommended that the patient be placed in protective isolation in the hospital and treated with appropriate measures to prevent systemic infection.
Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, arrhythmias, myocarditis, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of QT prolongation). These adverse events are more common in patients receiving continuous infusion of 5-fluorouracil rather than bolus injection. Prior history of coronary artery disease may be a risk factor for cardiac adverse reactions. Care should therefore be exercised in treating patients who experienced chest pain during courses of treatment, or patients with a history of heart disease. Cardiac function should be regularly monitored during treatment with fluorouracil. In case of severe cardiotoxicity the treatment should be discontinued.
Fluorouracil should be used 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 following administration of fluorouracil. Care should therefore be exercised in treating patients who experience chest pain during courses of treatment, or patients with a history of heart disease.
There are no adequate and well-controlled studies in pregnant women, however, fetal defects and miscarriages have been reported.
There are no adequate data from the use of topical fluorouracil in pregnant women.
Studies in animals have shown that fluorouracil is teratogenic. The potential risk for humans is unknown, hence fluorouracil should not be used during pregnancy.
Women of childbearing potential should be advised to avoid becoming pregnant and use an effective method of contraception during treatment with fluorouracil and upto 6 months afterwards. If the drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be fully informed of the potential hazard to the fetus and genetic counselling is recommended.
No information is available on the excretion of fluorouracil into breast milk. Studies in animals have shown the fluorouracil is teratogenic. A risk to the suckling child cannot be excluded, so fluorouracil should not be used in nursing mothers. If use during breastfeeding is absolutely necessary, breastfeeding must be discontinued.
Men treated with fluorouracil are advised not to father a child during and for up to 6 months following cessation of treatment. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with fluorouracil.
No clinical data in humans are available on the effects of topical fluorouracil on fertility.
Experiments in various species revealed an impairment of the fertility and reproductive performance of systemic 5-fluorouracil. The reduced systemic exposure to 5-FU following its topical administration will reduce the potential toxicity. The use of topical 5-fluorouracil may impair female and male fertility. Topical fluorouracil is not recommended in men attempting to father a child.
No studies on the effects on the ability to drive and use machinery have been performed.
Fluorouracil may induce side effects such as nausea and vomiting. It can also produce adverse event on nervous system and visual changes which could interfere driving or the usage of heavy machinery.
It is unlikely that treatment will have any effect on the ability to drive and use machines when used according to the dosage instructions.
Frequencies are defined using the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10000 to <1/1000), Very rare (<1/10000), Not known (cannot be estimated from the available data).
Common: febrile neutropenia
Very common: Myelosuppression (Onset: 7-10 days, Nadir: 9-14 days, Recovery: 21-28 days), neutropenia, thrombocytopenia, leucopenia, agranulocytosis, anaemia and pancytopenia.
Very common: Bronchospasm, immunosuppression with an increased risk of infection.
Rare: Generalized allergic reactions, anaphylaxis, anaphylactic shock.
Very common: Infections
Rare: Increase of T4 (total thyroxin), increase of T3 (total riiodothyronine).
Very common: Hyperuricemia.
Uncommon: Euphoria.
Rare: Reversible confusional state may occur
Very rare: Disorientation
Uncommon: Nystagmus, headache, dizziness, symptoms of Parkinson’s disease, pyramidal signs, euphoria, somnolence
Very rare: Symptoms of leucoencephalopathy including ataxia, Acute cerebellar syndrome, dysarthria, confusion, disorientation, myasthenia, aphasia, convulsion or coma, kidney failure.
Not Known: Peripheral neuropathy may occur, hyperammonaemic encephalopathy
Systemic fluorouracil treatment has been associated with various types of ocular toxicity.
Uncommon: Excessive lacrimation, blurred vision, eye movement disturbance, optic neuritis, diplopia, decrease in visual acuity, photophobia, conjunctivitis, blepharitis, ectropion, dacryostenosis
Very common: Ischemic ECG abnormalities.
Common: Angina pectoris-like chest pain.
Uncommon: Arrhythmia, myocardial infarction, myocardial ishchemia myocarditis, heart insufficiency, dilative cardiomyopathy, cardiac shock.
Very rare: Cardiac arrest, sudden cardiac death
Cardiotoxic adverse events mostly occur during or within hours following the first treatment cycle. There is an increased risk of cardiotoxicity in patients with previous coronary heart disease or cardiomyopathy.
Not known: Tachycardia, breathlessness, pericarditis
Rare: Cerebral, intestinal and peripheral ischemia, Raynaud’s syndrome, thromboembolism, thrombophlebitis/vein tracking,
Uncommon: Hypotension
Very common: Gastrointestinal adverse events are very common and may be life-threatening. Mucositis (stomatitis, eosophagitis, pharyngitis, proctitis), anorexia, watery diarrhoea, nausea, vomiting.
Uncommon: Dehydration, sepsis, gastrointestinal ulceration and bleeding (may result in therapy being discontinued), sloughing
Uncommon: liver cell damage
Very rare: Liver necrosis (cases with fatal outcome), Biliary sclerosis, Cholecystitis
Very common: Alopecia may be seen in a substantial number of cases, particularly females, but is reversible.
Palmar-plantar erythrodysaesthesia syndrome (hand-foot syndrome) has been noted with protracted and high dose continuous infusion.
The syndrome begins with dysaesthesia of the palms and soles that progress to pain and tenderness. There is associated symmetrical swelling and erythema of the hand and foot.
Uncommon: Dermatitis, skin alterations (e.g. dry skin, fissure erosion, erythema, pruritic maculopapular rash), exanthema, urticaria, photosensitivity, hyperpigmentation of the skin, streaky hyperpigmentation or depigmentation near the veins. Changes in the nails (e.g. diffuse superficial blue pigmentation, hyperpigmentation, nail dystrophy, pain and thickening of the nail bed, paronychia) and onycholyse.
Uncommon: Spermatogenesis and ovulation disorder
Very common: Delayed wound healing, epistaxis, malaise, weakness, fatigue.
Not Known: Fever, vein discolouration proximal to injection sites
Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <1/1,000), Very rare (<1/10,000), Frequency not known (cannot be estimated from the available data).
Adverse reactions associated with exacerbations of normal pattern of response which are related to pharmacological activity of fluorouracil on the skin are the most frequently reported reactions. Allergic type skin reactions and reactions related to systemic drug toxicity are very rarely reported.
Very rare: Haematological disorders, associated with systemic drug toxicity, e.g. pancytopenia, neutropenia, thrombocytopenia.
Very rare: Allergic conditions (e.g. hypersensitivity and allergic reactions).
Frequency not known: Dysgeusia, headache, dizziness.
Frequency not known: Conjunctival irritation, keratitis, increased lacrimation.
Very rare: Diarrhoea haemorrhagic, diarrhoea, vomiting, abdominal pain, stomatitis, associated with systemic drug toxicity.
Frequency not known: Nausea.
Very rare: Pruritus, urticaria, rash (usually local but also generalised if associated with systemic drug toxicity); erythemas including erythema multiforme; dermal and epidermal conditions (such as skin burning sensation, skin exfoliation, skin swelling); skin and subcutaneous skin ulcerations; dermatitis and eczema conditions (such as contact dermatitis, skin irritation); blisters, and alopecia.
Exposure to sunlight may increase the intensity of the reaction.
Very rare: Pyrexia, chills and mucosal inflammation, associated with systemic drug toxicity.
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