Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord Healthcare Limited, 319, Pinner Road, North Harrow, Middlesex, HA1 4HF, United Kingdom
Hypersensitivity to the fluorouracil or to any of the excipients listed in section 6.1.
Fluorouracil is contraindicated in the following
It is recommended that fluorouracil should only be given by, or under the strict supervision of, a qualified physician who is conversant with the use of potent antimetabolites and has the facilities for regular monitoring of clinical, biochemical and haematological effects during and after administration.
All patients should be admitted to hospital for initial treatment.
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 2000 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.
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.
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.
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.
Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of DPD activity.
Patients with low or absent DPD activity, an enzyme involved in fluorouracil degradation, are at increased risk for severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Although DPD deficiency cannot be precisely defined, it is known that patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene locus (e.g. DPYD*2A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3 variants), which can cause complete or near complete absence of DPD enzymatic activity (as determined from laboratory assays), have the highest risk of life-threatening or fatal toxicity and should not be treated with 5-fluorouracil (see section 4.3). No dose has been proven safe for patients with complete absence of DPD activity.
Patients with certain heterozygous DPYD variants (including DPYD*2A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3 variants) have been shown to have increased risk of severe toxicity when treated with fluoropyrimidines.
The frequency of the heterozygous DPYD*2A genotype in the DPYD gene in Caucasian patients is around 1%, 1.1% for c.2846A>T, 2.6-6.3% for c.1236G>A/HapB3 variants and 0.07 to 0.1% for c.1679T>G. Genotyping for these alleles is recommended to identify patients at increased risk for severe toxicity. Data on the frequency of these DPYD variants in other populations than Caucasian is limited. It cannot be excluded that other rare variants may also be associated with an increased risk of severe toxicity.
Patients with partial DPD deficiency (such as those with heterozygous mutations in the DPYD gene) and where the benefits of 5-fluorouracil are considered to outweigh the risks (taking into account the suitability of an alternative non-fluoropyrimidine chemotherapeutic regimen), must be treated with extreme caution and frequent monitoring with dose adjustment according to toxicity should be conducted. A reduction of the starting dose in these patients may be considered to avoid serious toxicity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by specific test. It has been reported that the DPYD*2A, c.1679T>G variants lead to a greater reduction in enzymatic activity compared to other variants with a higher risk of side effects. The consequences of a reduced dose on the efficacy are currently uncertain. Therefore, in the absence of serious toxicity the dose could be increased while carefully monitoring the patient.
The patients who are tested negative for the above-mentioned alleles may still have a risk of severe adverse events.
In patients with unrecognised DPD deficiency treated with 5-fluoruracil as well as in those patients who test negative for specific DPYD variations, life-threatening toxicities manifesting as acute overdose may occur (see section 4.9). In the event of grade 2-4 acute toxicity, treatment must be discontinued immediately. Permanent discontinuation should be considered based on clinical assessment of the onset, duration and severity of the observed toxicities.
Dihydropyrimidine dehydrogenase (DPD) plays an important role in the metabolism of fluorouracil. There have been reports of increased fluorouracil toxicity in patients who have reduced activity/deficiency of DPD. If applicable, determination of DPD enzyme activity is indicated prior to the treatment with 5-fluoropyrimidines.
Nucleoside analogues, e.g. brivudin and sorivudin, which affect DPD activity may cause increased plasma concentrations and increased toxicity of fluoropyrimidines (see section 4.5). Therefore, an interval of at least 4 weeks between administration of fluorouracil and brivudin, sorivudin or analogues should be kept. In the case of accidental administration of nucleoside analogues to patients treated with fluorouracil, effective measures should be taken to reduce fluorouracil toxicity. Immediate hospitalisation is recommended. Any measure to prevent systemic infections and dehydration should be commenced.
Vaccination with a live vaccine should be avoided in patients receiving fluorouracil due to the potential for serious or fatal infections. Contact should be avoided with people who have recently been treated with polio virus vaccine.
It is not advisable to prolonged exposure to sunlight because of the risk of photosensitivity.
Use with caution in patients who have had high-dose pelvic radiation.
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.
Particular care should be taken in the treatment of elderly or debilitated patients, as these patients may be at increased risk of severe toxicity.
Women of childbearing potential and men have to use effective contraception during and up to 6 months after treatment.
Patients taking phenytoin concomitantly with fluorouracil should undergo regular testing because of the possibility of an elevated plasma level of phenytoin.
Fluorouracil injection BP contains 7.78 mmol (178.2 mg) of sodium per maximum daily dose (600 mg/m²). This should be taken into consideration by patients on a controlled sodium diet.
Various agents have been reported to biochemically modulate the anti-tumour efficacy or toxicity of Fluorouracil. Common drugs include methotrexate, metronidazole, leucovorin interferon alfa and allopurinol.
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.
In combination with other myelosuppressive substances, dosage adjustment is necessary. Concomitant or previous radiation therapy may require dosage reduction. The cardiotoxicity of anthracyclines may be increased.
Fluorouracil should be avoided in combination with clozapine due to increased risk of agranulocytosis.
Increased incidence of cerebral infarction has been reported in oropharyngeal cancer patients treated with fluorouracil and cisplatin.
Marked elevations of prothrombin time and INR have been reported in a few patients stabilised on warfarin therapy following initiation of fluorouracil regimes.
The enzyme dihydropyrimidin dehydrogenase (DPD) plays an important role in the metabolism of fluorouracil. Nucleoside analogues, e.g. brivudin and sorivudin, may induce an increase in plasma concentrations of 5-FU or other fluoropyrimidines accompanied by toxicological reactions. Therefore, a time interval of minimum 4 weeks between administration of fluorouracil and brivudin, sorivudin and analogues should be kept.
If applicable, determination of DPD enzyme activity is indicated prior to treatment with 5- fluoropyrimidines.
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.
Fluorouracil enhances the action of other cytostatic drugs and irradiation therapy (see section 4.2).
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.
Hepatotoxicity (increase in alkaline phosphatases, transaminases or bilirubin) has been observed commonly in patients receiving 5-fluorouracil in combination with levamisol.
In patients with breast cancer, combination therapy with cyclophosphamide, methotrexate, 5-fluorouracil and tamoxifen has been reported to increase the risk of thromboembolic events.
Serious, potentially life-threatening mucositis may occur following co-administration of vinorelbine and 5-fluorouracil/folinic acid.
Vaccination with live vaccines should be avoided in immunocompromised patients.
There are no adequate and well-controlled studies in pregnant women, however, fetal defects and miscarriages have been reported.
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 (see section 4.4). 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. Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Men treated with fluorouracil are advised not to father a child during and for up to 6 months following cessation of treatment (see section 4.4). Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with fluorouracil.
Since it is not known whether fluorouracil passes into breast milk, breast-feeding must be discontinued if the mother is treated with fluorouracil.
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.
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
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Fluorouracil is incompatible with folinic acid, Carboplatin, Cisplatin, Cytarabine, Diazepam, Doxorubicin, Droperidol, Filgrastim, Gallium nitrate, Methotrexate, Metoclopramide, Morphine, Ondansetrone, parenteral nutrition, Vinorelbin, other Anthracyclines.
Formulated solutions are alkaline and it is recommended that admixture with acidic drugs or preparations should be avoided.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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