5-Fluorouracil Ebewe

5-Fluorouracil Ebewe



EBEWE Pharma




Mega Lifesciences
Full Prescribing Info
Excipients/Inactive Ingredients: Water for injection purposes, Sodium hydroxide (for pH adjustment).
Pharmacotherapeutic Group: Antineoplastic agents, antimetabolites, pyrimidine analogues. ATC Code: L01BC02.
Pharmacology: Pharmacodynamics: The antimetabolite fluorouracil constitutes a fluorinated pyrimidine. Fluorouracil is enzymatically activated to deoxy-fluorouracil monophosphate. It inhibits the activity of thymidylate synthase and thus deoxythymidine monophosphate synthesis through complex formation. This results in phase-specific DNA-synthesis inhibition. Furthermore, deoxy-fluoronucleosides inhibit de novo synthesis of pyrimidine nucleotides.
Calcium folinate with fluorouracil and thymidylate synthase form a relatively stable ternary complex and thus prolong the inhibiting action of fluorouracil on thymidylate synthase. The result is the increased cytotoxic effect of fluorouracil.
Fluorouracil has a phase-specific action in the cell cycle, particularly on the S-phase. The effect of the substance in rapidly proliferating tissue (bone marrow, skin and mucosa) is particularly pronounced.
Pharmacokinetics: Fluorouracil is only partially absorbed orally (0 - 80%).
The substance exhibits a distribution of 0.12 l/kg BW (following 15 mg/kg BW IV) and can be found especially in rapidly proliferating tissue like bone marrow, intestinal mucosa and neoplasia; fluorouracil passes the blood-brain barrier.
Metabolisation takes place in the liver and is similar to uracil metabolisation. Fluorouracil is rapidly transformed enzymatically into the active metabolite dihydro-fluorouracil, which exhibits a substantially longer half-life period than fluorouracil. Other non-toxic metabolites are carbon dioxide and urea.
The plasma half-life (alpha phase) is between 8 and 22 minutes. The elimination half-life (beta phase) reaches approx. 20 hours due to the active metabolites in the tissue and is dose-dependent.
Fluorouracil (60 - 80%) is primarily exhaled by the lungs as carbon dioxide. Fluorouracil is secondarily excreted unchanged by the renal system (approx. 7 - 20%), approx. 90% of which is excreted within the first hour. Renal clearance is approximately 170-180 ml/min. In impaired renal function, the substance is excreted slowly.
Maximum concentration in the liquor is reached after approximately 1.5 - 2 hours and accounts for approx. 50% of plasma concentration.
Kinetics in special clinical situations: Despite the low proportion (approx. 15%) eliminated renally, an adequate dose adjustment depending on the degree of renal insufficiency and the reaction of the individual patient is indicated due to impaired bone marrow function in azotaemia (due to renal insufficiency) and potential interference with the thrombocytes. In impaired liver function a dose adjustment should also be taken into consideration.
Toxicology: Preclinical safety data: Toxicity: The cell division inhibiting effect of fluorouracil mainly affects rapidly proliferating tissues - both tumorigenic and healthy tissues.
Accordingly, the toxicities show particularly in bone marrow, with leucopenia, thrombocytopenia, gastrointestinal bleeding and secondarily in infections.
Reproduction toxicity / mutagenicity / carcinogenicity: In different in vitro cultures, Fluorouracil shows mutagenic potential (various strains of Salmonella typhimurium, micronucleus test in mice, at high concentrations chromosome strand damage in hamster fibroblasts). In vivo in male rats, chromosome aberrations and altered spermatogenesis and even infertility were observed. In female rats, fluorouracil reduced fertility and induced chromosome aberrations in the embryos. The effects in rabbits were less substantial.
Antimetabolites in animal studies revealed carcinogenic properties. However the risk of secondary tumours in humans seems to be lower than with alkylating substances.
Adjuvant or palliative treatment of: advanced colorectal cancer; advanced gastric cancer; advanced pancreatic cancer; advanced and/or metastatic breast cancer; advanced tumours of the head and neck area; advanced cervical cancer.
Dosage/Direction for Use
Treatment with fluorouracil should be administered only by physicians with extensive experience in tumour therapy. Initial treatment in hospital should be considered.
Fluorouracil is used in mono-chemotherapy and as a component of poly-chemotherapy. Since the method of application and dose recommendation for fluorouracil vary significantly, only general reference values can be given.
The exact dose should be taken from treatment protocols that have proved successful in the particular disease.
Posology: Initial therapy in daily use: As IV infusion: 15 mg/kg or 600 mg/m2 over 4 hours daily; till the onset of side effects.
As IV injection: Slow IV (2 to 3 minutes) administration of 12 mg/kg or 480 mg/m2 on the 1st, 2nd and 3rd day.
If no signs of toxicity are observable: administration of 6 mg/kg or 240 mg/m2 on day 5, 7 and 9.
Initial therapy in weekly use: Slow IV administration of 15 mg/kg or 600 mg/m2 once weekly.
Maintenance therapy: Once remission has been achieved or rather after the resolution of side effects, the further increase in leucocytes up to 3,000 to 4,000/μl, in thrombocytes up to 80,000 to 100,000/μl: 5-10 mg/kg or 200-400 mg/m2 IV once weekly.
The maximum daily dose of 1 g must not be exceeded.
All doses apply to normal weight, i.e. in adiposities, ascites or oedema, an adequate standardisation must be conducted.
The duration of treatment depends on nature and progress of the disease and is determined by an experienced specialist or in accordance with the treatment protocol.
When fluorouracil is combined with other cytostatic agents with a similar side effect profile or with radiotherapy the dose must be reduced accordingly. The administration can take place in the form of a 24-hour continuous intravenous drip infusion.
Method of administration: Fluorouracil must be applied strictly by intravenous infusion. It can be injected or infused after dilution with 0.9% sodium chloride or glucose 5%.
Extravascular application should be avoided.
Special dose instructions: The recommended doses should be reduced by one third to one half in patients with poor nutritional condition, after a major surgical intervention, in myelosuppression (leucocytes <4,000/μl, thrombocytes <100,000/μl) and severely impaired hepatic and renal function.
Renal or hepatic dysfunction: In patients with renal or hepatic dysfunction, caution should be exercised and the dose reduced if necessary.
Elderly persons (aged 65 or more): No dose adjustment of the initial dose is required. However, a thorough medical monitoring of elderly patients is recommended.
Symptoms of intoxication: The following side effects mostly occur to an increased extent as a consequence of overdose: Nausea, vomiting, diarrhoea, severe mucositis, ulcerations and hemorrhages in the gastrointestinal tract, myelosuppression (thrombocytopenia, leukopenia, agranulocytosis).
Therapy of intoxication: If symptoms of intoxication occur, administration of fluorouracil should be discontinued immediately. Symptomatic therapeutic measures are to be initiated.
Pronounced myelosuppression must be treated under inpatient conditions. It involves - if necessary - substitution of missing blood components and antibiotic therapy. Transfer of the patient into an aseptic room may become necessary.
No specific antidote is available.
Haematological monitoring should be performed up to 4 weeks after overdose.
Fluorouracil must not be used in: hypersensitivity to the active substance or to any of the excipients; myelosuppression; severe blood count alterations; severe hepatic dysfunctions; serious infections; patients in poor physical state; during pregnancy and lactation (see Use in Pregnancy & Lactation).
Fluorouracil (5-FU) must not be used together with brivudine, sorivudine and analogues. Brivudine, sorivudine and analogues are potent inhibitors of the enzyme dihydropyrimidine dehydrogenase (DPD) degrading 5-FU (see also Precautions and Interactions).
In patients with dihydropyrimidine dehydrogenase (DPD) deficiency, usual fluorouracil doses provoke increased side effects. If severe undesired effects occur, monitoring of DPD activity may be indicated. Patients with DPD deficiency should not be treated with fluorouracil.
No live vaccinations should be carried out in temporal connection with fluorouracil therapy. Any contact with poliomyelitis vaccines should be avoided.
Special Precautions
The enzyme dihydropyrimidine dehydrogenase (DPD) plays an important role for the degradation of 5-FU. Nucleoside analogues, such as brivudine and sorivudine, may lead to a drastic increase in the plasma concentrations of 5-FU or other fluoropyrimidines and thus to an accompanying increase in toxicity.
For this reason, an interval of at least 4 weeks should be kept between intake of 5-FU and brivudine, sorivudine and analogues.
If necessary, determination of the DPD enzyme activity is indicated prior to therapy with 5-fluoropyrimidines. In case of inadvertent administration of brivudine to patients treated with fluorouracil, effective measures to reduce fluorouracil toxicity should be taken. Immediate hospitalisation is recommended. All measures to prevent systemic infections and dehydration should be initiated.
Patients taking phenytoin concomitantly with fluorouracil should be examined at regular intervals for an elevated phenytoin plasma level.
Damage to intestinal wall requires symptomatic treatment according to the degree of severity, e.g. fluid substitution. Mild diarrhoea may respond to antidiarrhoeals. However, they are not sufficient in moderate to severe diarrhoea.
Prior to and during therapy with fluorouracil, the subsequent examinations are recommended: daily inspection of oral cavity and pharynx in view of mucosal alterations; blood count including differential blood count and thrombocytes prior to each administration of fluorouracil; retention values; hepatic values.
In concurrent use of fluorouracil and oral anticoagulants, the Quick's value is closely to be monitored.
Patients should be advised additionally about the possible occurrence of stomatitis/mucositis, diarrhoea and bleeding (in particular from the gastrointestinal tract). Patients should be advised to consult the attending physician if first signs occur.
For injectable products containing FM27 in rubber material, e.g. in removable needle shields or tip caps: Latex-sensitive individuals: The [name of the affected part of the product, e.g. removable needle shield] of 5-Fluorouracil Ebewe contains a derivative of natural rubber latex. Although no natural rubber latex is detected in the [name of the affected part of the product], the safe use of 5-Fluorouracil Ebewe in latex-sensitive individuals has not been studied.
Effects on ability to drive and use machines: Fluorouracil may cause nausea and vomiting and thus indirectly lead to impaired ability to drive or to operate machinery. For this reason, driving and operating machinery should be refrained from during treatment with fluorouracil.
Use in Pregnancy: Pregnant personnel is to be excluded from handling with fluorouracil.
Use in Lactation: Due to the potentially mutagenic and carcinogenic effect, increased safety rules apply to nursing personnel and physicians. When handling with fluorouracil, any contact with skin and mucosae is to be avoided. Preparation must be performed by means of an absolutely aseptic technique. Use of a workbench with laminar air flow (LAF) is recommended. When handling with fluorouracil, protective clothing must be worn.
Use in Children: No sufficient experience is available regarding efficacy and safety of fluorouracil in children.
Use In Pregnancy & Lactation
Pregnancy: Fluorouracil may be mutagenic and must not be used during pregnancy. Women of childbearing age should ensure effective contraception during treatment with fluorouracil and up to 6 months afterwards. If pregnancy occurs during treatment, the possibility of genetic counseling is to be exploited.
Lactation: Fluorouracil must not be used during the lactation period.
Fertility: Fluorouracil can be genetically harmful. Men treated with fluorouracil are therefore recommended not to father a child during treatment as well as up to 6 months afterwards.
Advice on conservation of sperm should be sought prior to treatment because of the possibility of serious disturbances of spermatogenesis due to therapy with Fluorouracil.
Adverse Reactions
The most common and serious side effects of fluorouracil are bone marrow toxicity and gastrointestinal symptoms.
The evaluation of undesirable effects is based on the following information on frequency: 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), Not known (cannot be estimated from the available data).
Blood and lymphatic system disorders: Very common: Myelosuppression (leucopenia, neutropenia, thrombocytopenia), anaemia, epistaxis.
Common: Febrile neutropenia.
Very rare: Agranulocytosis, pancytopenia.
Immune system disorders: Very common: lmmunosuppression with elevated infection rate.
Rare: Generalised allergic reactions up to anaphylactic shock.
Endocrine disorders: Not known: Increase in total thyroxine (T4) and total triiodothyronine (T3) in serum without increase in free T4 and TSH and without clinical signs of hyperthyroidism.
Metabolism and nutrition disorders: Very common: Hyperuricaemia.
Nervous system disorders: Uncommon: Nystagmus, headache, vertigo, parkinsonian symptoms, pyramidal signs, euphoria.
Rare: Peripheral neuropathy (in combination with radiotherapy).
Very rare: Dysgeusia, (leuko-)encephalopathy with symptoms such as ataxia, speech impediments, confusion, impaired orientation, myasthenia, aphasia, seizures or coma after infusion of high doses of fluorouracil or in patients with dihydropyrimidine dehydrogenase deficiency, respectively.
Eye disorders: Uncommon: Excessive lacrimation, blurred vision, disorders of ocular motility, optic neuritis, diplopia, reduced visual acuity, photophobia, conjunctivitis, blepharitis, ectropion due to scars, lacrimal fibroses.
Cardiac disorders: Very common: ECG alterations typical for ischaemia.
Common: Angina pectoris-like chest pain.
Uncommon: Arrhythmia, myocardial infarction, myocardial ischaemia, myocarditis, cardiac insufficiency, dilative cardiomyopathy, cardiogenic shock.
Very rare: Cardiac arrest, sudden cardiac death.
Vascular disorders: Uncommon: Hypotension.
Rare: Thrombophlebitis.
Not known: Cerebral, intestinal and peripheral ischaemia, Raynaud's syndrome, thromboembolism.
Respiratory, thoracic and mediastinal disorders: Very common: Bronchospasm.
Gastrointestinal disorders: Very common: Gastrointestinal side effects (potentially life-threatening) such as mucositis (stomatitis, pharyngitis, oesophagitis, proctitis), anorexia, (watery) diarrhoea, nausea and vomiting (see also Precautions).
Uncommon: Dehydration, sepsis as well as ulcerations and haemorrhages in the gastrointestinal tract, sloughing.
Hepatobiliary disorders: Uncommon: Liver cell damage, stoneless cholecystitis.
Very rare: Liver necroses (partially fatal).
Skin and subcutaneous tissue disorders: Very common: Alopecia, delayed wound healing, hand-and-foot syndrome (see as follows) associated with dysaesthesia as well as reddening, swelling, pain and desquamation of the skin in palms and soles.
Uncommon: Exanthemas, skin alterations (dry skin, erosions/fissures, erythema, pruritic maculopapular rash), dermatitis, urticaria, photosensitivity, hyperpigmentation of the skin, striated hyperpigmentation or depigmentation in the area of the venous course, ungual alterations (e.g. diffuse superficial blue pigmentation, hyperpigmentation, onychodystrophy, pain and thickening of the nail bed, paronychia), onycholysis.
General disorders and administration site conditions: Very common: Exhaustion, general asthenia, fatigue, lack of impulse, fever.
Description of selected adverse events: Blood and lymphatic system disorders: Myelosuppression is one of the dose-limiting side effects (see also Dosage & Administration and Precautions).
The degree (NCI grades I - IV) of myelosuppression depends on the mode of administration (i.v. bolus injection or i.v. continuous infusion) and the dose.
Neutropenia occurs after each therapeutic cycle with i.v. bolus injection at adequate dose. The nadir is generally reached between the 9th and 14th day of treatment, sometimes also until the 20th day of treatment; normal values usually after day 30.
Cardiac disorders: Cardiotoxic side effects mostly occur during or few hours after the first therapeutic cycle.
Patients with pre-existing coronary heart disease or cardiomyopathy are at aggravated risk of developing cardiotoxic side effects.
Gastrointestinal side effects: The severity (NCl grades I-IV) of gastrointestinal side effects depends on the dose and the mode of administration. In i.v. continuous infusion, stomatitis more likely proves to be dose-limiting than myelosuppression.
Skin and subcutaneous tissue disorders: The so-called hand-and-foot syndrome associated with dysaesthesia as well as reddening, swelling, pain and desquamation of the skin in palms and soles is very common after i.v. continuous infusion and common after i.v. bolus injection.
Drug Interactions
All therapeutic measures aggravating the patient's physical status or impairing myeloid functions (e.g. other cytostatics) may increase the toxicity of fluorouracil.
Fluorouracil can potentiate the cutaneous toxicity of radiotherapies.
Calcium folinate enhances the effect of fluorouracil. Severe, partially lethal diarrhoea may occur as clinical sequel of this interaction. Accumulation of such deaths has been reported especially in association with an administration scheme of an i.v. bolus of 600 mg/m2 body surface area fluorouracil once weekly in combination with calcium folinate.
The enzyme dihydropyrimidine dehydrogenase (DPD) plays an important role for the degradation of 5-FU. Nucleoside analogues, such as brivudine and sorivudine, may lead to a drastic increase in the plasma concentrations of 5-FU or other fluoropyrimidines and thus to an accompanying increase in toxicity.
For this reason, an interval of at least 4 weeks should be kept between intake of 5-FU and brivudine, sorivudine and analogues. If necessary, determination of the DPD enzyme activity is indicated prior to therapy with 5-fluoropyrimidines.
In case of concomitant administration of phenytoin and fluorouracil, an increase in the plasma level of phenytoin has been reported, which led to symptoms of phenytoin intoxication.
Cimetidine, metronidazole and interferons may increase the plasma level of fluorouracil. This can potentiate the toxic effects of fluorouracil.
In female patients receiving a diuretic of the thiazide type additionally to cyclophosphamide, methotrexate and fluorouracil, the granulocyte count was more reduced than after equal cytostatic cycles without thiazide.
Isolated cases of a decline in the Quick's value were observed in patients treated with warfarin and additionally receiving fluorouracil alone or in combination with levamisole.
During treatment with fluorouracil and levamisole, hepatotoxic effects (increase in alkaline phosphatase, transaminases or bilirubin) are frequently observed.
Patients with mammary carcinoma receiving combination treatment with cyclophosphamide, methotrexate, fluorouracil and tamoxifen showed an aggravated risk of the occurrence of thromboembolic events.
In case of coincident administration of vinorelbine and fluorouracil/folinic acid, severe mucositis resulting in death may occur.
The assay techniques for bilirubin and 5-hydroxyindole acetic acid in urine may yield elevated or false positive values.
General notes: Cytostatics can reduce the antibody formation after influenza vaccination. Cytostatics may elevate the risk of an infection after live vaccine.
Caution For Usage
Special precautions for disposal and other handling: Due to the possible mutagenic and carcinogenic effects, enhanced safety precautions for hospital staff and physicians apply. While handling fluorouracil any contact with skin and mucous membranes should be avoided. Failing this, immediately wash with soap and water.
In the event of contact with the eyes, the affected area should be washed with copious amounts of water; and medical attention should be sought. All provisions must be made to allow for absolutely aseptic work. The use of a workspace with laminar flow is recommended. Protective clothing must be worn while handling fluorouracil.
Pregnant staff must not work with fluorouracil.
Inactivation: 700 °C Sodium hypochlorite (liquor natrii hypochlorosi) diluted with 10 parts of water; Concentrated NaOH over several hours.
The ready solution should be used immediately after preparation.
If a precipitate has formed as a result of exposure to low temperatures, redissolve by careful heating to 60°C accompanied by shaking. Allow to cool prior to use.
Loss of efficacy due to the adsorption of fluorouracil in the glass infusion container has been described in the literature.
The handling and disposal regulations for cytostatic agents must be met.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Fluorouracil should only be diluted with physiological saline or 5% glucose solution.
Fluorouracil must not be diluted with strongly buffered solutions with pH <8, since fluorouracil precipitates in this environment. Do not mix with other chemotherapeutic solutions.
Incompatibilities with following substances have been reported: Cisplatin, cytarabine, diazepam, doxorubicin, droperidol, filgrastim, gallium nitrate, leucovorin, methotrexate, metoclopramide, morphine, ondansetron, parenteral nutrition solutions, vinorelbine.
Calcium folinate: Fluorouracil must not be mixed in the same infusion with calcium folinate because a precipitate may form. Fluorouracil 50 mg/ml with calcium folinate 20 mg/ml, with or without dextrose 5% in water, has been shown to be incompatible when mixed in different amounts and stored at 4°C, 23°C or 32°C in polyvinyl chloride containers.
Do not store above 25°C. Do not refrigerate or freeze.
Store in the original packaging in order to protect the content from light.
For single use only.
Only use clear and colourless to slightly yellowish solutions.
If a precipitate has formed as a result of exposure to low temperatures, redissolve by carefully heating to 60°C accompanied by shaking. Allow to cool prior to use.
Shelf-life: 2 years.
Shelf life after dilution: Dilution can be done with 0.9% sodium chloride solution or 5% glucose solution. Stability data in concentrations of 0.35 mg/ml and 15 mg/ml have shown that the maximum shelf life of ready-made fluorouracil infusion solution is 28 days.
This shelf life refers both to refrigerator storage (2 - 8°C) including protection from light and storage at ambient temperature (20 - 25°C) with or without protection from light.
The prepared infusate demonstrated chemical and physical stability for 28 days. From a microbiological point of view, however, the product should be used immediately. If not used immediately, storage times and conditions of the prepared infusate prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 - 8°C, unless dilution has taken place under controlled and validated aseptic conditions.
MIMS Class
Cytotoxic Chemotherapy
ATC Classification
L01BC02 - fluorouracil ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.
Conc for soln for inj/infusion (vial) 50 mg/mL x 10 mL, 20 mL.
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