Pharmacological properties
Pharmacodynamics. Fluorouracil (5-fluorouracil) is an antitumor agent from the group of antimetabolites. As a pyrimidine antagonist, it disrupts DNA synthesis and thus inhibits cell division. Fluorouracil itself does not have antineoplastic activity, its antitumor effect is manifested in the body after enzymatic transformation of fluorouracil into phosphorylated forms - 5-fluorouridine and 5-fluorodeoxyuridine.
Pharmacokinetics. There is significant interindividual and intraindividual variability in the absorption of fluorouracil from the gastrointestinal tract after oral administration. Fluorouracil is also metabolized during the first pass through the liver. The bioavailability of fluorouracil is 0-80%.
Only IV and IV administration of fluorouracil is possible. After IV administration, fluorouracil is distributed in the body, especially in rapidly proliferating tissues such as bone marrow, gastrointestinal mucosa, and neoplasms. Fluorouracil penetrates the blood-brain barrier and the placental barrier. The volume of distribution of fluorouracil is 0.12 l/kg body weight, and plasma protein binding is approximately 10%.
The metabolism of fluorouracil is carried out in the liver and is similar to the metabolism of uracil. There is a rapid enzymatic transformation of fluorouracil into the active metabolite dihydro-5-fluorouracil, the half-life of which is significantly longer than that of fluorouracil. During metabolism, non-toxic compounds are also formed - carbon dioxide and urea.
The average half-life of fluorouracil from blood plasma is 10-20 minutes and depends on the dose. 3 hours after intravenous administration, unchanged fluorouracil is not detected in blood plasma.
Fluorouracil is excreted mainly through the lungs as carbon dioxide (60-80%). Fluorouracil is also excreted through the kidneys as unchanged parent compound (7-20%), approximately 90% within the first hour. Renal clearance of fluorouracil is approximately 170-180 ml/min. In patients with impaired renal function, fluorouracil is excreted more slowly.
Indication
Treatment of breast cancer and colorectal cancer (as monotherapy or in combination with other antineoplastic agents).
Treatment of stomach, head and neck, and pancreatic cancer.
Application
The dose and treatment regimen are determined individually depending on the patient's condition and the type of cancer, as well as whether 5-fluorouracil "Ebeve" is used as monotherapy or in combination with other types of treatment.
Treatment with 5-fluorouracil "Ebeve" should be started in a hospital setting. The total daily dose for adults should not exceed 1 g.
Usually, the dose for adults is determined based on 1 kg of the patient's actual body weight, however, for patients with significant obesity, edema, ascites, and other forms of abnormal fluid retention in the body, the dose is determined based on 1 kg of ideal body weight.
5-fluorouracil "Ebeve" is administered by intravenous injection, intravenous infusion, or intravenous infusion.
Below are approximate recommendations for dosage of the drug.
Colorectal cancer treatment
During the initial course of therapy, the drug can be administered by infusion or injection. Administration by infusion is preferred because it is associated with fewer toxic effects.
In / in infusion. A daily dose of 15 mg / kg body weight (600 mg / m 2 body surface area), but not more than 1 g per infusion, is diluted in 300-500 ml of 5% glucose solution or 0.9% sodium chloride solution. The solution for infusion is administered i / v over 4 hours. In the following days, the drug is administered in the same dose until toxic effects appear or the total dose reaches 12-15 g. Some patients were administered up to 30 g of fluorouracil at 1 g / day (maximum daily dose). If side effects from the hematopoietic system or gastrointestinal tract occur, the next administration of the drug is postponed until the recovery of hematological parameters and the disappearance of toxic effects. Alternatively, 5-fluorouracil "Ebeve" can be administered by continuous 24-hour infusion.
In / in injections. At 12 mg / kg body weight (480 mg / m 2 body surface area) is administered by daily i / v injections for 3 days. In the absence of signs of toxic effects, you can continue to administer the drug at a dose of 6 mg / kg body weight (240 mg / m 2 body surface area) on the 5th, 7th and 9th days of the course.
For maintenance therapy, the drug is administered at a dose of 5-10 mg/kg body weight (200-400 mg/m2 body surface area) once a week.
If side effects occur, the next administration of the drug is postponed until the toxic effects disappear.
Breast cancer treatment
For the treatment of breast cancer, 5-fluorouracil "Ebewe" is used in combination with other chemotherapy drugs, such as methotrexate and cyclophosphamide or doxorubicin and cyclophosphamide.
With such treatment regimens, 5-fluorouracil "Ebeve" is administered intravenously at a dose of 10-15 mg/kg body weight (400-600 mg/m 2 body surface area) on the 1st and 8th days of a course lasting 28 days.
5-fluorouracil "Ebewe" can also be administered by continuous 24-hour intravenous infusion, with the usual dose being 8.25 mg/kg body weight (350 mg/m2 body surface area).
Other methods of administration
Intravenous infusion. A daily dose of 5-7.5 mg/kg body weight (200-300 mg/m2 body surface area) is administered by continuous 24-hour intravenous infusion. In some cases, regional intravenous infusions may be used to treat primary tumors or metastases.
A dose reduction is recommended in case of cachexia, major surgery in the previous 30 days, impaired bone marrow function, and in the presence of impaired liver or kidney function.
There is no need for dose adjustment in the treatment of elderly patients.
Instructions for personnel
It is necessary to withdraw the solution from the vial/ampoule immediately before use.
If a precipitate forms in the preparation as a result of cooling, it is dissolved by heating to 60 °C and shaking vigorously. Before use, the preparation is cooled to body temperature.
As with other cytotoxic drugs, when handling 5-fluorouracil "Ebeve", safety rules must be followed: wear protective clothing (gown, cap, overalls, goggles, and disposable gloves), and if possible, work in a room specially designated for these purposes.
It is necessary to avoid contact of fluorouracil solutions with the skin and mucous membranes. If this happens, they are thoroughly washed with soap and water. If fluorouracil solution gets into the eyes, they must be rinsed with plenty of water.
Pregnant women are not allowed to work with the drug.
Contraindication
Hypersensitivity to fluorouracil; bone marrow suppression, especially after radiotherapy or treatment with other antitumor drugs; significant deviations in the number of formed elements in the blood; bleeding; stomatitis, ulcers of the oral mucosa and gastrointestinal tract; severe diarrhea; severe liver and/or kidney dysfunction; severe infectious diseases; severe cachexia; bilirubin level in blood plasma 85 μmol/l. During treatment with fluorouracil, active vaccination should be avoided.
Side effects
Infections and infestations
Uncommon (0.1%, but 1%) - fever.
Blood and lymphatic system disorders
Very common (10%) - leukopenia and thrombocytopenia. The preventive measures described below should be observed.
Common (1%, but 10%) - agranulocytosis, anemia, bone marrow depression.
On the part of the immune system
Uncommon (0.1%, but 1%) - allergic reactions.
metabolic disorders
Rare (0.01%). The risk of developing severe and prolonged adverse reactions soon after starting fluorouracil treatment is highest in patients with low levels of dihydropyrimidine dehydrogenase (DPD) activity (for any reason, in particular due to taking DPD inhibitors such as eniluracil or the antiviral drug sorividin). It is recommended to monitor DPD activity at the beginning of treatment.
From the nervous system
Common (1% but 10%). A transient reversible cerebral syndrome may occur, with ataxia, confusion, and extrapyramidal motor and cortical disorders. These phenomena usually resolve after discontinuation of the drug.
Uncommon (0.1%, but 1%) - drowsiness.
Isolated (0.01%). Cases of leukoencephalopathy have been reported, reversible upon immediate discontinuation of fluorouracil. The risk of leukoencephalopathy is higher in patients with BPH deficiency. Diffusion-weighted magnetic resonance imaging is appropriate for the diagnosis of leukoencephalopathy. Cases of ischemic stroke have been reported with combination chemotherapy (particularly fluorouracil in combination with mitomycin C or cisplatin).
ophthalmological disorders
Rare (0.01%, but 0.1%) - conjunctivitis, excessive lacrimation, dacryostenosis, visual impairment, photophobia, optic neuritis.
From the heart
Uncommon (0.1%, but 1%) - chest pain, ischemia, ECG changes, left ventricular dysfunction.
Rare (0.01%, but 0.1%) - myocardial infarction.
Isolated (0.01%) - cardiogenic shock.
vascular disorders
Uncommon (0.1%, but 1%) - nosebleeds, arterial hypotension, thrombophlebitis.
Gastrointestinal tract
Very common (10%) - inflammation of the mucous membranes (including stomatitis, esophagitis, pharyngitis, proctitis).
Common (1%, but 10%) - diarrhea, nausea, vomiting, anorexia.
Uncommon (0.1%, but 1%) - gastrointestinal ulcers, gastrointestinal bleeding.
Rare (0.01%) - liver cell damage, liver necrosis with fatal outcome.
Skin and subcutaneous tissue disorders
Frequent (1%, but 10%) - reversible alopecia.
Uncommon (0.1%, but 1%) - dermatitis, skin changes (including dry skin, cracks, erosions, erythema, rash, itching, photosensitivity, skin-allergic reactions, pigmentation, hyperpigmentation or depigmentation in the form of stripes near the veins, nail changes, nail loss). A rare complication with bolus high doses of the drug and with prolonged continuous infusions is palmar-plantar erythrodysaesthesia syndrome.
Musculoskeletal and connective tissue disorders
Uncommon (0.1%, but 1%) - necrosis of the nasal bones.
Renal and urinary tract disorders
Uncommon (0.1%, but 1%) - renal failure.
From the reproductive system
Uncommon (0.1%, but 1%) - disorders of spermatogenesis and ovulation.
General effects and local reactions
Uncommon (0.1%, but 1%) - increased fatigue.
Changes in laboratory parameters
Isolated (0.01%). Isolated cases of increased prothrombin time have been reported with the combined use of fluorouracil and warfarin.
The effects of fluorouracil monotherapy during pregnancy have not been sufficiently studied. During treatment with fluorouracil in combination with other cytotoxic drugs and radiotherapy, both cases of birth of children with developmental defects and cases of birth of healthy children were noted, despite the use of fluorouracil in the first and second trimesters of pregnancy.
Studies in various animal species have shown that fluorouracil is teratogenic and fetotoxic, and also adversely affects fertility.
5-fluorouracil "Ebeve" is not recommended for use during pregnancy, especially in the first trimester. In each individual case, the expected benefit to the mother and the potential risk to the fetus must be carefully weighed.
It is not known whether fluorouracil is excreted in breast milk. Breastfeeding should be discontinued during treatment with fluorouracil.
Recommendations for the use of fluorouracil in children have not been developed.
Treatment with 5-fluorouracil "Ebeve" should be carried out under the supervision of a qualified oncologist who has experience in the use of antimetabolites. Treatment with fluorouracil should be initiated in a hospital setting.
With adequate treatment with fluorouracil, leukopenia usually develops. The maximum decrease in the number of leukocytes is usually observed between the 7th and 14th day of the first course of therapy, but sometimes the maximum decrease can be observed after 20 days of treatment. The number of leukocytes usually normalizes by the 30th day.
It is recommended to monitor platelet and leukocyte counts daily and discontinue treatment if platelet counts decrease to 100 × '10 9 / l and leukocytes to 3 × '10 9 / l. If leukocytes decrease to 2 × '10 9 / l, especially in the presence of granulocytopenia, it is recommended to hospitalize patients in a hospital isolation room and take measures to prevent the development of systemic infections.
Treatment should also be discontinued at the first signs of stomatitis or oral ulcers, severe diarrhea, gastrointestinal ulcers, gastrointestinal bleeding, as well as bleeding and hemorrhage of any location.
Fluorouracil has a low therapeutic index - the difference between its therapeutic and toxic doses is small. It is unlikely that a therapeutic effect of the drug can be achieved without some manifestation of toxicity, so careful selection of patients and dosage of the drug is necessary.
Fluorouracil should be administered with caution to patients with impaired renal or hepatic function (including jaundice). Caution is also required when treating patients who have experienced chest pain during previous courses of therapy, as well as patients with a history of cardiac disease. In the event of severe cardiotoxic effects, treatment with fluorouracil should be discontinued.
Particular caution is required when treating high-risk patients (those who have received high-dose pelvic radiotherapy, alkylating agents, and those who have undergone adrenalectomy or hypophysectomy).
During treatment with fluorouracil and for 3 months after the end of therapy, patients (both men and women) must use effective contraceptives.
Depending on individual sensitivity, 5-fluorouracil "Ebeve" may affect the ability to drive vehicles and operate machinery.
Interactions
The medical literature describes combination therapy with fluorouracil in combination with calcium folinate (folinic acid). In such combination therapy, fluorouracil may cause the development of more severe side effects, in particular severe diarrhea.
The effectiveness and toxicity of therapy increases when fluorouracil is used in combination with other cytotoxic drugs (cyclophosphamide, vincristine, methotrexate, cisplatin, doxorubicin), interferon alpha, or folinic acid.
In combination therapy with other drugs that suppress bone marrow function, dose adjustment of fluorouracil is necessary. Dose reduction may also be necessary in the case of concomitant or previous radiotherapy. Cardiotoxicity of anthracyclines may be enhanced when used in combination with fluorouracil.
Aminophenazone, phenylbutazone, and sulfonamides should not be taken before or during treatment with fluorouracil.
With simultaneous administration of allopurinol, the toxicity and effectiveness of fluorouracil therapy may decrease.
Chlordiazepoxide, disulfiram, griseofulvin, and isoniazid may enhance the effectiveness of fluorouracil therapy.
Fluorouracil weakens the body's general defense mechanisms, so the immune response is reduced. The use of live vaccines during treatment with fluorouracil may lead to increased viral replication.
Hemolytic uremic syndrome has been reported after prolonged treatment with fluorouracil in combination with mitomycin.
Cimetidine may increase the concentration of fluorouracil in blood plasma.
Metronidazole may increase the concentration of fluorouracil in the blood plasma and enhance toxic effects.
Levamisole may enhance the hepatotoxicity of fluorouracil.
Thiazides may enhance the myelotoxicity of antineoplastic drugs.
Vinorelbine in combination with fluorouracil and folic acid can cause severe inflammation of the mucous membranes.
5-fluorouracil "Ebeve" must be diluted with 0.9% sodium chloride solution or 5% glucose solution.
No incompatibility was found with any of the tested carrier solutions.
A mixture of 1000 mg of Calcium Folinate "Ebeve" (100 ml of Calcium Folinate "Ebeve" 10 mg/ml), 5000 mg of 5-fluorouracil "Ebeve" (100 ml of 5-fluorouracil "Ebeve" 50 mg/ml) and 40 ml of 0.9% sodium chloride solution in an infusion pump (e.g. "Easy pump" type) is stable at room temperature for 48 hours.
There is no information on the possibility of mixing 5-fluorouracil "Ebeve" with other medicines. Therefore, 5-fluorouracil "Ebeve" cannot be mixed with other medicines (in particular with calcium folinate from other manufacturers).
Overdose
symptoms
Acute: psychotic reactions, drowsiness, increased effect of sedatives, increased toxic effect of alcohol. If necessary, sedation can be administered with diazepam IV in low doses (for example, starting from 5 mg) with constant monitoring of the functions of the cardiovascular and respiratory systems.
Chronic: bone marrow suppression, up to the development of agranulocytosis and critical thrombocytopenia, bleeding tendency, gastrointestinal ulcer, diarrhea, alopecia.
treatment
No one knows the specific antidote to fluorouracil. For prophylactic purposes, it is advisable to carry out transfusions of leukocyte or platelet mass. It is necessary to ensure adequate hydration and diuresis, as well as correct electrolyte imbalance. The need for hemodialysis usually does not arise. The patient should be under close medical supervision for the earliest possible detection of hematological and late gastrointestinal complications. Further treatment is symptomatic.
Storage conditions
In the original packaging at a temperature of 15-25 ° C. do not refrigerate or freeze!
Solutions for infusion with a concentration of 0.35 mg/ml and 15.0 mg/ml, prepared by diluting 5-fluorouracil "Ebewe" with 5% glucose solution or 0.9% sodium chloride solution, are chemically and physically stable for 28 days when stored in a refrigerator or at room temperature in a place protected or not protected from light.
From a microbiological point of view, the diluted solution should be used immediately. If the solution for infusion is not used immediately, in-use storage times and conditions should be observed by the person responsible for the solution. The solution should not be stored longer than 24 hours at 2-8°C, unless prepared in controlled and validated aseptic conditions.
