Fluorouracil - instructions for use, doses, side effects, contraindications

Analog of pyrimidine. Antitumor activity is due to the conversion of fluorouracil in tissues to active metabolites, including 5-fluoro-2'-deoxyuridine-5-monophosphate and 5-fluorouridine tri-phosphate. The action of 5-fluoro-2'-deoxyuridine-5-monophosphate is associated with blockade of the methylation reaction of deoxyuridic acid and its conversion into thymidyl acid by inhibiting thymidylate synthetase, which leads to thymidine deficiency and inhibition of DNA synthesis. 5-fluorouridine trisphosphate is inserted into RNA instead of uridine triphosphate, which leads to disruption of RNA processing and protein synthesis.

A few hours after the administration, the concentration of the drug in the tumor tissue is higher than in the healthy tissue

Pharmacokinetics:

Penetrates through the blood-brain barrier. Rapidly metabolized in tissues with the formation of an active metabolite - fluorouridine monophosphate. Catabolic cleavage occurs in the liver.

The half-life of fluorouracil in the initial phase is 10-20 minutes. The half-life in the final phase may be about 20 hours, presumably due to the deposition of metabolites in the tissues.

It is released through the respiratory tract - 60-80% in the form of carbon dioxide, and also by the kidneys - 7-20% unchanged.

Indications:Cancer of the colon and rectum, cancer of the breast, esophagus, stomach, pancreas, primary liver cancer, bladder cancer, prostate, ovary, cervix, malignant head and neck tumors, adrenal cancer, vulvar cancer, penile cancer, carcinoid .

ICD-10

II.C64-C68.C67 Malignant neoplasm of bladder

II.C60-C63.C61 Malignant neoplasm of prostate

II.C60-C63.C60 Malignant neoplasm of penis

II.C51-C58.C53 Malignant neoplasm of cervix

II.C51-C58.C51 Malignant neoplasm of vulva

II.C50.C50 Malignant neoplasm of breast

II.C15-C26.C26 Malignant neoplasm of other and inaccurately indicated digestive organs

II.C15-C26.C25 Malignant neoplasm of pancreas

II.C15-C26.C20 Malignant neoplasm of rectum

II.C15-C26.C18 Malignant neoplasm of colon

II.C15-C26.C16 Malignant neoplasm of stomach

II.C15-C26.C15 Malignant neoplasm of esophagus

II.C15-C26.C22.0 Hepatic cell carcinoma

II.C73-C75.C74 Malignant neoplasm of adrenal gland

II.C00-C14.C14 Malignant neoplasm of other and inaccurately marked localizations of the lip, oral cavity and pharynx

Contraindications:Hypersensitivityterminal stages of the disease, cachexia, bone marrow aplasia (the number of leukocytes is less than 5 ·10⁹/ l, the number of platelets is less than 100 ·10⁹/ l ), stomatitis, peptic ulcer and duodenal ulcerbowel colitis, expressed functional deficiency of the liver and kidneys, severe systemic infections (or the threat of their development), pregnancy, breast-feeding, severe anemia, leukopenia, thrombocytopenia; insufficiency dihydropyrimidinedehydrogenase (increased metabolism of fluorouracil by anabolic pathway with increased cytotoxicity and the possibility of developing life-threatening side effectseffects - diarrhea, neurotoxicity, neutropenia, stomatitis); combination with dihydropyrimidine inhibitorsdehydrogenase (brivudine, sorivudine); weakened patients; postoperativeth period less than 30 days after extensive surgical intervention; childhood.

Carefully:

Renal and / or hepatic insufficiency, acute infectious diseases of viral, fungal or bacterial nature (including tuberculosis, chicken pox, shingles), bone marrow infiltration by tumor cells, previously intensive radiation or chemotherapy, cachexia.

Caution is prescribed for elderly patients (age-related renal dysfunction is more likely, which may require a lower dose).

Pregnancy and lactation:

Action category for the fetus by FDA-D. Contraindicated in pregnancy.

For the duration of treatment, breastfeeding should be discontinued.

Dosing and Administration:

The route of administration, regimen and dose in each case are determined individually and depend on the indications, the stage of the disease, the state of the hematopoietic system, the chemotherapy regimen. Enter intravenously struino or drip, intraarterially, intracavitary.

Intravenously drip, 1 g / m2 per day, constantly for 96-120 h; in combination with other drugs - 600 mg / m2 intravenously on days 1 and 8 of the course. When used in combination with calcium folinate, fluorouracil doses are usually reduced by 25-30%.

Use in children

The drug is prescribed in doses recommended for adults. Efficiency and safety have not been studied.

Side effects:

From the side nervous system and sense organs: dizziness, ataxia, dysarthria, nystagmus, impaired spatial orientation, confusion, euphoria, optic neuritis, visual impairment, photophobia, cataract, excessive lacrimation, stenosis of lacrimal ducts, impaired taste.

From the side cardiovascular system (hematopoiesis, hemostasis): leukopenia (usually occurs 9-14 days after each course, the number of white blood cells is restored after about 30 days), neutropenia (including hemolytic), thrombocytopenia, arrhythmia, angina pectoris, ischemia, myocardial infarction, cardiomyopathy, heart failure, thrombophlebitis.

From the side respiratory system: pulmonitis (cough, shortness of breath), bronchospasm.

From the side organs of the digestive tract: nausea, vomiting, heartburn, mucositis (ulcerative stomatitis, ulcerative lesions of the gastrointestinal mucosa, esophagitis, proctitis), diarrhea, decreased appetite, bleeding from the digestive tract, impaired liver function.

From the side skin integument: dryness and cracked skin; in some cases - alopecia (reversible), partial loss of nails, hyperpigmentation in the nail bed and other body parts, palmar-plantar erythrodysesthesia (sensation of tingling in the hands and feet, followed by pain, redness and swelling), photosensitization.

Allergic reactions: skin rash, dermatitis (itching and skin rash, usually on the limbs and less often on the body), anaphylactic shock.

Other: infections (usually asymptomatic, less frequent - fever or chills, cough or hoarseness, pain in the lower back or side, painful or difficult urination), muscle weakness, epistaxis, azoospermia, amenorrhea, hyperuricemia.

Overdose:

Not described. Supposed to increase the side effects: bone marrow suppression; severe diarrhea and ulcerative enterocolitis, severe stomatitis, peptic ulcer of the gastrointestinal tract,gastrointestinal bleeding, neurotoxicity, severe skin reactions, suppression of bone marrow function (thrombocytopenia, leukopenia and agranulocytosis).

Treatment is symptomatic: colony-stimulating factors, antibacterial drugs (with febrile neutropenia and ulcerative colitis), blood transfusion and transfusion of platelet mass, antidiarrheal agents, infusion therapy (with dehydration).

Interaction:

Vaccines killed viral - due to the development of immunosuppression with the use of fluorouracil, there may be a decrease in the immune response to the vaccine; between the end of treatment and immunization, it is necessary to observe the interval necessary to restore the reactivity of the organism (depending on the severity of immunosuppression, the type of vaccine and other factors - from 3 months to 1 year).

Live viral vaccines - administration of live vaccines during treatment with fluorouracil should be avoided (immune response disorder, increased likelihood of side effects), and within 3 months -1 after the end of treatment (depending on the severity of immunosuppression, type of vaccine and other factors); Immunization with live vaccine for the prevention of poliomyelitis should be postponed to persons directly in contact with the patient.

Interferon alfa-2b - a significant increase in the concentration of fluorouracil in the blood plasma and a decrease in its clearance.

Calcium folinate - may increase the therapeutic and toxic effects; may require a decrease in the dose of fluorouracil.

Coumarin anticoagulants (warfarin) - may increase the anticoagulant effect; it is necessary to correct the dose of anticoagulant based on the prothrombin time.

Metronidazole is an increase in the toxicity of fluorouracil, probably due to a decrease in clearance, without increasing the expression of its cytotoxic effect in vitro in colorectal cancer.

Myelo-depressants demonstrating predictable dose-dependent myelotoxicity [abacavir, azathioprine, aldesleukin, alemtuzumab, altretamine, amphotericin B (for systemic use), liposomal amphotericin B, anastrozole, busulfan, valganciclovir, vidarabin (with systemic use in high doses), vinblastine, vincristine, vinorelbine, ganciclovir, gemcitabine, hydroxyurea preparations, dacarbazine, dactinomycin, daunorubicin, liposomal daunorubicin, didanosine, doxorubicin, liposomal doxorubicin, docetaxel, zidovudine, zoledronic acid, idarubicin, imatinib, alpha interferons, irinotecan, ifosfamide, capecitabine, carboplatin, carmustine (with systemic application), clozapine, colchicine, lamivudine, lomustine, melphalan, mercaptopurine, methotrexate, mitoxantrone, mitomycin, sodium iodide I131, sodium phosphate, oxaliplatinum, paclitaxel, plikamycin, procarbazine, pegasgas, strontium [89 Sr] chloride, streptozocin, temozolomide, teniposide, thioguanine, thiotepa, topotecan, fludarabine, flucytosine, chlorambucil, chloramphenicol, cyclophosphamide, cisplatin, cytarabine, epirubicin, etoposide] or radiotherapy - enhancing myelotoxicity; with the simultaneous use of two or more myelo-depressants and the appointment of radiation therapy or their taking in anamnesis, it may be necessary to reduce the dose of fluorouracil based on the parameters of peripheral blood.

Mitomycin - increased risk of hemolytic-uremic syndrome in children with simultaneous application.

Oxaliplatin combined with calcium folinate - reduced fluorouracil clearance with an increase in toxicity that persists for 15 days. Sorivudine ρ is a heavy,in some cases fatal leukopenia (a sorivudine metabolite is an inhibitor of dihydropyrimidine dehydrogenase blocking the inactivation of fluorouracil).

Means that have unpredictable, dose-independent myelotoxicity [alemtuzumab, aminopyrine, antidepressants, tricyclics, antithyroid agents, valproic acid, derivatives of hydantoin and succinimide (anticonvulsants), dapsone, gold compounds, angiotensin converting enzyme inhibitors, carbamazepine, clozapine, levamisole, loxapine, maprotiline, mirtazapine, NSAIDs (especially phenylbutazone), penicillamine, pentamidine, pimozide, primidon, Primarch, procainamide, propafenone, pyrimethamine (in high doses), pseudoephedrine, peginterferon alfa-2b, rituximab, sulfamethoxazole, sulfonamides (with systemic application), sulfasalazine, derivatives of sulfonylureas (antidiabetics), temozolomide, ticlopidine, thioxanthenes, trastuzumab, trimethoprim, felbamate, phenothiazines, flecainide, foscarnet, chloramphenicol, cetirizine, epirubicin] - increased leukopenia and / or thrombocytopenia; It may be necessary to reduce the dose of fluorouracil based on the values of peripheral blood.

Chemically incompatible with drugs that have acid reaction and are unstable in alkaline environment (fluorouracil solution has an alkaline reaction), cytarabine, diazepam, droperidol, doxorubicin and, possibly, other anthracyclines (unstable in alkaline medium), calcium folinate.

Cimetidine (intake for 4 weeks before the use of fluorouracil) - an increase in the concentration of the latter in blood plasma (probably due to inhibition of hepatic enzyme activity and a decrease in hepatic blood flow). With a single administration of cimetidine, this effect is not established. It should be combined with caution.

Special instructions:

The use of fluorouracil should be carried out under the supervision of a qualified physician with experience in antitumor therapy. Patients should be in a hospital at least during the first course of treatment. An additional course of fluorouracil should be given only if toxicity is resolved after a previous course.

Fluorouracil is recommended exclusively for parenteral administration, should not be administered intrathecally due to the risk of neurotoxic action.

During treatment, the blood is examined at least 3 times a week, with the first signs of oppression of hematopoiesis - daily. With severe oppression, hematopoiesis is transfused with erythrocyte mass, hemopoietic stimulants are used. During treatment, prescribe vitamins (thiamine and etc.); Careful oral care is needed.

The most significant decrease in the number of leukocytes is usually observed between the 9th and 14th day of the first course of therapy, but delayed myelodepression (up to 20 days) is possible. The normalization of the number of leukocytes occurs by the 30th day.

In experimental studies, a carcinogenic and mutagenic effect of fluorouracil has been established.

After radiotherapy or the use of other antitumor agents, the administration of fluorouracil is permissible after 1-1.5 months, provided that the blood picture is completely restored. Do not also prescribe the drug earlier than 3-4 weeks after complicated surgery. It is not recommended to administer the drug with extensive metastases to the bone marrow.

Dental interventions should be completed before the start of therapy or postponed until the normalization of the blood picture (possibly increased risk of microbial infections, slowing healing, bleeding gums).During treatment, use caution when using toothbrushes, threads or toothpicks.

It is necessary to provide a reduction of the initial dose in patients with insufficient bone marrow function, a violation of the liver or kidney function. Be particularly careful in patients previously treated with cytotoxic drugs, including alkylating agents or radiation therapy in high doses.

Application fluorouracil immediately stopped at the first sign of complications: diarrhea, inflammation of the esophageal mucosa and pharynx, ulceration and bleeding in the gastrointestinal tract, any bleeding at other sites, expressed leukopenia or rapid decrease in the number of leucocytes (particularly granulocytes). With the resolution (disappearance) of adverse events, treatment is continued at a lower dose.

Special precautions (rejection of intramuscular injections holding urinalysis, and stool occult blood secrets, non-acetylsalicylic acid, and platelet transfusion possible al.) To be observed in the case of thrombocytopenia. Patients with advanced leukopenia should be carefully monitored to identify signs of infection.In patients with neutropenia with increasing body temperature, the use of antibiotics must begin empirically.

Take care to avoid accidental cuts with sharp objects (safety razor, scissors), avoid contact sports or other situations in which a hemorrhage or injury is possible. During the treatment period, avoid contact with people who received a vaccine against poliomyelitis, with sick bacterial infections.

It is not recommended to use fluorouracil in patients with chickenpox (including recently transferred or after contact with the diseased), herpes zoster and other acute infectious diseases.

Appearance of signs of oppression of bone marrow function (unusual bleeding or hemorrhages, black tar stools, blood in urine or feces or dot red spots on the skin, etc.) require immediate consultation of a doctor.

Be careful with combination therapy; take each drug at the appointed time.

In the syndrome of palmar-plantar erythrodysesthesia, pyridoxine Inside at a dose of 100-150 mg per day.

Impact on the ability to drive vehicles and manage mechanisms.

The drug causes nausea, vomiting, disorientation, confusion, headache, lacrimation, photophobia, visual impairment and other symptoms that affect the general condition, so it is recommended to refrain from driving vehicles and performing other potentially dangerous jobs that require concentration of attention when taking the drug.

Instructions

Fluorouracil (Phthoruracilum)