Fluroratsil

General characteristics. Structure:

Active ingredient: 50 mg of a fluroratsil in 1 ml.

Drug with the expressed antineoplastic and cytostatic action.

Pharmacological properties:

Pharmacodynamics. Antineoplastic activity is caused by transformation of a ftoruratsil in fabrics in active metabolites, including 5-fluorine-2-dezoksiuridin-5-monophosphate and a 5-ftoruridin triphosphate. Effect of 5-fluorine-2-dezoksiuridin-5-monophosphate is connected with blockade of reaction of methylation of dezoksiuridilovy acid and its transformation into timidilovy acid at the expense of timidilatsintetaza inhibition that results in deficit of thymidine and inhibition of synthesis of DNA. the 5-ftoruridina triphosphate is built in RNA instead of triphosphate uridine that leads to disturbance of processing of RNA and synthesis of protein.

Easily passes gistogematichesky barriers, including GEB, and it is distributed on fabrics (tumors, marrow, a liver, etc.) and to organism liquids (spinal, extracellular). Concentration in tumoral fabric in several hours after introduction is higher, than in healthy. Active metabolites are localized in a cell.

Pharmacokinetics. Catabolic splitting happens preferential in a liver (inactive products — carbon dioxide, urea and alpha fluorine - beta alanine are formed). At in introduction of T1/2  of a ftoruratsil makes about 16 min. of plasma (in diapazone8-20 mines), depends on the entered dose. It is removed through respiratory tracts (60–80% in the form of dioxide carbon) and kidneys (about 7-20% in not changed look, 90% – within the first hour). Very small amount of a ftoruratsil can be allocated with bile.

Possesses a high miyelotoksichnost and gastrointestinal toxicity.

High concentration of a ftoruratsil cause oncogenous changes in the cultivated embryonic cells of C3H/10T1/2 of mice. THAT has mutagen effect concerning some strains of Salmonella typhimurium, including strains 1535, TA 1537 THAT 1538, and Saccharomyces cerevisiae strains, but THAT does not influence strains of 92, TA 98, TA 100 Salmonella typhimurium. The positive effect was noted in micronuclear test on mice with use of cells of marrow, in vitro in very high concentration caused ruptures of chromosomes in hamster fibroblasts.

Has reversible toxic effect on sex cells. At intraperitoneal introduction to males of rats in doses of 125 or 250 mg/kg caused aberation chromosomes and changes of the structural organization of chromosomes in spermatogones. The inhibition ftoruratsily led differentiations of spermatogones to temporary infertility. However in doses to 80 mg/kg/days ftoruratsit did not cause any disturbances in the linear mice sensitive to induction of anomalies of a head of spermatozoa at influence of a number of chemicals with mutagen and cancerogenic action. At females of rats ftoruratsit in a dose led 25 or 50 mg/kg a week during 3 weeks to essential decrease in frequency of fertile pairings, delay of development of embryos to implantation of an oospore, increase in death of embryos up to implantation and caused chromosomal anomalies in these embryos. Caused moderately expressed inducing action concerning destruction of zygotes in females of rabbits.

It was reported about one case of multiple malformations at a fruit of the person at use of a ftoruratsil during the I trimester of pregnancy.

In researches on mice, rats, hamsters teratogenic action of a ftoruratsil is shown (caused malformations, including sky crevices, defects of a skeleton, anomaly of appendages, deformation of paws and tails). At the monkeys receiving 40 mg/kg in the divided doses from the 20th to the 24th day of pregnancy, the teratogenic effect is noted. In experiences on rats it is shown that ftoruratsit passes through a placenta and comes to a fruit blood stream; use of a ftoruratsil led to increase in a resorption of a fruit and death of embryos. At pregnant monkeys at introduction of a ftoruratsil in the doses exceeding 40 mg/kg abortions of all embryos were observed.

Indications to use:

Cancer thick and rectum, breast cancer, gullet, stomach, pancreas, primary cancer of a liver, cancer of a bladder, prostate, ovaries, necks of uterus, malignant tumors of the head and neck, cancer of adrenal glands, vulva cancer, penis cancer, carcinoid.

Route of administration and doses:

The way of introduction, the mode and doses in each case are defined individually and stages of a disease, a condition of the hemopoietic system, the scheme of chemotherapy depend on indications. Enter in/in struyno or kapelno, in / and, in-band.

In/in kapelno, 1 g/m2/days, it is constant during 96–120 h; in a combination with other HP — 600 mg/sq.m  in / вв the 1 and 8 days of a course. At use in a combination from calcium folinaty doses of a ftoruratsil usually reduce by 25–30%.

Features of use:

Use at pregnancy and feeding by a breast. Contraindicated at pregnancy. Category of action on a fruit on FDA — D. For the period of treatment it is necessary to stop breastfeeding.

Use of a ftoruratsil has to be carried out under control of the qualified doctor having experience of performing antineoplastic therapy. Patients have to be in the conditions of a hospital at least during the first course of treatment. It is necessary to appoint an additional course of a ftoruratsil only at permission of toxicity after earlier conducted course.

Ftoruratsil is recommended only for parenteral administration, it is not necessary to enter intratekalno because of danger of neurotoxic action.

During treatment blood is investigated at least 3 weekly, at the first signs of oppression of a hemopoiesis — daily. At sharp oppression of function of a hemopoiesis pour a packed red cells, apply hemopoiesis stimulators. During treatment appoint vitamins (thiamin, etc.); careful care of an oral cavity is necessary.

After radiation therapy or use of other antineoplastic means purpose of a ftoruratsil is admissible in 1–1,5 months on condition of a complete recovery of a picture of blood. It is also not necessary to appoint drug what in 3–4 weeks after difficult surgeries earlier. It is not recommended to administer the drug at extensive metastasises in marrow.

With care appoint the elderly patient (age renal failures are more probable that can demand a dose decline).

Dental interventions should be completed prior to therapy or to postpone until normalization of a picture of blood (possibly increase in risk of microbic infections, delay of processes of healing, bleeding of gums). During treatment to be careful when using toothbrushes, threads or toothpicks.

It is necessary to provide a reduction of an initial dose at patients with insufficient function of marrow, an abnormal liver function or kidneys. It is necessary to observe extra care at the patients who were earlier receiving cytotoxic drugs, including the alkylating means, or radiation therapy in high doses.

As there are no data on safety of appointment during pregnancy, at women with the kept genital function it is necessary to use only in combination with adequate contraception.

Use of a ftoruratsil is immediately stopped at the first signs of complications: diarrhea, an inflammation of a mucous membrane of a gullet and throat, an ulceration and bleeding in a GIT, bleeding of any other localization, the expressed leukopenia or bystry decrease in number of leukocytes (especially granulocytes). At permission (disappearance) of by-effects treatment is continued in lower dose.

Special precautionary measures (refusal of injections in oil, carrying out analyses of urine, a calla and secrets on the occult blood, refusal of reception of acetylsalicylic acid, possible transfusion of thrombocytes, etc.) need to be observed in case of development of thrombocytopenia. Patients with the developed leukopenia should be observed carefully for identification of signs of developing of an infection. At patients with a neutropenia at fervescence use of antibiotics needs to be begun empirically.

To be careful in order to avoid accidental cuts sharp objects (a safety razor, scissors), to avoid occupations contact sports or other situations at which hemorrhage or an injury are possible. During treatment to avoid contact with the people who received a vaccine against poliomyelitis with sick bacterial infections.

Emergence of signs of oppression of function of marrow (unusual bleedings or hemorrhages, a black tar-like chair, blood in urine or Calais or dot red spots on skin, etc.) demand immediate consultation of the doctor.

To be careful at a combination therapy; to accept each drug in due time.

At a syndrome of a palmar and bottom eritrodizesteziya it is possible to appoint a pyridoxine inside in a dose of 100-150 mg/days.

Special instructions. It is necessary to follow necessary rules of use and destruction of drug. Cultivation of a ftoruratsil has to be carried out by the trained personnel in specially equipped place (in special cases with an extract), with use of protective clothes (one-time gloves, goggles, masks), with observance of precautionary measures at preparation of injection solutions and destruction of needles, syringes, ampoules and the rest of unused drug.

Side effects:

From a nervous system and sense bodys: dizziness, ataxy, dysarthtia, nystagmus, disturbance of space orientation, confusion of consciousness, euphoria, optic neuritis, vision disorder, photophobia, cataract, excess slezootdeleniye, stenosis of the lacrimal tubules, taste disturbance.

From cardiovascular system (a hemopoiesis, a hemostasis): a leukopenia (usually arises cherez9-14 days after each course, the number of leukocytes is recovered approximately in 30 days), a neutropenia (including hemolitic), thrombocytopenia, arrhythmia, stenocardia, ischemia, a myocardial infarction, a cardiomyopathy, heart failure, thrombophlebitis.

From respiratory system: seldom — a pulmonitis (cough, short wind), a bronchospasm.

From bodies of a GIT: nausea, vomiting, heartburn, mukozita (a stomacace, cankers of a mucous membrane of a GIT, an esophagitis, a proctitis), diarrhea, a loss of appetite, bleeding from a GIT, an abnormal liver function.

From integuments: dryness and cracks of skin; in some cases — an alopecia (reversible), partial loss of nails, a hyperpegmentation in the field of a nail bed and other parts of a body, a palmar and bottom eritrodizesteziya (feeling of a pricking in brushes and feet with the subsequent emergence of pain, reddening and swelling), a photosensitization.

Allergic reactions: skin rash, dermatitis (an itch and skin rash, usually on extremities and it is less frequent on a trunk), an acute anaphylaxis.

Others: infections (usually asymptomatic, it is less frequent — the increased body temperature or a fever, cough or hoarseness, lower back pain or a side, the painful or complicated urination), muscular weakness, nasal bleeding, an azoospermism, an amenorrhea, a hyperuricemia.

Interaction with other medicines:

Efficiency and/or toxicity of a ftoruratsil modulate interferon альфа−2а, a methotrexate, calcium фолинат. Mitomitsin at prolonged use exponentiates emergence of a gemolitiko-uraemic syndrome.

Drugs + radiation therapy, causing a miyelosupressiya, strengthen the leukopenia and/or thrombocytopenia induced ftoruratsily.

At introduction of live virus vaccines the intensification of replication of a vaccinal virus and strengthening of side effects or decrease in development of antibodies in the patient's organism in response to introduction of a vaccine is possible; the inactivated vaccines — decrease in development of antiviral antibodies.

Contraindications:

Hypersensitivity, disease end-stages, cachexia, marrow aplasia (number of leukocytes less than 5·10 9/l, quantity of thrombocytes less than 100·10 9/l), stomatitis, a peptic ulcer of a stomach and duodenum, ulcer colitis, the expressed functional hepatic unsufficiency and kidneys, heavy system infections (or threat of their development), pregnancy, feeding by a breast.

Overdose:

At use in the recommended doses emergence of overdose is improbable. The specific antidote is not known.

Hypersensitivity to drug at people with deficit of enzyme of a degidropirimidindegidrogenaza is possible.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. At lower temperatures can lead storages of drug to emergence of a deposit. In such cases it is necessary to warm up an ampoule do60 °C, to shake vigorously, then to cool up to 35 °C. If the deposit was dissolved and solution became transparent, drug is ready to the use. Period of validity 2 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for injections of 5%, on 5 ml in ampoules or bottles. On 5 or on 10 ampoules, or on 1 or 5 bottles, together with the application instruction in cardboard packaging.