Ftorafur® [Tegafur]

Pharmacological properties

tegafur and its sodium salt have an antitumor effect and are similar in biological properties to fluorouracil. tegafur can be considered as a transport form of fluorouracil, which is formed in the body due to the activation of tegafur by microsomal liver enzymes. The metabolite tegafur circulates in the body for a long time, thus ensuring the high effectiveness of the drug.

In the process of fluorouracil metabolism, 5-fluoro-2ʹ-deoxyuridine-5ʹ-monophosphate is formed, which significantly reduces the activity of thymidyl synthetase. Under such conditions, a deficiency of thymidine-5ʹ-monophosphate (which can be considered a specific precursor of DNA) occurs, which causes a halt in the process of cell division, including malignant ones. In addition, another metabolite of tegafur 5-fluorouracil-5-fluoruridin-5ʹ-triphosphate is incorporated into the RNA chain and replaces uracil, which is also accompanied by RNA disorders. It is important to emphasize that tegafur causes more pronounced biosynthesis disturbances than fluorouracil. This indicates that tegafur acts not only as a transport form of fluorouracil, but also independently. The cytostatic effect of tegafur is based on its ability to influence the RNA metabolism of slowly growing tumor cells (with slight proliferation). Such tumors include gastrointestinal adenocarcinoma.

The best results were obtained with the use of Fluorofur for the treatment of tumors of the gastrointestinal tract (stomach, colon and rectum) and breast cancer. The duration of remission in case of cancer of the rectum and colon is 5–8 months; with breast cancer - 10-19 months.

Ftorafur has a positive therapeutic effect in cases of malignant tumors of the bile duct, pancreas, urinary system, as well as skin lymphoma and diffuse neurodermatitis.

Ftorafur is effective in the treatment of cervical cancer (in combination with radiation therapy and chemotherapy (cisplatin, capecitabine and interferon)).

In animal experiments, a high antitumor efficacy of tegafur was revealed. Greater sensitivity to tegafur was noted in many experimental tumors (for example, breast tumors, 180 sarcomas, Walker carcinosarcomas, Harding-Passy melanoma). Tegafur has a strong antitumor effect in L-1210 leukemia, La hemocytoblastosis and lymphocytic leukemia, while Plis lymphosarcoma, Jensens sarcoma, NK carcinoma and 755 adenocarcinoma are less sensitive. Leukemia P-388, L-5178, Lewis pulmonary carcinoma, melanoma B16 and sarcoma 45 are resistant to tegafur.

The drug also has anti-inflammatory and analgesic effects, reduces itching.

Pharmacokinetics The pharmacokinetic properties of tegafur are based on its high lipophilicity (250 times the lipophilicity of fluorouracil).

Suction: when ingested, tegafur is rapidly absorbed in the digestive tract, C_max achieved after 3 hours and detected in the blood for at least 24 hours after its single administration.

Distribution: the drug quickly passes through biological membranes and spreads throughout the body, including into brain tissue. The bioavailability of tegafur from the digestive tract is 3 times greater than that of fluorouracil.

Bioavailability orally and in / in the used tegafur is similar (AUC is respectively 668 and 510 ng / ml / h).

Metabolism and excretion: tegafur is metabolized in the liver with the formation of metabolites, among which the pharmacologically active fluorouracil occupies a central place. Isolation of fluorouracil from a tegafur molecule depends on the dose and type of administration; a plasma concentration of 0.1–1 mg / ml is maintained for 48–96 hours. Bioactivation is carried out not only in the liver, but can also be local in the tumor tissue, which is characterized by a high content of cytosolic hydrolytic enzymes.

Tegafur is mainly excreted in the urine and only 0.8% with feces. In experiments, it was proved that in urine 60% is invariable tegafur, 10% is fluorouracil and only 5% is active metabolites of tegafur. After 12 hours, a significant decrease in the amount of active substance occurs; therefore, it is recommended to use tegafur with an interval of 12 hours.

Pharmacokinetics in special patient groups

In elderly patients, tegafur should be used with caution in connection with a possible violation of the liver, kidneys and heart, as well as the presence of concomitant diseases.

For children and adolescents, the safety and effectiveness of the use of tegafur have not been established.

Patients with impaired renal and / or liver function when using tegafur should monitor the activity of these organs. In severe renal and / or liver failure, tegafur should not be used.

Indications

Cancer of the colon and rectum, stomach, breast, cervix, skin lymphomas.

Application

Take the capsules orally 1 hour before or after a meal. dose should be selected individually depending on the tolerability of the drug by the patient.

Monotherapy with tegafur. With oral administration, the daily dose of tegafur is 20–30 mg / kg body weight (1.2–1.6 g or 3-4 capsules), but can reach 2 g (5 capsules); the dose should be divided into 2 doses and taken every day every 12 hours or 2–4 times a day. The course dose for oral administration is 30–40 g. The course of treatment is usually 28 days, the interval between courses is 7 days.

In elderly patients with hepatic and / or renal failure and in the case of prolonged therapy, as well as in the advanced stages of the disease, the dose of tegafur should be reduced.

In combination therapy regimens and as an adjunct to radiation therapy, tegafur should be used at a dose equal to or lower than the dose used in monotherapy.

For chemoradiotherapy of cervical cancer, use 800–1200 mg of tegafur 2 times a day. Depending on the individual tolerance of chemoradiotherapy, increase the daily dose of tegafur from 800 to 1200 mg in 2 divided doses during the course of treatment (12–20 mg / kg tegafur per day with an average patient’s body weight of 60 kg). The exact dose of tegafur during radiomodification is determined by the doctor depending on the body weight and associated diseases of the patient.

Children. The safety of tegafur in children and adolescents has not been proven, so its use is contraindicated.

Contraindications

Hypersensitivity to the drug; terminal stage of the disease; acute profuse bleeding; severe functional impairment of the liver and / or kidneys; leukopenia (3 · 109 / l), thrombocytopenia (100 · 109 / l) and anemia (hemoglobin level 30 units).

Side effects

The following side effects are classified according to organ systems and frequency: very often (1/10), often (1/100 to 1/10), infrequently (1/1000 to 1/100), rarely (1/10 000 to 1/1000), very rarely (1/10 000), including isolated cases.

Infections and infestations: rarely - symptoms of leukoencephalitis.

On the part of the blood and lymphatic system: very often - inhibition of blood formation, anemia, thrombocytopenia, leukopenia; rarely febrile neutropenia.

On the part of the immune system: often - hypersensitivity reactions.

When used in doses of a therapeutic course, tegafur causes a slight immunosuppressive effect on the general reactivity of the body, on indicators of nonspecific cellular and humoral immunity.

From the side of metabolism and nutrition: often - dehydration of the body.

From the nervous system: often - dizziness, drowsiness, loss of smell, change in taste.

When comparing oral and intravenous use of tegafur in the case of oral administration, lower toxicity and weaker intensity of side effects were found, especially with regard to undesirable symptoms from the central nervous system.

On the part of cardiac activity: very rarely - angina pectoris, also angina pectoris.

On the part of the respiratory system, diseases of the chest and mediastinum: rarely - interstitial pneumonia.

From the digestive system: very often - nausea, vomiting, anorexia, diarrhea, intestinal colic, especially at the beginning of therapy.

If the toxic effect of the drug is enhanced, you must either adjust the dose of tegafur, or stop its use.

Often - stomatitis.

Especially severe side effects are stomatitis and diarrhea, which usually develop at the final stage of therapy, when a total dose of tegafur of 50 g or more is reached.

Rarely, in especially severe cases, ulcerative esophagopharyngitis, duodenitis, or duodenal ulcer develops.

Very rarely - acute pancreatitis.

On the part of the liver and / or biliary tract: often - impaired liver function; rarely, acute hepatitis.

On the part of the skin and subcutaneous tissue: often - dermatitis with maculopapular rashes that itch; hair loss, damage to nails, dry skin.

From the kidneys and urinary tract: rarely - impaired renal function. In case of impaired renal function, tegafur metabolites can accumulate in the body, which sometimes cause an increase in the toxic effect of the drug.

Laboratory studies: often - increase in the level of AlAT and AsAT.

Tegafur is not peculiar to the accumulation of toxic effects.

special instructions

When prescribing tegafur, special attention should be paid to patients with impaired hematopoiesis, liver and kidney function, glucose metabolism, with a stomach ulcer and duodenal ulcer, a tendency to hemorrhage, and infectious diseases. regularly monitor the blood picture, the functional state of the liver and kidneys. with prolonged use of the drug, its side effect increases.

A common side effect of using tegafur is diarrhea. Patients with severe diarrhea should be carefully monitored and prescribed fluid and electrolyte replacement therapy to prevent possible fatal dehydration.

The severity of dizziness, nausea and vomiting decreases with fractionation of the daily dose. With the development of serious side effects, it is necessary to stop the use of the drug.

It should be borne in mind that the drug inhibits the reproductive function of the patient.

The capsule lid contains dye - crimson 4R (E124), which can cause allergic reactions.

Use during pregnancy and lactation. There are no clinical studies on the use of tegafur during pregnancy. Tegafur, like other cytostatics, can adversely affect the fetus, so its use during pregnancy is contraindicated.

Women of reproductive age and men during the use of the drug and up to 3 months after withdrawal must use an effective contraceptive method.

It is not known whether tegafur passes into breast milk. If therapy with tegafur mother is really necessary, breast-feeding should be discontinued.

The ability to influence the reaction rate when driving vehicles or other mechanisms. If drowsiness or dizziness occurs during the use of tegafur, one should refrain from driving vehicles and working with mechanisms.

Interactions

High efficacy and relatively good tolerance allow fluorofur to be included in combination therapy regimens. in the case of combined chemotherapy, fluorofur successfully replaces fluorouracil. combined chemotherapy is more effective in those patients who have not previously been given specific therapy with tegafur. after combination chemotherapy, inoperable tumors can become operable, moreover, during prolonged remission, metastases regress.

The cytostatic effect of fluorofur is promoted by uracil, thymidine, methotrexate, cisplatin, N- (phosphate acetyl) -L-aspartic acid, leucovorin, tamoxifen and other antitumor drugs that do not have cross-resistance to tegafur.

The combination of tegafur with leucovorin provides patients with gastrointestinal cancer with more pronounced efficacy of therapy and easier tolerance of side effects.

The simultaneous use of tegafur, non-specific immunomodulators and agents that increase the protective properties of the body (levomizole, interferon) has a beneficial effect.

Under certain conditions, tegafur can be used as an aid in radiation therapy. The best treatment results were obtained in patients with small limited tumors of the stomach and rectum.

With the simultaneous use of tegafur and phenytoin, the effect of phenytoin may increase.

Tegafur should not be used simultaneously with the antiviral drug sorivudine and its chemical analogue brivudin, since these substances increase the toxicity of tegafur.

The simultaneous use of tegafur and coumarins (warfarin) can enhance the anticoagulant effect of warfarin, so patients who use tegafur and warfarin should regularly monitor prothrombin time or an international normalized ratio.

The simultaneous use of filgrastim and tegafur may increase the severity of neutropenia.

Metronidazole may increase the risk of developing toxic effects of tegafur.

Tegafur (since it is a cytotoxic drug) cannot be prescribed simultaneously with clozapine (risk of developing agranulocytosis).

Overdose

Symptoms: increased toxic effects from the gastrointestinal tract, central nervous system and inhibition of hematopoiesis (leukopenia, anemia).

Treatment: control of hematopoiesis function for at least 4 weeks, if necessary, symptomatic therapy is carried out.

The specific antidote is unknown.

It should also take into account the disruption of the activity of some enzyme systems involved in the metabolism of tegafur, as a result of which the active metabolites of tegafur accumulate in the body, which leads to an increase in the toxic effects of the drug.

In subsequent courses of therapy, tegafur is metabolized worse, as evidenced by the removal of a significant amount of tegafur from the body unchanged. In addition, the tumor becomes more resistant to tegafur.

Storage conditions

In the original packaging to protect from the effects of light at a temperature not exceeding 25 ° c.