Instructions for use FARESTON

Pharmacological properties of the drug Fareston

Toremifene (2-(p-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]phenoxy)-N,N-dimethylamine citrate) is a non-steroidal derivative of triphenylethylene. Like other members of this class (for example, tamoxifen), toremifene binds to estrogen receptors and has an antiestrogenic (or estrogen-like) effect depending on the duration of treatment, type of animal, gender, target organ and other characteristics. In humans, nonsteroidal triphenylethylene derivatives have a predominantly antiestrogenic effect. Toremifene competitively binds to estrogen receptors and inhibits estrogen-mediated stimulation of DNA synthesis and cell replication. In experimental cancer models, when used in high doses, toremifene has an estrogen-independent antitumor effect. The antitumor effect of toremifene in breast cancer is mediated primarily by its antiestrogenic effect, but it cannot be ruled out that other mechanisms (changes in oncogene expression, secretion of growth factors, induction of apoptosis, and effects on cell cycle kinetics) may also play a role in the antitumor effect of the drug. When treating postmenopausal breast cancer patients with toremifene, a moderately pronounced decrease in the level of total cholesterol and LDL cholesterol in the blood serum is also noted. Toremifene is rapidly absorbed after oral administration. The maximum concentration in the blood plasma is achieved after 3 (2–5) hours. Food intake does not affect the degree of absorption, but may increase the time to reach the maximum concentration in the blood plasma by 1.5–2 hours. Changes in pharmacokinetics associated with food intake, clinically insignificant. The dynamics of plasma concentration is described by a biexponential curve. The half-life in the first phase (distribution) is 4 (2-12) hours, in the second phase (elimination) - 5 (2-10) days. More than 99.5% of toremifene is bound to plasma proteins, mainly albumin. The pharmacokinetics of toremifene when taken orally in doses of 11–680 mg/day is linear. The steady-state concentration of toremifene when taken at the recommended dose (60 mg/day) averages 0.9 (0.6–1.3) mcg/ml. Toremifene is actively metabolized in the body. The main metabolite of toremifene detected in blood plasma is N-dimethyltoremifene with a half-life of 11 (4–20) days. It also has an antiestrogenic effect, however, somewhat less than toremifene. More than 99.9% of the metabolite binds to blood plasma proteins. Three more less significant metabolites are also determined in blood plasma - deaminohydroxytoremifene, 4-hydroxytoremifene and N,N-didemethyltoremifene. Toremifene is eliminated mainly in feces in the form of metabolites. May enter into enterohepatic recirculation. About 10% of the dose taken is excreted in the urine in the form of metabolites. Due to slow elimination, equilibrium concentrations are reached within 4–6 weeks. There was no positive correlation between serum concentrations and the antitumor effect when taken at the recommended dose (60 mg/day). The metabolism of toremifene is carried out with the participation of a cytochrome P450-dependent enzyme complex. The main pathway is CYP3A-mediated N-demethylation. The pharmacokinetics of toremifene in patients with renal failure does not change significantly. Elimination of toremifene and its metabolites was significantly accelerated in patients with increased activity of liver microsomal enzymes and slowed down in liver failure.

Fareston

Active substance:

Toremifene*

Pharmgroup:

Antitumor hormonal agents and hormone antagonists

Average price in pharmacies

Side effects of the drug Fareston

common or less common (≤1/100) side effects: hot flashes (flushing), increased sweating, vaginal bleeding or discharge, fatigue, nausea, rash, itching in the genital area, peripheral edema, dizziness and depression. These side effects are usually mild and are caused by the antiestrogenic effect of toremifene. Less frequently or rarely (≤1/1000, ≤1/100) the following adverse reactions were noted: weight gain, anorexia, vomiting, constipation, shortness of breath, headache, insomnia, skin rash, visual disturbances, including corneal changes, cataracts, thrombosis deep veins, pulmonary embolism, alopecia, changes in liver enzyme levels (increased transaminase levels). Very rarely , including isolated reports (≤1/10,000) - severe damage to liver function (jaundice). In patients with bone metastases, cases of hypercalcemia have been reported at the very beginning of treatment. The risk of endometrial changes such as hyperplasia, polyposis and cancer increases. This may be caused by the main pharmacological property of the drug - estrogen stimulation.

Instructions:

Clinical and pharmacological group

15.056 (Antiestrogen drug with antitumor effect)

Release form, composition and packaging

The tablets are white, round, flat, with a beveled edge, with the code “TO20” on one side.

Excipients: corn starch, lactose, povidone, sodium starch glycolate (type A), magnesium stearate, microcrystalline cellulose, colloidal anhydrous silicon.

10 pieces. — contour cell packaging (3) — cardboard packs. 10 pcs. — contour cell packaging (10) — cardboard packs. 30 pcs. — polyethylene bottles (1) — cardboard packs. 60 pcs. — polyethylene bottles (1) — cardboard packs. 100 pcs. — polyethylene bottles (1) — cardboard packs.

Tablets are white, round, flat, with a beveled edge, with the code “TO60” on one side.

Excipients: corn starch, lactose, povidone, sodium starch glycolate (type A), magnesium stearate, microcrystalline cellulose, colloidal anhydrous silicon.

10 pieces. — contour cell packaging (3) — cardboard packs. 30 pcs. — polyethylene bottles (1) — cardboard packs. 60 pcs. — polyethylene bottles (1) — cardboard packs. 100 pcs. — polyethylene bottles (1) — cardboard packs.

pharmachologic effect

Antitumor antiestrogenic non-steroidal drug, triphenylethylene derivative.

Toremifene specifically binds to estrogen receptors, competing with estradiol, and inhibits estrogen-induced DNA synthesis and cell replication. In high doses, toremifene may have an antitumor effect that is not associated with an estrogen-dependent effect.

In patients with breast cancer, the antitumor effect of toremifene is mainly associated with its antiestrogenic activity, although other mechanisms cannot be excluded (regulation of oncogene expression, growth factor secretion, induction of apoptosis, effect on cell cycle kinetics).

Pharmacokinetics

Suction

After oral administration, toremifene is completely absorbed. Cmax in blood plasma is achieved after 3 hours (2-5 hours). Eating does not affect the completeness of absorption, but may increase the time to reach Cmax by 1.5-2 hours. These changes are not clinically significant.

Distribution

Binding to plasma proteins (mainly albumin) is 99.5%. Css in blood plasma is established within 3-4 weeks (at a dose of 60 mg/day).

Metabolism and excretion

The fast distribution phase with an average T1/2 of about 4 hours (2-12 hours) is followed by a slow elimination phase with an average T1/2 of about 5 days (2-10 days).

Toremifene is metabolized in the liver by hydroxylation and demethylation with the participation of the CYP3A4 isoenzyme to form the active metabolite - N-demethyltoremifene. The average T1/2 of N-demethyltoremifene is 11 days (4-20 days). Three more metabolites were found in the blood serum: deaminohydroxytoremifene, 4-hydroxytoremifene and N,N-didemethyltoremifene. General clearance - 5 l/h.

Excreted through the intestines, mainly in the form of metabolites; about 10% - by the kidneys.

Dosage

Prescribed internally. The dosage regimen is set individually.

As a standard dose for first-line hormone therapy, a dose of 60 mg daily is recommended for a long time.

When Fareston is prescribed as a second line of hormonal treatment, the dose of the drug can be increased to 240 mg/day (120 mg 2 times/day).

If signs of disease progression appear, the drug should be discontinued.

Overdose

Symptoms: with a daily dose of Fareston 680 mg, dizziness, headaches, nausea and/or vomiting were observed. Theoretically, overdose may result in increased antiestrogenic effects (hot flashes) or increased estrogenic effects (vaginal bleeding).

Treatment: symptomatic therapy.

Drug interactions

Drugs that reduce renal excretion of calcium (including thiazide diuretics) may increase the risk of hypercalcemia.

Inducers of microsomal oxidation (for example, phenobarbital, phenytoin or carbamazepine) may accelerate the metabolism of toremifene, reducing its serum concentration. In such cases, the daily dose should be doubled.

The interaction between antiestrogens and warfarin can lead to a marked increase in bleeding time (simultaneous use of toremifene and drugs of this group should be avoided).

Theoretically, the metabolism of toremifene may be slowed down by drugs that inhibit the CYP3A4 isoenzyme, which is involved in the metabolism of toremifene. Such drugs include ketoconazole and other similar antifungal drugs, as well as erythromycin, oleandomycin.

Use during pregnancy and lactation

Fareston is contraindicated for use during pregnancy and lactation (breastfeeding).

Side effects

Effects due to anti-estrogenic action: most often - paroxysmal sensations of heat (hot flashes), increased sweating, vaginal bleeding or discharge, increased fatigue, nausea, rash, itching in the genital area, fluid retention, dizziness, depression. These effects are usually mild.

From the endocrine system: rarely - weight gain.

From the digestive system: rarely - anorexia, vomiting, constipation.

From the side of the central nervous system: rarely - headache, insomnia, increased transaminase levels; in some cases - severe liver dysfunction (jaundice).

From the organ of vision: rarely - visual impairment, including changes in the cornea, cataracts.

From the cardiovascular system: rarely - deep vein thrombosis, pulmonary embolism.

Dermatological reactions: rarely - skin rash, alopecia.

Other: rarely - shortness of breath.

In patients with bone metastases, cases of hypercalcemia have been reported at the very beginning of treatment.

The risk of endometrial changes such as hyperplasia, polyposis and cancer increases. This may be caused by the main pharmacological property of the drug - estrogen stimulation.

Storage conditions and periods

The drug should be stored in a dry place, out of reach of children, at a temperature of 15° to 25°C. Shelf life: 5 years.

Indications

- estrogen-dependent breast cancer in postmenopausal women.

Contraindications

— endometrial hyperplasia (including history);

- severe liver failure (including a history);

— thromboembolism (including history);

- pregnancy;

- lactation (breastfeeding);

- hypersensitivity to the drug.

The drug is prescribed with caution for leukopenia, thrombocytopenia, hypercalcemia (including metastases to bone tissue).

special instructions

Before starting treatment, the patient must undergo an examination by a gynecologist. Particular attention should be paid to the condition of the endometrial mucosa. Then gynecological examinations must be repeated at least once a year.

Patients suffering from diseases such as arterial hypertension, diabetes mellitus, having a high body mass index (>30) or receiving long-term HRT are at risk for endometrial cancer and therefore require careful monitoring.

Toremifene is not recommended for use in patients with a history of severe thromboembolic disease.

Patients with decompensated heart failure or severe angina require careful monitoring.

Since hypercalcemia may develop in patients with bone metastases at the beginning of treatment with the drug, these patients require careful monitoring.

Use for liver dysfunction

Contraindicated in severe liver failure (including history).

Conditions for dispensing from pharmacies

The drug is available with a prescription.

Special instructions for the use of the drug Fareston

Careful medical supervision is required when using the drug in patients with decompensated heart failure and severe angina, hypertension (arterial hypertension), labile diabetes mellitus, who have a high level of body mass index (30), as well as those who have received long-term hormone replacement therapy, are in endometrial cancer risk group. In the presence of bone metastases at the beginning of treatment, hypercalcemia may develop. It is not recommended to use the drug in patients with a history of severe thromboembolic disorders. Due to the lack of data, the use of toremifene during pregnancy and lactation is not recommended. In experimental studies, toremifene prevented the implantation of a fertilized egg, caused weakness in labor, and reduced perinatal survival. Its use during the period of organogenesis led to disturbances of ossification, anomalies in the development of ribs, and the development of edema in the fetus. Does not affect the ability to drive vehicles or operate machinery.

Drug interactions Fareston

With the simultaneous administration of drugs that reduce calcium excretion by the kidneys (thiazide diuretics), the risk of developing hypercalcemia increases. Inducers of microsomal liver enzymes (phenobarbital, phenytoin, carbamazepine) can accelerate the metabolism of toremifene in the liver and lead to a decrease in its concentration in the blood plasma; in this case, it may be necessary to double the daily dose. The simultaneous use of antiestrogens and indirect anticoagulants can significantly increase blood clotting time, so their simultaneous use should be avoided. Theoretically, some CYP3A4–6 inhibitors (ketoconazole, erythromycin) may slow down the metabolism of toremifene.