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Pharmacological properties

Toremifene is a non-steroidal derivative of triphenylethylene. like other representatives of this class (for example, tamoxifen and clomiphene), Toremifene binds to estrogen receptors and exerts an estrogen-like and / or anti-estrogenic effect depending on the duration of treatment, gender, target organ, and other features.

When treating patients with breast cancer with Toremifene in the postmenopausal period, a moderate decrease in plasma cholesterol and LDL was detected.

Toremifene competes with estrogen receptors and inhibits estrogen-mediated stimulation of DNA synthesis and cell replication. In experimental cancer models when used in high doses, Toremifene had an estrogen-independent antitumor effect.

The antitumor effect of Toremifene in breast cancer is mediated by an antiestrogenic effect, however, it cannot be ruled out that other mechanisms (changes in the expression of oncogenes, secretion of growth factors, induction of apoptosis and the effect on the kinetics of the cell cycle) can also have an antitumor effect.

Pharmacokinetics

Absorption. After oral administration, Toremifene is rapidly absorbed. Cmax in blood plasma is determined on average after 3 hours (within 2-5 hours). Eating does not affect the duration of absorption, but may delay the achievement of Cmax by 1.5–2 hours. Changes in food intake are clinically insignificant.

Distribution. Plasma concentration is described by a biexponential curve. T½ in the first phase (distribution) is 4 (2–12) hours, in the second (elimination) - 5 (2–10) days. CL and V were not evaluated due to the lack of IV infusion studies. More than 99.5% of Toremifene binds to plasma proteins (albumin). The kinetics of Toremifene in blood plasma when administered orally 11-680 mg / day is linear. The average equilibrium concentration of Toremifene when taking the recommended dose of 60 mg / day is 0.9 (0.6–1.3) μg / ml.

Metabolism. Toremifene is actively metabolized. In plasma, the main metabolite is N-dimethyl toramiphene with an average T½ 11 (4–20) days It has a similar antiestrogenic effect, but somewhat less pronounced than Toremifene. More than 99.9% are associated with plasma proteins. Another 3 less significant metabolites are determined in blood plasma: deaminohydroxytoremiphene, 4-hydroxytoremiphene and N, N-didemethylToremifene.

Elimination. Toremifene is eliminated mainly in the form of metabolites with feces. Enterohepatic recirculation may be noted. About 10% of the dose taken is excreted in the urine as metabolites. Due to the slow elimination, the equilibrium concentration in the blood plasma is reached within 4-6 weeks.

Indications

Treatment of hormone-dependent metastatic breast cancer in the postmenopausal period as a first-line drug.

Prevention and treatment of dishormonal breast hyperplasia.

Fareston is not recommended for patients with estrogen-receptor-negative tumors.

Application

The drug is taken orally, regardless of the meal.

Dyshormonal breast hyperplasia. The recommended dose is 20 mg / day.

Estrogen-dependent breast cancer. For the first line of hormone therapy, the recommended dose is 60 mg / day.

Renal failure. In renal failure, dose adjustment is not required.

Liver failure. With liver failure, Toremifene should be prescribed with caution.

Contraindications

A history of endometrial hyperplasia and severe liver failure are a contraindication to prolonged use of Toremifene.

Hypersensitivity to Toremifene or any of the excipients.

When using Toremifene, changes in cardiac conductivity were noted, namely, lengthening of the Q – T interval, therefore, the drug is contraindicated in patients with:

  • congenital or acquired prolongation of the Q – T interval;
  • electrolyte imbalance, especially uncorrected hypokalemia;
  • clinically significant bradycardia;
  • clinically significant heart failure with a decrease in the ejection fraction of the left ventricle;
  • a history of symptomatic arrhythmias.

Toremifene is not recommended for use simultaneously with drugs that extend the Q – T interval.

Side effects

The most common adverse reactions are: flushing, sweating, uterine bleeding, vaginal discharge, fatigue, nausea, rash, itching, dizziness, and depression. usually these side effects are mild and are caused by the antiestrogenic effect of Toremifene.

The incidence of adverse reactions has the following classification: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); rarely (≥1 / 10,000 to 1/1000); very rarely (1/10 000); frequency unknown (cannot be determined from available data).

Benign and malignant neoplasms: very rarely - endometrial cancer.

Metabolic and nutritional disorders: infrequently - loss of appetite.

Mental disorders: often - depression; infrequently - insomnia.

Violations of the nervous system: often - dizziness; infrequently - a headache.

Violations of the organ of vision: very rarely - short-term clouding of the cornea, cataract.

Hearing impairment: rarely - vertigo.

Violations of the vessels: very often - flushing; infrequently - thromboembolic episodes.

Disorders of the respiratory system: infrequently - dyspnea.

Violations of the digestive tract: often - nausea, vomiting; infrequently - constipation.

Disorders from the hepatobiliary system: rarely - increased levels of transaminases; very rarely - jaundice.

Violations of the skin and subcutaneous tissue: very often - increased sweating; often - rash, itching; very rarely - alopecia.

Violations of the reproductive system: often - uterine bleeding, vaginal discharge; infrequently - endometrial hypertrophy; rarely - endometrial polyps; very rarely - endometrial hyperplasia.

General disorders: often - increased fatigue, edema; infrequently - weight gain.

Thromboembolic episodes include deep vein thrombosis, thrombophlebitis, and pulmonary embolism.

Treatment with Toremifene is associated with changes in liver enzyme levels (increased levels of transaminases) and very rarely with severe impaired liver function (jaundice).

At the beginning of therapy, cases of development of hypercalcemia were reported in patients with bone metastases. During therapy with Toremifene, endometrial hypertrophy may occur as a result of the partial estrogenic effect of Toremifene. There is a risk of endometrial changes, such as hyperplasia, polyposis, and cancer. This can be caused by the main mechanism of action of the drug - estrogen stimulation.

The lengthening of the Q – T interval with the use of the drug Fareston is dose-dependent.

special instructions

Before starting treatment, patients must undergo a gynecological examination. special attention should be paid to the condition of the endometrial mucosa. then gynecological examinations must be repeated at least 1 time per year. patients with arterial hypertension, diabetes mellitus and a high level of body mass index (30) or who have received long-term hormone replacement therapy are at risk for endometrial cancer and therefore need to be closely monitored.

Cases of anemia, leukopenia, and thrombocytopenia have been reported. Red blood cells, white blood cells or platelets should be monitored when using the drug Fareston.

With the use of Toremifene, cases of liver damage have been reported, including an increase in the level of liver enzymes (more than 10 times the upper limit of the norm), cases of hepatitis and jaundice. Most of these cases occurred during the first months of treatment. The nature of liver damage was predominantly hepatocellular.

Toremifene is not recommended for the treatment of patients who have had a history of severe thromboembolic diseases.

Toremifene is not recommended for the treatment of patients with a history of severe thromboembolic diseases.

In some patients, Fareston may cause a dose-dependent lengthening of the Q – T interval. Fareston should be used with caution in patients with proarrhythmic conditions (especially in elderly patients), such as myocardial ischemia or prolonged Q-T interval, which can lead to an increased risk of ventricular arrhythmia (including atrial flutter / atrial fibrillation) and cardiac arrest. If symptoms occur that may be associated with cardiac arrhythmia and occur during the use of the drug Fareston, therapy should be stopped and an ECG performed.

The drug should not be used if the interval Q – Tc is 500 ms.

Patients with decompensated heart failure or severe angina pectoris require close monitoring.

Since patients with bone metastases may develop hypercalcemia at the beginning of treatment with the drug, they need careful monitoring.

There is no data on the use of the drug in patients with decompensated diabetes mellitus, heart failure, or a severe general condition.

The drug contains lactose (20 mg tablets - 19.0 mg / tablet, 60 mg tablets - 28.5 mg / tablet). With rare hereditary galactose intolerance, Lapp lactase deficiency or glucose / galactose malabsorption, the drug is not used.

During pregnancy and breastfeeding. The drug is recommended for use in the menopausal period.

Fareston should not be used during pregnancy and lactation due to lack of data regarding the safety and effectiveness of the drug during this period.

Children. Information on the use in children is not available, therefore, the drug is not indicated for use in this category of patients.

The ability to influence the reaction rate when driving vehicles and working with other mechanisms. Typically, the drug does not affect the reaction rate when driving vehicles and working with other mechanisms, but in some cases dizziness may occur. In such cases, it is necessary to refrain from driving vehicles and working with other mechanisms.

Interactions

It is possible that an additional lengthening of the q – t interval can occur with the use of fareston together with other drugs that can prolong the q – t interval. this may lead to an increased risk of ventricular arrhythmias, including atrial flutter / fibrillation. therefore, the simultaneous use of fareston with the following drugs is contraindicated:

  • class IA antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide);
  • class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetilide, ibutilide);
  • antipsychotics (e.g. phenothiazine, pimozide, sertindole, haloperidol, sulpiride);
  • certain antibacterial drugs (e.g. moxifloxacin, iv erythromycin, pentamidine, antimalarials, especially halofantrine);
  • some antihistamines (e.g. terfenadine, astemizole, misolastine);
  • others (cisapride, vincamine iv, bepridil, diphemanil).

With the simultaneous use of drugs that reduce renal excretion of calcium (thiazide diuretics), the development of hypercalcemia is possible.

Inducers of liver enzyme systems (e.g. phenobarbital, phenytoin, carbamazepine) can accelerate the metabolism of Toremifene in the liver and lead to a decrease in the equilibrium concentration of Toremifene in the blood plasma. In this case, it may be necessary to double the daily dose.

The simultaneous use of antiestrogens and warfarin-like anticoagulants can significantly increase bleeding time. Their simultaneous use should be avoided.Theoretically, some drugs that inhibit the CYP 3A enzyme system can slow down the metabolism of Toremifene. This group of drugs includes antimycotics - imidazole derivatives (ketoconazole) and other similar antimycotic drugs (itraconazole, voriconazole, posaconazole), protease inhibitors (ritonavir, nelfinavir), macrolides (clarithromycin, erythromycin and telithromycin). With the simultaneous administration of such drugs, this fact should be taken into account.

Overdose

Dizziness, headache, vertigo, nausea and / or vomiting may occur when using the drug at a dose of 680 mg / day. the lengthening of the q – t interval, which can occur with an overdose, should also be taken into account. symptomatic overdose therapy, there is no specific antidote.

Storage conditions

At a temperature not exceeding 25 ° c.