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Active ingredients
Toremifen
Release form
Pills
Composition
Toremifene (in the form of citrate) 20 mg; Excipients: corn starch, lactose monohydrate, povidone, sodium starch glycolate (type A), magnesium stearate, microcrystalline cellulose, colloidal silicon dioxide.
Pharmacological effect
Antitumor antiestrogenic nonsteroidal agent, triphenylethylene derivative. Toremifene binds to estrogen receptors and has an estrogen-like, anti-estrogenic (or simultaneously) effect, depending on the duration of treatment, gender, target organ and other features .; In the treatment of toremifene patients with postmenopausal breast cancer, a moderate decrease in serum cholesterol and LDL was detected .; Toremifene binds to estrogen receptors competitively and inhibits estrogen-mediated stimulation of DNA synthesis and cell replication. In experimental models of cancer, toremifene in high doses had an estrogen-independent antitumor effect .; The antitumor effect of toremifene on breast cancer is mediated by anti-estrogenic action, but it cannot be ruled out that other mechanisms (changes in the expression of oncogenes, secretion of growth factors, induction of apoptosis and influence on the kinetics of the cell cycle) can also have an antitumor effect.
Pharmacokinetics
After oral administration, toremifene is completely absorbed. Cmax in plasma is reached after 3 hours (2-5 hours). Meal does not affect the duration of absorption, but may increase the time to reach Cmax by 1.5-2 hours. These changes have no clinical significance .; The kinetics of toremifene in plasma when administered orally from 11 to 680 mg / day is linear in nature .; Plasma protein binding (mainly albumin) - 99.5%. Css at a dose of 60 mg / day is 0.9 (0.6-1.3) mcg / ml. Due to the slow elimination of Css in plasma is achieved within 4-6 weeks .; Toremifene is metabolized in the liver by hydroxylation and demethylation with the participation of the CYP3A4 isoenzyme with the formation of the active metabolite, N-demethyl-toremifene. It has a similar anti-estrogenic effect, but somewhat less than toremifene. The metabolite binding to plasma proteins is more than 99.9%. The average T1 / 2 of N-demethyltoremifene is 11 days (4-20 days).Three more less significant metabolites were detected in the blood serum: deaminogidroksitoremifene, 4-hydroxytremifene and N, N-didemethyltremifene .; Concentration in the blood plasma is described by a biexponential curve. T1 / 2 in the first phase (distribution) is 4 (2-12) hours, in the second (elimination) - 5 (2-10) days. Toremifene is derived mainly in the form of metabolites with feces. Enterohepatic recirculation may be observed. About 10% of the dose is excreted in the urine as metabolites.
Indications
Hormone-dependent metastatic breast cancer in postmenopause (first-line therapy); prevention and treatment of dyshormonal hyperplasia of the breast.
Contraindications
Endometrial hyperplasia in history; severe liver failure; changes in cardiac conduction with congenital or acquired prolongation of the QT interval; electrolyte imbalance, especially uncorrected hypokalemia; clinically significant bradycardia; clinically significant heart failure with a decrease in the left ventricular ejection fraction; symptomatic asystole in history; hypersensitivity to toremifene.
Use during pregnancy and lactation
It should not be used during pregnancy and during breastfeeding due to the lack of safety and efficacy of toremifene.
Dosage and administration
Is ingested, regardless of the meal .; With estrogen-dependent breast cancer, the recommended dose is 60 mg / day; For dyshormonal hyperplasia of the breast, the recommended dose is 20 mg / day.
Side effects
On the part of the reproductive system: often - flushing, uterine bleeding, vaginal discharge; rarely - endometrial hypertrophy, endometrial polyps; very rarely - endometrial hyperplasia, endometrial cancer .; On the part of the nervous system: often - increased fatigue, dizziness, edema, nausea, vomiting, excessive sweating, rash, itching, depression; rarely - disorientation in space, insomnia, headache .; On the part of the digestive system: rarely - loss of appetite, increased transaminase activity, constipation; very rarely - jaundice .; Cardiovascular: rarely - thromboembolic episodes (deep vein thrombosis, thrombophlebitis and pulmonary embolism) .; On the part of the metabolism: rarely - weight gain, hypercalcemia, especially in patients with bone metastases .; Other: rarely - dyspnea; very rarely - short-term clouding of the cornea, alopecia.
Overdose
Dizziness, headache, vertigo may occur when using the drug at a dose of 680 mg per day. You should also take into account the prolongation of the QT interval, which can occur during overdose .; Overdose therapy is symptomatic, there is no specific antidote.
Interaction with other drugs
When toremifene is used simultaneously with other drugs that prolong the QT interval, an additional effect of lengthening the QT interval may occur. This may lead to an increased risk of ventricular arrhythmias, including flutter / flicker. Therefore, simultaneous use with the following drugs is contraindicated: class I A antiarrhythmic drugs (for example, quinidine, hydroquinidine, disopyramide); class III antiarrhythmic drugs (eg, amiodarone, sotalol, dofetilide, ibutilide); antipsychotics (for example, phenothiazine derivatives, pimozide, sertindole, haloperidol, sultopyrid); antibacterial drugs (for example, moxifloxacin, erythromycin IV, pentamidine, antimalarials, especially halofantrine); antihistamines (eg, terfenadine, astemizole, mizolastine); cisapyrid, Vincamine IV, bepridil, difemanil; With the simultaneous use of drugs that reduce renal calcium excretion (thiazide diuretics), hypercalcemia may develop .; Inducers of the enzyme systems of the liver (for example, phenobarbital, carbamazepine) can accelerate the metabolism of toremifene in the liver and lead to a decrease in Css of toremifene in the blood plasma (this combination may require a doubling of the daily dose) .; With the simultaneous use of anti-estrogens and anticoagulants (for example, warfarin), a significant increase in bleeding time is possible (this combination should be avoided) .; Some drugs that inhibit CYP3A isoenzyme can slow down the metabolism of toremifene, which should be taken into account with simultaneous use of ketoconazole, erythromycin, troleandomycin.
special instructions
Before starting treatment should conduct a gynecological examination. Special attention should be paid to the state of the endometrial mucosa. Then gynecological examinations should be repeated at least 1 time per year .; Patients with arterial hypertension,diabetes mellitus and high body mass index (> 30) or who received long-term hormone replacement therapy are at risk for endometrial cancer and therefore need to be carefully monitored .; Toremifene is not recommended for the treatment of patients who have had a history of severe thromboembolic disease .; In some patients, a dose-dependent prolongation of the QT interval may be observed. Toremifene should be used with caution in patients (especially the elderly) with proarrhythmic conditions such as myocardial ischemia or prolongation of the QT interval, which can lead to an increased risk of ventricular arrhythmias (including flutter / blink) and cardiac arrest. If symptoms occur that may be associated with cardiac arrhythmia and occur during the use of toremifene, the therapy should be stopped and an ECG should be made; Toremifene should not be used if the QTs interval is> 500 ms; Patients with decompensated heart failure, or patients with severe angina, as well as patients with bone metastases at the beginning of treatment who may develop hypercalcemia, must be carefully monitored .; There is no information on the use of toremifene in patients with unstable diabetes mellitus, heart failure, or a severe general condition .; Influence on the ability to drive vehicles and control mechanisms; Usually, toremifene does not affect the reaction rate when driving vehicles or working with other mechanisms, but in isolated cases dizziness, weakness and visual impairment are possible. In such cases, it is necessary to refrain from driving or working with other mechanisms.