Fareston (Tablets) Instructions for Use

Marketing Authorization Holder

Santen Service, JSC (Russia)

Manufactured By

Orion Corporation (Finland)

ATC Code

L02BA02 (Toremifene)

Active Substance

Toremifene (Rec.INN registered by WHO)

Dosage Forms

	Fareston	Tablets 20 mg: 30, 60, or 100 pcs.
		Tablets 60 mg: 30, 60, or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat with beveled edges, with the code “TO20” on one side.

Excipients: corn starch, lactose monohydrate, microcrystalline cellulose 50M, sodium carboxymethyl starch, povidone K30, magnesium stearate, colloidal silicon dioxide.

30 pcs. – HDPE bottles (1) – cardboard packs.
60 pcs. – HDPE bottles (1) – cardboard packs.
100 pcs. – HDPE bottles (1) – cardboard packs.

Tablets white or almost white, round, flat with beveled edges, with the code “TO60” on one side.

Excipients: corn starch, lactose monohydrate, microcrystalline cellulose 50M, sodium carboxymethyl starch, povidone K30, magnesium stearate, colloidal silicon dioxide.

30 pcs. – HDPE bottles (1) – cardboard packs.
60 pcs. – HDPE bottles (1) – cardboard packs.
100 pcs. – HDPE bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug, antiestrogen

Pharmacotherapeutic Group

Antineoplastic agent, antiestrogen

Pharmacological Action

Antitumor antiestrogenic nonsteroidal agent, a derivative of triphenylethylene. Toremifene binds to estrogen receptors and exerts an estrogen-like, antiestrogenic (or simultaneous) effect, depending on the duration of treatment, sex, target organ, and other characteristics.

Treatment with toremifene in postmenopausal patients with breast cancer revealed a moderate decrease in serum cholesterol and LDL.

Toremifene competitively binds to estrogen receptors and inhibits estrogen-mediated stimulation of DNA synthesis and cell replication. In experimental cancer models, Toremifene in high doses exerted an estrogen-independent antitumor effect.

The antitumor effect of toremifene on breast cancer is mediated by an antiestrogenic action; however, 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 exert an antitumor effect.

Pharmacokinetics

After oral administration, Toremifene is completely absorbed. C_max in plasma is reached in 3 h (2-5 h). Food intake does not affect the absorption duration but may increase the time to reach C_max by 1.5-2 h. These changes are not clinically significant.

The kinetics of toremifene in plasma after oral administration from 11 to 680 mg/day is linear.

Binding to plasma proteins (mainly albumin) is 99.5%. C_ss at a dose of 60 mg/day is 0.9 (0.6-1.3) µg/ml. Due to slow elimination, C_ss in plasma is achieved within 4-6 weeks.

Toremifene is metabolized in the liver by hydroxylation and demethylation involving the CYP3A4 isoenzyme to form an active metabolite, N-demethyltoremifene. It has a similar antiestrogenic effect, although somewhat less than Toremifene. The binding of the metabolite to plasma proteins is more than 99.9%. The mean T_1/2 of N-demethyltoremifene is 11 days (4-20 days). Three other less significant metabolites have been detected in serum: deaminohydroxytoremifene, 4-hydroxytoremifene, and N,N-didemethyltoremifene.

The plasma concentration is described by a biexponential curve. T_1/2 in the first phase (distribution) is 4 (2-12) h, in the second (elimination) – 5 (2-10) days. Toremifene is excreted mainly as metabolites in the feces. Enterohepatic recirculation may occur. About 10% of the dose is excreted in the urine as metabolites.

Indications

Hormone-dependent metastatic breast cancer in postmenopausal women (first-line therapy); prevention and treatment of dishormonal hyperplasia of the mammary gland.

ICD codes

Dosage Regimen

Take orally, once daily, with a glass of water. Administer regardless of meals.

For the treatment of hormone-dependent metastatic breast cancer in postmenopausal women, the standard dose is one 60 mg tablet daily.

For the prevention and treatment of dishormonal hyperplasia of the mammary gland, the standard dose is one 20 mg tablet daily.

Continue therapy for as long as directed by the treating physician, based on clinical assessment and treatment response. Do not discontinue therapy without medical consultation.

Swallow the tablet whole; do not crush or chew.

In patients receiving concomitant therapy with potent liver enzyme inducers (e.g., phenobarbital, carbamazepine), a dose adjustment may be necessary; monitor clinical efficacy.

Regularly monitor serum calcium levels, particularly in patients with bone metastases at treatment initiation, due to the risk of hypercalcemia.

Undergo a baseline gynecological examination before initiating treatment, with follow-up examinations at least annually to monitor endometrial status.

Perform periodic ECG monitoring for QT interval; discontinue therapy if the QTc interval exceeds 500 ms.

Adverse Reactions

From the reproductive system: frequently – hot flashes, uterine bleeding, vaginal discharge; rarely – endometrial hypertrophy, endometrial polyps; very rarely – endometrial hyperplasia, endometrial cancer.

From the nervous system: frequently – increased fatigue, dizziness, edema, nausea, vomiting, increased sweating, rash, itching, depression; rarely – disorientation, insomnia, headache.

From the digestive system rarely – loss of appetite, increased transaminase activity, constipation; very rarely – jaundice.

From the cardiovascular system rarely – thromboembolic episodes (deep vein thrombosis, thrombophlebitis, and pulmonary embolism).

From metabolism rarely – weight gain, hypercalcemia, especially in patients with bone metastases.

Other rarely – dyspnea; very rarely – transient corneal opacity, alopecia.

Contraindications

History of endometrial hyperplasia; severe hepatic insufficiency; cardiac conduction disturbances with congenital or acquired QT interval prolongation; electrolyte imbalances, especially uncorrected hypokalemia; clinically significant bradycardia; clinically significant heart failure with reduced left ventricular ejection fraction; history of symptomatic asystole; hypersensitivity to toremifene.

Use in Pregnancy and Lactation

Should not be used during pregnancy and breastfeeding due to the lack of data on the safety and efficacy of toremifene.

Special Precautions

Before starting treatment, a gynecological examination should be performed. Particular attention should be paid to the condition of the endometrial mucosa. Then, gynecological examinations should be repeated at least once a year.

Patients with arterial hypertension, diabetes mellitus, and a high body mass index (>30) or who have received long-term hormone replacement therapy are at risk for endometrial cancer and therefore require careful monitoring.

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

Some patients may experience a dose-dependent prolongation of the QT interval. Toremifene should be used with caution in patients (especially the elderly) with proarrhythmic conditions, such as myocardial ischemia or QT interval prolongation, which may lead to an increased risk of ventricular arrhythmia (including torsades de pointes/fibrillation) and cardiac arrest. If symptoms that may be associated with cardiac arrhythmia occur during the use of toremifene, therapy should be discontinued and an ECG performed.

Toremifene should not be used if the QTc interval is > 500 ms.

Patients with decompensated heart failure or patients with severe angina, as well as patients with bone metastases at the start of treatment who may develop hypercalcemia, require careful monitoring.

Information on the use of toremifene in patients with unstable diabetes mellitus, heart failure, or severe general condition is lacking.

Effect on the ability to drive vehicles and operate machinery

Usually, Toremifene does not affect the reaction speed when driving vehicles or operating other machinery, but in rare cases, dizziness, weakness, and visual disturbances are possible. In such cases, it is necessary to refrain from driving vehicles or operating other machinery.

Drug Interactions

When toremifene is used concomitantly with other drugs that prolong the QT interval, an additional effect of QT interval prolongation may occur. This may lead to an increased risk of developing ventricular arrhythmias, including torsades de pointes/fibrillation. Therefore, concomitant use with the following drugs is contraindicated: class I A antiarrhythmic drugs (e.g., quinidine, hydroquinidine, disopyramide); class III antiarrhythmic drugs (e.g., amiodarone, sotalol, dofetilide, ibutilide); antipsychotics (e.g., phenothiazine derivatives, pimozide, sertindole, haloperidol, sultopiride); antibacterial drugs (e.g., moxifloxacin, intravenous erythromycin, pentamidine, antimalarials, especially halofantrine); antihistamines (e.g., terfenadine, astemizole, mizolastine); cisapride, intravenous vincamine, bepridil, diphemanil.

Concomitant use of drugs that reduce renal excretion of calcium (thiazide diuretics) may lead to the development of hypercalcemia.

Inducers of liver enzyme systems (e.g., phenobarbital, carbamazepine) may accelerate the metabolism of toremifene in the liver and lead to a decrease in the C_ss of toremifene in plasma (with this combination, doubling the daily dose may be required).

Concomitant use of antiestrogens and anticoagulants (e.g., warfarin) may lead to a significant increase in bleeding time (this combination should be avoided).

Some drugs that inhibit the CYP3A isoenzyme can slow down the metabolism of toremifene, which should be considered when used concomitantly with ketoconazole, erythromycin, troleandomycin.

Storage Conditions

Store at 15°C (59°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.