Tamoxifen-zdorovya

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAMOXIFEN-ZDOROVYE (TAMOXIFEN-ZDOROVYE)

Composition:

active substance: tamoxifen;

1 tablet contains 10 mg or 20 mg of tamoxifen;

excipients: potato starch; lactose monohydrate; calcium stearate; povidone; colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physico-chemical properties: tablets are white or white with a yellowish tint, flat cylindrical shape, with a bevelled edge.

Pharmacotherapeutic group. Hormone antagonists and related agents. Anti-estrogenic agents. ATC code L02B A01.

Pharmacological Properties

Pharmacodynamics

Tamoxifen is a potent nonsteroidal estrogen antagonist. It may also exhibit partial or full agonistic properties, depending on the tissue and animal species. In humans, a predominantly antiestrogenic effect is observed, which is explained by the binding of tamoxifen to the hormone-binding domain of the estrogen receptor and subsequent blockade of estradiol action.

Pharmacokinetics

After oral administration, tamoxifen is rapidly absorbed. Maximum plasma concentration of tamoxifen is reached within 4–7 hours after intake, and steady-state concentration is achieved after 4–6 weeks of therapy. After a single dose of tamoxifen administered as a solution, maximum plasma concentration in men was 42 μg/L, and the concentration of the metabolite N-desmethyltamoxifen was 12 μg/L. The elimination half-lives of tamoxifen and its metabolite were approximately 4 days and 9 days, respectively. The ratio of N-desmethyltamoxifen to tamoxifen concentrations in blood gradually increases from about 20% after the first dose to 200% at steady state, likely due to the longer half-life of the metabolite. During tamoxifen therapy at a dose of 20 mg twice daily, the mean steady-state plasma concentration of tamoxifen in patients was 310 μg/L (range: 164–494 μg/L), and that of N-desmethyltamoxifen was 481 μg/L (range: 300–851 μg/L).

During tamoxifen therapy at a dose of 40 mg/day, concentrations of tamoxifen and N-desmethyltamoxifen in tumor tissues were 5.4–117 ng/mg protein (mean: 25.1 ng/mg) and 7.8–210 ng/mg protein (mean: 52 ng/mg), respectively. Plasma concentrations of tamoxifen and N-desmethyltamoxifen were 27–520 ng/mL (mean: 300 ng/mL) and 210–761 ng/mL (mean: 462 ng/mL), respectively. Over 99% of tamoxifen is bound to plasma proteins.

In the human body, tamoxifen is metabolized in the liver and primarily excreted via bile. Renal excretion of the unchanged compound is very low. The main metabolic pathway of tamoxifen in humans is demethylation, leading to the formation of the active metabolite N-desmethyltamoxifen, followed by further N-demethylation to form the N-didesmethyl metabolite.

The elimination process of tamoxifen is biphasic. In women, the half-life during the initial phase ranges from 7 to 14 hours, and during the terminal phase is approximately 7 days. The elimination half-life of N-desmethyltamoxifen is approximately 14 days.

A clinical response to therapy is observed at plasma tamoxifen concentrations exceeding 70 μg/L.

Pharmacokinetic characteristics of tamoxifen and its major metabolites in elderly patients, patients with impaired liver function, as well as the effects of administration on an empty stomach or after food intake, have not been studied.

Clinical characteristics.

Indications.

• Breast cancer and endometrial cancer in women.
• Adjuvant chemotherapy for breast cancer with lymph node involvement in women, treatment of metastatic breast cancer in women and men.

Contraindications.

• Hypersensitivity to tamoxifen or to any of the excipients.
• Severe thrombocytopenia, leukopenia.
• Severe hypercalcemia.
• Concomitant use of anastrozole and tamoxifen.
• Pregnancy and breastfeeding.

Interaction with other medicinal products and other forms of interaction.

The concomitant use of tamoxifen with other hormonal preparations containing estrogens may result in reduced efficacy of both agents (including unreliable contraceptive effect of such preparations).

Combined use of tamoxifen and aromatase inhibitors (including anastrozole) during adjuvant therapy has not demonstrated increased efficacy compared to tamoxifen alone. When tamoxifen and the aromatase inhibitor letrozole are used concomitantly, plasma concentrations of letrozole are reduced by 37%.

Tamoxifen may enhance the effect of coumarin anticoagulants, such as warfarin. Patients receiving coumarin anticoagulants together with tamoxifen should be closely monitored for coagulation status, especially at the beginning of treatment.

When tamoxifen is used concomitantly with platelet aggregation inhibitors, the tendency to bleeding may be increased during possible thrombocytopenic phases.

An increased incidence of thromboembolic events has been reported during tamoxifen therapy when combined with other cytotoxic agents.

Increased serum concentrations of tamoxifen and its active metabolite, N-desmethyltamoxifen, have been reported when co-administered with bromocriptine.

Medicinal products that inhibit CYP2D6 activity reduce plasma concentrations of endoxifen, the active metabolite of tamoxifen, by 65–75%, leading to reduced therapeutic efficacy. Reduced efficacy of tamoxifen has been observed when used concomitantly with certain antidepressants—selective serotonin reuptake inhibitors (SSRIs) (e.g., paroxetine). Therefore, whenever possible, strong CYP2D6 inhibitors such as paroxetine, fluoxetine, quinidine, cinacalcet, or bupropion should be avoided.

The primary known metabolic pathway of tamoxifen in humans is demethylation mediated by CYP3A4 enzymes. A pharmacokinetic interaction has been reported with the CYP3A4 inducer rifampicin, which reduces plasma levels of tamoxifen. The clinical significance of this reduction is unknown.

Pharmacokinetic interactions with CYP2D6 inhibitors affecting reduced plasma levels of the active metabolite of tamoxifen, 4-hydroxy-N-desmethyltamoxifen (endoxifen), have been reported.

Special precautions.

Patients with estrogen receptor-positive tumors and postmenopausal women respond better to tamoxifen therapy.

Tamoxifen should be administered with caution in patients with impaired liver or kidney function, diabetes mellitus, or ophthalmological disorders.

In premenopausal women receiving tamoxifen for the treatment of breast cancer, cessation of menstruation may occur.

Increased incidence of endometrial changes, including hyperplasia, polyps, endometrial cancer, and uterine sarcoma (predominantly malignant mixed Müllerian tumors), has been reported in patients treated with tamoxifen. The frequency and nature of these changes suggest they may be due to the estrogenic effect of tamoxifen.

Before initiating treatment and every 6 months thereafter, patients should undergo gynecological examination. Any unusual symptoms (particularly abnormal vaginal bleeding, menstrual cycle disturbances, vaginal discharge, pelvic pain, or pressure sensation) require immediate and thorough evaluation.

Careful monitoring for signs of possible endometrial hyperplasia is necessary in patients receiving tamoxifen for breast cancer prevention. In cases of atypical endometrial hyperplasia, tamoxifen should be discontinued, appropriate treatment initiated, and the need for hysterectomy assessed before considering continuation of tamoxifen therapy.

After tamoxifen treatment for breast cancer, cases of other primary tumors not located in the endometrium or contralateral breast have been observed. A causal relationship has not been established, and the clinical significance of these observations remains unclear.

Visual disturbances, including decreased visual acuity, corneal clouding, cataract development, and retinopathy, have been reported in patients taking tamoxifen. Therefore, ophthalmological examinations are recommended before starting therapy and periodically during treatment to detect early corneal or retinal lesions, which may be reversible if treatment is promptly discontinued.

In patients with a history of liver disease, liver function should be closely monitored. In all patients, periodic monitoring of blood cell counts (especially platelets), liver and kidney function tests, and serum calcium and glucose levels is necessary. To detect possible metastases early, periodic radiological examinations of the lungs and bones, as well as liver ultrasound, are recommended. Periodic monitoring of blood cell counts (including platelets), liver function tests, and serum calcium levels is advised.

Data indicate that patients with reduced metabolic biotransformation capacity mediated by CYP2D6 exhibit lower levels of endoxifen, one of the most important active metabolites of tamoxifen. Concomitant use of drugs that inhibit CYP2D6 may reduce the concentration of the active metabolite endoxifen. Therefore, if possible, strong CYP2D6 inhibitors such as paroxetine, fluoxetine, quinidine, cinacalcet, or bupropion should be avoided during tamoxifen therapy.

Tamoxifen treatment increases the risk of venous thromboembolism. This risk is higher in patients with severe obesity, increasing age, concomitant chemotherapy, or other risk factors for thromboembolic events. For certain patients with breast cancer who have multiple risk factors for venous thromboembolism, long-term anticoagulant therapy should be considered. If venous thromboembolism occurs, tamoxifen therapy must be immediately discontinued and antithrombotic treatment initiated. Tamoxifen should not be used in patients with a history of thromboembolic events.

Severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN), have been reported with tamoxifen treatment, which may be life-threatening or result in death. Patients should be informed about the signs and symptoms of severe skin reactions, and closely monitored during treatment. If signs or symptoms suggestive of these reactions occur, the drug should be immediately discontinued and alternative therapy considered (if necessary). If a patient develops a serious reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis while receiving tamoxifen, treatment must be immediately and permanently discontinued.

In patients with hereditary angioedema, tamoxifen may induce or exacerbate symptoms of angioedema.

During delayed microsurgical breast reconstruction, tamoxifen may increase the risk of microvascular complications associated with the transplanted flap.

Tamoxifen use may lead to positive doping test results.

The effect of food on tamoxifen absorption has not been studied. However, it is unlikely that food intake significantly affects the steady-state pharmacokinetic parameters of tamoxifen.

If a patient has known intolerance to certain sugars, consultation with a physician is recommended before taking this medication.

Use during pregnancy or breastfeeding.

Tamoxifen is contraindicated during pregnancy and breastfeeding. Isolated cases of spontaneous abortions and congenital malformations have been reported in children whose mothers took tamoxifen during pregnancy; however, a causal relationship has not been established.

Before initiating tamoxifen therapy, it must be confirmed that the patient is not pregnant. Patients of reproductive potential should use effective contraception during treatment and for at least 3 months after completion of tamoxifen therapy. Due to potential interactions, hormonal contraceptives should not be used.

Tamoxifen at a dose of 20 mg twice daily suppresses lactation in women, which does not recover even after therapy discontinuation.

Limited data indicate that tamoxifen and its active metabolites are excreted and accumulate over time in human breast milk; therefore, the drug is not recommended during breastfeeding. The decision to discontinue breastfeeding or discontinue tamoxifen therapy should take into account the importance of the drug to the mother.

Ability to affect reaction speed when driving vehicles or operating machinery.

The effect of tamoxifen on reaction speed during driving or operating machinery is unlikely. However, during tamoxifen treatment, fatigue, somnolence, and decreased visual acuity have been reported. Patients experiencing these symptoms should exercise caution when driving or operating machinery.

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Method of administration and dosage.

The recommended daily dose of tamoxifen for adults is 20 mg. In cases of advanced cancer, doses may be increased up to 30 mg or 40 mg per day.

The maximum daily dose of tamoxifen is 40 mg. Objective therapeutic effect is usually observed after 4–10 weeks of treatment; however, in the presence of bone metastases, a positive effect may be achieved only after several months of therapy.

Tablets should be swallowed whole, without chewing, with sufficient fluid.

If two or more tablets are prescribed per day, they may be taken in one or two divided doses.

The duration of treatment depends on the severity and course of the disease. Treatment is usually long-term.

Use in special patient groups. Dose adjustment is not required for elderly patients or for patients with impaired liver or kidney function.

Children. Recommendations for the use of tamoxifen in children have not been established.

Overdose.

Symptoms. High doses of tamoxifen have caused estrogenic effects in animals. In theory, overdose is expected to intensify antiestrogenic adverse effects.

Cases of acute overdose in humans have not been reported. Information on human overdose is limited. Doses of 160 mg/m² and higher have been associated with ECG changes (prolonged QT interval), and daily doses of 300 mg/m² have led to neurotoxicity (tremor, hyperreflexia, unsteady gait, and vertigo).

Treatment. There is no specific antidote. In case of overdose, symptomatic treatment should be administered.

Adverse Reactions

Most of the adverse effects listed below are reversible and often resolve after dose reduction.

The frequency of adverse reactions is classified as follows: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Benign and malignant neoplasms (including cysts and polyps).

Disease exacerbation has been reported. In a small number of patients with bone metastases, hypercalcemia may develop at the beginning of tamoxifen therapy. During this initial period, bone and tumor pain may intensify, and erythema around skin lesions may increase, which are signs of a therapeutic response. Existing skin lesions may also enlarge or new lesions may appear.

Tamoxifen therapy is associated with an increased incidence of proliferative endometrial changes, including polyps and endometrial cancer. The risk of developing endometrial cancer increases with longer duration of tamoxifen treatment and is approximately 2–3 times higher than in women not taking the drug. There is also a slightly increased risk of uterine sarcoma (predominantly malignant mixed Müllerian tumors). However, the clinical benefit of tamoxifen in treating breast cancer outweighs the potential risk of developing endometrial neoplasms.

Common: uterine fibroids.

Uncommon: endometrial cancer.

Rare: uterine sarcoma (mainly mixed malignant Müllerian tumors).

Reproductive system and breast disorders.

Very common: vaginal discharge, menstrual cycle disturbances and suppression of menstruation in the premenopausal period, vaginal bleeding.

Common: genital pruritus, increase in size of uterine fibroids, proliferative endometrial changes (endometrial neoplasia, hyperplasia and polyps, rarely endometriosis).

Rare: impotence in men, ovarian cystic swelling, vaginal polyps.

Blood and lymphatic system disorders.

Common: transient anemia.

Uncommon: leukopenia, transient thrombocytopenia.

Rare: agranulocytosis, neutropenia.

Very rare: pancytopenia.

Immune system disorders.

Common: hypersensitivity reactions.

Endocrine system disorders.

Very common: hot flushes.

Uncommon: hypercalcemia.

Metabolism and nutrition disorders.

Very common: fluid retention.

Common: increased serum triglyceride levels, anorexia.

Very rare: severe hypertriglyceridemia, sometimes associated with pancreatitis.

Psychiatric disorders.

Rare: depression.

Nervous system disorders.

Common: dizziness, headache, somnolence, sensory disturbances (paresthesia, dysgeusia).

Eye disorders.

Common: decreased visual acuity, corneal opacity, cataract and retinopathy development. These effects are likely dose- and duration-dependent. They may be partially reversible after discontinuation of tamoxifen therapy.

Rare: optic neuropathy, optic neuritis (in rare cases, vision loss has been observed).

Vascular disorders.

Common: facial flushing, ischemic cerebrovascular events, leg cramps, thrombosis. When tamoxifen is used in combination with other cytotoxic agents, the risk of thromboembolic events may increase, including venous thromboembolism (deep vein thrombosis, microvascular thrombosis) and pulmonary embolism.

Uncommon: stroke.

Frequency not known: thrombophlebitis.

Respiratory, thoracic and mediastinal disorders.

Uncommon: interstitial pneumonitis.

Gastrointestinal disorders.

Very common: nausea.

Common: vomiting, constipation, diarrhea.

Uncommon: pancreatitis.

Rare: loss of taste sensation, appetite disturbances.

Hepatobiliary disorders.

Common: changes in liver enzyme levels, fatty infiltration of the liver.

Uncommon: cirrhosis, fatty hepatosis.

Very rare: cholestasis, hepatitis, jaundice, necrotic hepatitis, hepatocellular injury, liver failure.

Occasionally, more severe liver disorders have led to fatal outcomes.

Skin and subcutaneous tissue disorders.

Very common: skin rashes.

Common: alopecia, increase in existing or development of new skin lesions.

Rare: hypertrichosis, cutaneous vasculitis, angioneurotic edema, toxic epidermal necrolysis.

Very rare: isolated cases of erythema multiforme, Stevens-Johnson syndrome, or bullous pemphigoid have been reported; cases of cutaneous lupus erythematosus have also been documented.

Frequency not known: exacerbation of hereditary angioedema.

Musculoskeletal and connective tissue disorders.

Common: leg cramps, myalgia.

Congenital, genetic and hereditary disorders.

Very rare: chronic hematoporphyria.

General disorders and administration site conditions.

Very common: hot flushes (partially due to the antiestrogenic effect of tamoxifen), fatigue.

Rare: at the beginning of therapy – bone pain and pain in the area of affected tissue as a response to tamoxifen therapy.

Changes in laboratory parameters.

Alterations in serum lipid profile, increased liver enzyme activity.

Injury, poisoning and procedural complications.

Very rare: radiation reactions.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 mg tablets, 10×6 in blisters in a box; 60 tablets in a container in a box. 20 mg tablets, 10×3, 10×6 in blisters in a box.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business.

Ukraine, 61013, Kharkiv region, Kharkiv city, Shevchenko street, 22.