Description

PHARMACOLOGICAL PROPERTIES: Pharmacodynamics. Tamoxifen is a potent non-steroidal estrogen antagonist. It may also act as a partial or full estrogen agonist, depending on the target tissues and animal species studied. In humans, the predominantly antiestrogenic effect of tamoxifen is noted.
The antiestrogenic activity of tamoxifen in the human body is due to its binding to the hormone-binding domain of the estrogen receptor. Thus, tamoxifen blocks the action of estradiol.
Pharmacokinetics. When taken orally, tamoxifen is well absorbed. The maximum plasma concentration is observed 4-7 hours after administration, and the equilibrium concentration is reached after 4-6 weeks of therapy. After a single oral dose of the drug, the maximum plasma concentration of tamoxifen in volunteers was 42 µg/l, and the maximum concentration of the N-desmethyl tamoxifen metabolite was 12 µg/l. The half-lives of tamoxifen and its metabolite were 4 and 9 days, respectively. The ratio between the concentrations of N-desmethyltamoxifen and tamoxifen varies from 20% after the first dose to approximately 200% after reaching an equilibrium state. This is probably due to the longer half-life of the metabolite. During therapy with tamoxifen at a dose of 20 mg 2 times a day, the mean steady-state plasma concentration of tamoxifen was 310 μg/l (range 164–494 μg/l), and the mean steady-state concentration of N-desmethyl tamoxifen was 481 μg/l (range 300–851 µg/l).
After treatment with tamoxifen at a dose of 40 mg/day, the concentrations of tamoxifen and N-desmethyltamoxifen in tumor samples were 5.4–117 (mean 25.1) ng/mg protein and 7.8–210 (mean 52) ng/mg, respectively. squirrel. Plasma concentrations of the compounds were 27–520 (average 300) ng/mL and 210–761 (average 462) ng/mL, respectively. More than 99% of tamoxifen binds to plasma proteins.
In humans, tamoxifen is metabolized in the liver and excreted primarily in the bile. Removal of tamoxifen in the urine unchanged is very small. By demethylation, tamoxifen is metabolized to N-desmethyl tamoxifen, which in turn is transformed by N-demethylation into the N-desdimethyl metabolite. The elimination process of tamoxifen is biphasic. In women, the half-life in the initial phase is 7-14 hours, and in the terminal phase – about 7 days. The half-life of N-desmethyltamoxifen is about 14 days. A clinical response is observed at plasma tamoxifen concentrations ≥70 mcg/l. Special studies of the pharmacokinetics of tamoxifen and its main metabolites in the elderly and patients with impaired liver function have not been performed. There is also no data on changes in pharmacokinetics in the case of taking the drug after meals or on an empty stomach.

INDICATIONS: breast and endometrial cancer.
Tamoxifen is used for the adjuvant treatment of breast cancer in women with affected lymph nodes, as well as metastatic breast cancer in men and women.

APPLICATION: The recommended daily dose of tamoxifen for adults is 20 mg.In the case of common forms of the disease, the dose may be increased to 30-40 mg / day.
The maximum daily dose of tamoxifen is 40 mg. An objective response to therapy is usually observed after 4-10 weeks of treatment, however, in the case of bone metastases, the effect may be observed only after several months of treatment.
Tablets should be swallowed without chewing with water.
In the case of the appointment of 2 or more tablets of Tamoxifen "Ebeve" per day, they can be taken in 1 or 2 doses.
The duration of treatment with tamoxifen is determined by the severity and course of the disease. Usually treatment is long and lasts until remission is achieved.
In the treatment of elderly patients or patients with impaired liver or kidney function, there is no need to adjust the dose of the drug.
Doses and regimens for tamoxifen treatment in children have not yet been determined.

CONTRAINDICATIONS: hypersensitivity to tamoxifen or other components of the drug, severe thrombocytopenia, leukopenia or hypercalcemia, pregnancy.

SIDE EFFECTS: Due to the anti-estrogen action of tamoxifen, side effects such as hot flashes, abnormal vaginal bleeding, menstrual irregularities, vaginal discharge, genital itching are most often noted. Fluid retention in the body, nausea, and vomiting are also possible. Transient acceleration of tumor growth, dizziness, skin rash, alopecia, fatigue, headache are less common.
In men, possible impotence or loss of libido.
In rare cases, anorexia, taste disturbance, constipation, diarrhea, leg muscle cramps, depression, alopecia, or intense hair growth are observed.
In premenopausal women, the cessation of menstruation is possible, sometimes – reversible cystic ovarian edema.
A small number of patients with bone metastases develop hypercalcemia at the start of therapy. There may be an initial increase in bone pain and swelling, as well as the spread of erythema around skin lesions, which may be evidence of a therapeutic effect. Existing skin lesions may also enlarge or new ones may appear.
Possible more serious side effects such as leukopenia and/or thrombocytopenia (platelet count usually drops to 80,000-90,000/mm3). Very rarely, neutropenia and pancytopenia develop.
Tamoxifen therapy is associated with an increased risk of proliferative changes in the endometrium, in particular endometrial hyperplasia, polyps, endometriosis, and in rare cases endometrial cancer. The likelihood of developing endometrial cancer increases with increasing duration of tamoxifen therapy and is approximately 2-3 times higher than the likelihood of endometrial cancer in women who did not receive the drug. However, the clinical benefit of tamoxifen in the treatment of breast cancer in women outweighs the possible risk of developing endometrial neoplastic lesions.
During therapy with tamoxifen, ophthalmic disorders are noted, in particular, a decrease in visual acuity, corneal clouding, the development of cataracts and retinopathy. These effects are likely to be dose and duration dependent and may be partially reversible upon discontinuation of tamoxifen treatment.
Quite often, thrombosis is noted, very rarely – pulmonary embolism.
With the simultaneous use of tamoxifen and cytotoxic drugs, the risk of developing thromboembolic complications increases.
Tamoxifen can affect the lipid spectrum of blood serum. Hypertriglyceridemia is very rarely noted, sometimes with the development of pancreatitis.
Tamoxifen therapy has been associated with increased serum levels of liver enzymes and, in isolated cases, with more severe lesions such as fatty liver, cholestasis, and hepatitis.
Hypersensitivity reactions are occasionally noted, in particular skin rash, angioedema, erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid.
Most of these side effects are reversible and can be reduced or eliminated by reducing the dose of the drug.

SPECIAL INSTRUCTIONS: Patients with estrogen receptor-positive tumors and postmenopausal women respond better to tamoxifen therapy.
Tamoxifen can be used in combination with other chemotherapy drugs and radiation therapy.
Particular caution and regular monitoring are necessary in the treatment of tamoxifen in patients with liver and kidney disease, patients with diabetes mellitus, with a history of thromboembolism, as well as with ophthalmic disorders.
Treatment with tamoxifen is associated with an increased incidence of endometrial changes, in particular hyperplasia, polyps, and cancer. This is likely due to the estrogenic properties of tamoxifen.
Before starting treatment in patients who have previously taken tamoxifen, it is necessary to conduct gynecological and therapeutic examinations for at least 6 months and, if any uncharacteristic symptoms (abnormal vaginal bleeding, menstrual irregularity, vaginal discharge, pain or pressure in the pelvic area) are detected, find out their reasons.
Women taking tamoxifen for the treatment of breast cancer should be monitored regularly for early detection of endometrial hyperplasia. If atypical hyperplasia develops, tamoxifen should be discontinued and appropriate treatment instituted. Hysterectomy should be considered before continuing tamoxifen therapy.
Cases of ophthalmic disorders (decreased visual acuity, clouding of the cornea, development of cataracts, retinopathy) have been recorded during treatment with tamoxifen. Therefore, before starting therapy and periodically during treatment, it is recommended to conduct an ophthalmological examination in order to detect early lesions of the cornea or retina, which may be reversible if treatment with tamoxifen is stopped in time.
Before starting treatment with tamoxifen, women should undergo a comprehensive gynecological examination (in particular to exclude pregnancy), as well as a therapeutic examination. During the period of treatment with tamoxifen, gynecological examinations should be carried out at least once every 6 months for the timely detection of changes or lesions of the endometrium.
If patients have liver disease, liver function should be carefully monitored.
During treatment with tamoxifen, the number of blood cells (especially platelets), liver and kidney function, calcium and glucose levels in the blood serum should be periodically monitored.
For the purpose of early detection of metastases, it is recommended to conduct an x-ray examination of the lungs and bones, as well as ultrasound of the liver.
Tamoxifen should not be given during pregnancy. In women treated with tamoxifen, there have been isolated cases of spontaneous miscarriages, birth defects, or fetal death, although the relationship of these phenomena with tamoxifen therapy has not been definitely established.
Reproductive toxicity studies in rats, rabbits and monkeys showed no teratogenic effects of tamoxifen.
A study of the fetal development of the reproductive tract in rodents has shown that tamoxifen therapy is associated with changes similar to those caused by estradiol, ethinyl estradiol, clomiphene, and diethylstilbestrol. Although the clinical significance of these changes is unknown, some of them, especially vaginal adenosis, are similar to those seen in young women who have been exposed to diethylstilbestrol in utero and have a risk of developing clear cell carcinoma of the vagina or cervix of about 1:1000.
Before starting therapy with tamoxifen, it is necessary to make sure that the patient is not pregnant. During the entire period of treatment (and at least for 3 months after its completion), contraceptives should be used. Oral contraceptives should not be used.
It is not known whether tamoxifen is excreted in breast milk, so breastfeeding during tamoxifen therapy is not recommended.Before starting therapy, it is recommended to wean the baby from the breast.
It is unlikely that tamoxifen therapy may have a negative effect on the ability to drive vehicles and work with mechanisms.

INTERACTIONS: with concomitant therapy with hormonal preparations containing estrogens, the effectiveness of both drugs may decrease (in particular, contraceptives may not provide a reliable effect).
Tamoxifen can enhance the effect of coumarin anticoagulants (cause a significant increase in prothrombin time).
With the simultaneous use of tamoxifen and inhibitors of platelet aggregation, the likelihood of bleeding increases. Regular monitoring of the coagulogram is recommended.
When using tamoxifen in combination with cytotoxic drugs, the frequency of thromboembolic complications increases.
In the case of simultaneous therapy with bromocriptine, the concentration of tamoxifen and its active metabolite N-desmethyltamoxifen in the blood serum increases.
The effect of foods on the absorption of tamoxifen has not been studied, but it is unlikely that they can affect the pharmacokinetic parameters at steady state.