Tamoxifen

Pharmacological properties

tamoxifen is a potent non-steroidal estrogen antagonist. can also manifest itself as a partial or complete estrogen agonist, depending on the target tissues and species of the animals studied. in humans, the antiestrogenic effect of tamoxifen is predominantly observed.

The antiestrogenic activity of tamoxifen in the human body is explained by 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 concentration in the blood plasma is observed 4-7 hours after administration, and the equilibrium concentration is reached after 4-6 weeks of therapy. After a single oral administration of the drug, the maximum concentration of tamoxifen in the blood plasma of volunteers was 42 μg / L, and the maximum concentration of the metabolite of N-desmethyltamoxifen 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 about 200% after reaching equilibrium. This is probably due to a longer half-life of the metabolite. During therapy with tamoxifen at a dose of 20 mg 2 times a day, the average equilibrium concentration of tamoxifen in the blood plasma was 310 μg / L (range 164–494 μg / L), and the average equilibrium concentration of N-desmethyltamoxifen 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 respectively 5.4–117 (average 25.1) ng / mg protein and 7.8–210 (average 52) ng / mg squirrel. Concentrations of compounds in blood plasma 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 the human body, tamoxifen is metabolized in the liver and excreted mainly with bile. Excretion of tamoxifen in urine unchanged is very insignificant. By demethylation, tamoxifen is metabolized to N-desmethyltamoxifen, which in turn is converted by N-demethylation to an N-desdemethyl metabolite. The process of removing tamoxifen is biphasic. In women, the half-life in the initial phase is 7-14 hours, and in the terminal phase is about 7 days. The half-life of N-desmethyltamoxifen is about 14 days. A clinical response is observed at tamoxifen plasma concentrations of ≥70 μg / L. Special studies of the pharmacokinetics of tamoxifen and its main metabolites in the elderly and patients with impaired liver function have not been carried out. There is also no data on changes in pharmacokinetics in case of taking the drug after a meal or on an empty stomach.

Indications

Breast and endometrial cancer.

Tamoxifen is used for 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 can 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 metastases in the bones, the effect can be observed only after several months of treatment.

The tablets should be swallowed without chewing, washed down 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 treatment regimens for tamoxifen in children have not yet been determined.

Contraindications

Hypersensitivity to tamoxifen or other components of the drug; severe thrombocytopenia, leukopenia, or hypercalcemia; period of pregnancy.

Side effects

Due to the antiestrogenic effect of tamoxifen, side effects such as hot flashes, abnormal vaginal bleeding, irregular menstruation, vaginal discharge, and genital itching are most often noted. fluid retention, nausea, and vomiting are also possible. Transient acceleration of tumor growth, dizziness, skin rash, alopecia, increased fatigue, headache are less common.

In men, possible impotence or loss of libido.

In isolated cases, anorexia, taste impairment, constipation, diarrhea, leg muscle cramps, depression, alopecia, or intense hair growth are observed.

In premenopausal women, cessation of menstruation is possible, sometimes reversible cystic edema of the ovaries.

In a small number of patients with bone metastases, hypercalcemia develops at the beginning of therapy. Perhaps an initial increase in pain in bones and tumors, as well as the spread of erythema around skin lesions, which may be evidence of a therapeutic effect. It is also possible to increase existing skin lesions or the appearance of new ones.

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 are possible. 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 have not received the drug. However, the clinical benefit of using tamoxifen in the treatment of breast cancer in women exceeds the possible risk of developing neoplastic endometrial formations.

During therapy with tamoxifen, ophthalmic disorders are noted, in particular, a decrease in visual acuity, clouding of the cornea, the development of cataracts and retinopathy. These effects are likely to depend on the dose and duration of therapy and may be partially reversible after treatment with tamoxifen is discontinued.

Thrombosis is quite common, very rarely - pulmonary embolism.

With the simultaneous use of tamoxifen and cytotoxic drugs, the risk of developing thromboembolic complications increases.

Tamoxifen may affect the serum lipid spectrum. Hypertriglyceridemia is very rare, sometimes with the development of pancreatitis.

Tamoxifen therapy is associated with increased levels of hepatic enzymes in the blood serum and, in rare cases, with more severe lesions, such as fatty liver, cholestasis and hepatitis.

Hypersensitivity reactions are rare, in particular a skin rash, angioedema, polymorphic erythema, Stevens-Johnson syndrome, bullous pemphigoid.

Most of these side effects are reversible and can be reduced or eliminated by lowering 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 chemotherapeutic agents and radiation therapy.

Particular caution and regular monitoring are necessary in the treatment of tamoxifen with patients with liver and kidney diseases, patients with diabetes mellitus, with a history of thromboembolism, as well as with ophthalmic disorders.

Treatment with tamoxifen is associated with an increased frequency of changes in the endometrium, in particular with hyperplasia, polyps and cancer. This is probably due to the estrogenic properties of tamoxifen.

Before starting treatment for 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, irregular menstruation, vaginal discharge, pain or a sensation of pressure in the pelvic area) are detected their reasons.

Women taking tamoxifen for breast cancer should be screened regularly to detect endometrial hyperplasia in a timely manner. In the case of the development of atypical hyperplasia, tamoxifen must be discontinued and appropriate treatment prescribed. Before continuing tamoxifen therapy, the appropriateness of a hysterectomy should be considered.

Cases of ophthalmic disorders (decreased visual acuity, clouding of the cornea, development of cataracts, retinopathy) during treatment with tamoxifen have been recorded. Therefore, before the start of therapy and periodically during the treatment process, it is recommended to conduct an ophthalmic examination in order to identify early lesions of the cornea or retina, which may be reversible if tamoxifen treatment is stopped promptly.

Before starting treatment with tamoxifen, women should undergo a comprehensive gynecological examination (in particular to exclude pregnancy), as well as a therapeutic examination. During treatment with tamoxifen, gynecological examinations should be performed at least 1 time in 6 months for the timely detection of changes or lesions of the endometrium.

If patients have liver disease, it is necessary to carefully monitor liver function.

During treatment with tamoxifen, the number of blood cells (especially platelets), liver and kidney function, serum calcium and glucose 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 prescribed during pregnancy. In women treated with tamoxifen, isolated cases of spontaneous miscarriages, congenital defects in the development or death of the fetus were noted, although the connection of these phenomena with tamoxifen therapy was not clearly established.

A study of reproductive toxicity in rats, rabbits and monkeys did not reveal the teratogenic effects of tamoxifen.

A study of the fetal development of the reproductive tract in rodents showed that tamoxifen therapy is associated with changes similar to those that cause 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 who have a risk of developing clear cell carcinoma of the vagina or cervix uteri.

Before starting tamoxifen therapy, you must make sure that the patient is not pregnant. Throughout the entire period of treatment (and at least 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 breast-feeding during tamoxifen therapy is not recommended. Before starting therapy, it is recommended that the baby be weaned.

It is unlikely that tamoxifen therapy can have a negative effect on the ability to drive vehicles and operate machinery.

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 platelet aggregation inhibitors, the likelihood of bleeding increases. Regular coagulogram monitoring 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 tamoxifen absorption has not been studied, but it is unlikely that they can affect the pharmacokinetic parameters in equilibrium.

Overdose

High doses of tamoxifen cause estrogenic effects in animals. cases of acute overdose in humans are unknown.

Storage conditions

In a dry, dark place at a temperature of no higher than 25 ° c.