Instructions Tamoxifen-Zdorovye tablets 20 mg blister No. 30
Composition
active ingredient: tamoxifen;
1 tablet contains tamoxifen 20 mg;
Excipients: potato starch; lactose monohydrate; calcium stearate; povidone; colloidal anhydrous silicon dioxide.
Dosage form
Pills.
Main physicochemical properties: tablets of white or white with a yellowish tinge, flat-cylindrical shape, with a bevel.
Pharmacotherapeutic group
Hormone antagonists and similar drugs. Antiestrogens. ATX code L02B A01.
Pharmacological properties
Pharmacodynamics
Tamoxifen is a potent nonsteroidal estrogen antagonist. It can also have partial or full agonist properties, depending on the tissues and animal species. In humans, it has a predominantly antiestrogenic effect, which is explained by the binding of tamoxifen to the hormone-binding domain of the estrogen receptor and blocking the action of estradiol.
Pharmacokinetics
When administered orally, tamoxifen is rapidly absorbed. Peak plasma concentrations of tamoxifen are reached 4–7 hours after dosing, and steady-state concentrations are reached after 4–6 weeks of therapy. After a single dose of tamoxifen solution, peak plasma concentrations of tamoxifen in men were 42 μg/L and those of the metabolite N-desmethyltamoxifen were 12 μg/L. The half-lives of tamoxifen and its metabolite were 4 and 9 days, respectively. The ratio of N-desmethyltamoxifen to tamoxifen concentrations in the blood gradually increases from approximately 20% after the first dose to 200% at steady state, probably due to the longer half-life of the metabolite. During tamoxifen therapy at a dose of 20 mg twice daily, the average steady-state concentration of tamoxifen in the blood plasma of patients was 310 μg/l (range 164–494 μg/l), and of N-desmethyltamoxifen – 481 μg/l (range 300–851 μg/l).
When treated with tamoxifen at a dose of 40 mg/day, the concentrations of tamoxifen and N-desmethyltamoxifen in tumor tissues were 5.4–117 ng/mg (mean 25.1 ng/mg) protein and 7.8–210 ng/mg (mean 52 ng/mg) protein, respectively. The concentrations of tamoxifen and N-desmethyltamoxifen in plasma were 27–520 ng/ml (mean 300 ng/ml) and 210–761 ng/ml (mean 462 ng/ml), respectively. More than 99% of tamoxifen is bound to plasma proteins.
In humans, tamoxifen is metabolized in the liver and excreted mainly in the bile. The excretion of the parent compound in the urine is very small. The main metabolic pathway of tamoxifen in humans is demethylation to the active metabolite N-desmethyltamoxifen, followed by N-demethylation to the N-desdimethyl metabolite.
The elimination process of tamoxifen is biphasic. In women, the half-life in the initial phase is 7 to 14 hours, and in the terminal phase is approximately 7 days. The half-life of N-desmethyltamoxifen is approximately 14 days.
Clinical response to therapy is observed at plasma tamoxifen concentrations above 70 μg/L.
The pharmacokinetics of tamoxifen and its major metabolites have not been studied in elderly patients, patients with impaired liver function, and when taken on an empty stomach or after a meal.
Indication
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.
Contraindication
Hypersensitivity to tamoxifen or to other components of the drug. Severe thrombocytopenia, leukopenia. Severe hypercalcemia. Simultaneous use of anastrazole and tamoxifen. Pregnancy and breastfeeding.
Interaction with other medicinal products and other types of interactions
When using tamoxifen in combination with other hormonal drugs containing estrogens, the effectiveness of both drugs may be reduced (in particular, the contraceptive effect of the respective drugs may be unreliable).
Concomitant use of tamoxifen and aromatase inhibitors (including anastrazole) in the adjuvant setting has not shown increased efficacy compared with tamoxifen alone. When tamoxifen was coadministered with the aromatase inhibitor letrozole, plasma concentrations of letrozole were reduced by 37%.
Tamoxifen may enhance the effects of coumarin anticoagulants, such as warfarin. Patients taking coumarin anticoagulants with tamoxifen are advised to closely monitor their coagulation status, especially at the beginning of treatment.
The combined use of tamoxifen and platelet aggregation inhibitors may increase the tendency to bleed during a possible thrombocytopenic phase.
An increased incidence of thromboembolic events has been reported with tamoxifen therapy in combination with other cytotoxic drugs.
Drugs that inhibit CYP2D6 reduce the concentration of endoxifen, the active metabolite of tamoxifen, by 65–75%, leading to a decrease in the effectiveness of its therapeutic action. Concomitant use of tamoxifen with some antidepressants - selective serotonin reuptake inhibitors (SSRIs) (e.g. paroxetine) - has been reported to reduce the effectiveness of tamoxifen. Therefore, if possible, the use of potent CYP2D6 inhibitors, such as paroxetine, fluoxetine, quinidine, cinacalcet or bupropion, should be avoided.
The main known route of metabolism of tamoxifen in humans is demethylation mediated by CYP3A4 enzymes. A pharmacokinetic interaction with the CYP3A4 inducer rifampicin is known, resulting in decreased plasma levels of tamoxifen. The clinical significance of this decrease is unknown.
Pharmacokinetic interactions have been reported with CYP2D6 inhibitors, which result in decreased plasma levels of the active metabolite of tamoxifen, 4-hydroxy-N-desmethyltamoxifen (endoxifen).
Application features
Patients with estrogen receptor-positive tumors and postmenopausal patients respond better to tamoxifen therapy.
Tamoxifen should be administered with caution to patients with impaired liver or kidney function, diabetes mellitus, and ophthalmological disorders.
Premenopausal women who use tamoxifen to treat breast cancer may experience cessation of menstruation.
An increased incidence of endometrial changes, including hyperplasia, polyps, carcinoma and uterine sarcoma (predominantly malignant mixed Müllerian tumors) has been reported in patients treated with tamoxifen. The frequency and nature of these changes suggest that they may be due to the estrogenic effects of tamoxifen.
Patients should undergo a gynecological examination before starting treatment and every 6 months thereafter. If any unusual symptoms (including abnormal vaginal bleeding, menstrual irregularities, vaginal discharge, pelvic pain or pressure) occur, a thorough examination should be performed immediately.
Patients taking tamoxifen for breast cancer prevention should be closely monitored for signs of endometrial hyperplasia. If atypical endometrial hyperplasia develops, tamoxifen should be discontinued, appropriate treatment should be initiated, and hysterectomy should be considered before continuing tamoxifen therapy.
Cases of the development of other primary tumors, not located in the endometrium or the contralateral breast, have been reported following tamoxifen treatment for breast cancer. The causal relationship of these events has not been established and the clinical significance of these observations remains unclear.
Visual disturbances, including decreased visual acuity, corneal opacities, cataracts, and retinopathy, have been reported in patients receiving tamoxifen. Therefore, ophthalmological examinations are recommended prior to initiation of therapy and periodically during tamoxifen therapy for early detection of corneal or retinal lesions, which may be reversible upon timely discontinuation of the drug.
If the patient has a history of liver disease, liver function should be closely monitored. All patients should have periodic blood counts (especially platelets), liver and kidney function tests, and serum calcium and glucose levels. Periodic lung and bone X-rays and liver ultrasound are recommended for early detection of possible metastases. Periodic blood counts, including platelets, liver function tests, and serum calcium levels are recommended.
There is evidence that patients with insufficient metabolic biotransformation rates involving CYP2D6 have low levels of endoxifen, one of the major active metabolites of tamoxifen. Concomitant use of drugs that inhibit CYP2D6 may result in decreased concentrations of the active metabolite of endoxifen. Accordingly, if possible, the use of potent 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 increases in patients with high obesity, with increasing age, with concomitant chemotherapy and in the presence of other factors for the development of thromboembolic events. For some patients with breast cancer who have multiple risk factors for venous thromboembolism, long-term anticoagulant treatment should be considered. If a patient develops venous thromboembolism, tamoxifen should be discontinued immediately and antiplatelet therapy should be initiated. Tamoxifen should not be used to treat patients with a history of thromboembolic events.
In delayed microsurgical breast reconstruction, tamoxifen may increase the risk of microvascular complications associated with the transplanted flap.
The effect of food on the absorption of tamoxifen has not been studied. However, it is unlikely that food intake would affect the steady-state pharmacokinetics of tamoxifen.
If the patient has been diagnosed with an intolerance to some sugars, consult a doctor before taking this medicine.
Ability to influence reaction speed when driving vehicles or other mechanisms
Tamoxifen is unlikely to affect the ability to drive or use machines. However, fatigue, drowsiness, and blurred vision have been reported during tamoxifen treatment. Patients experiencing these symptoms should be cautious when driving or using machines.
Use during pregnancy or breastfeeding
Tamoxifen is contraindicated for use during pregnancy or breastfeeding. Isolated cases of spontaneous abortion and congenital malformations have been reported in children whose mothers took tamoxifen during pregnancy, but a causal relationship has not been established.
Before starting tamoxifen therapy, it is necessary to ensure that the patient is not pregnant. Patients of reproductive age should use effective contraception during and for at least 3 months after stopping tamoxifen therapy. Given the possibility of interaction, hormonal contraceptives should not be used.
Tamoxifen at a dose of 20 mg 2 times a day suppresses lactation in women, which does not resume even after the end of therapy. It is not known whether tamoxifen penetrates into breast milk, therefore it is recommended to stop breastfeeding during treatment with this drug.
Method of administration and doses
The recommended daily dose of tamoxifen for adults is 20 mg. In cases of advanced cancer, doses may be increased to 30 mg or 40 mg per day.
The maximum daily dose of tamoxifen is 40 mg. An 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.
The tablets should be swallowed without chewing, with sufficient liquid.
If two or more tablets of the drug are prescribed per day, they can be taken in 1 or 2 doses.
The duration of treatment depends on the severity and course of the disease. Treatment is usually long-term.
Treatment of special patient groups. No dose adjustment is required for elderly patients or patients with impaired liver or kidney function.
Children
Recommendations for tamoxifen treatment of children have not yet been developed.
Overdose
Symptoms: Tamoxifen has been shown to produce estrogenic effects in animals at high doses. In theory, overdose would be expected to cause increased antiestrogenic side effects.
There have been no reports of acute overdose in humans. Little is known about overdose in humans. At doses of 160 mg/m2 and above, ECG changes (prolonged QT interval) occurred, and at doses of 300 mg/m2 daily, neurotoxicity (tremor, hyperreflexia, unsteady gait, and vertigo) occurred.
Treatment: There is no specific antidote. In case of overdose, symptomatic treatment should be carried out.
Adverse reactions
Most of the side effects listed below are reversible, often disappearing after dose reduction.
The frequency of adverse reactions is classified as follows: very common (> 1/10), common (≥ 1/100 - < 1/10), uncommon (≥ 1/1000 - < 1/100), rare (< 1/10000), frequency unknown (cannot be estimated from the available data).
Benign and malignant neoplasms (including cysts and polyps).
Exacerbations of disease have been reported. A small number of patients with bone metastases develop hypercalcemia at the beginning of tamoxifen therapy. During this initial period, bone and tumor pain may increase, as may erythema around skin lesions, indicating a response to therapy. Existing skin lesions may also enlarge or new ones may appear.
Tamoxifen therapy is associated with an increased incidence of endometrial proliferative changes, including polyps and endometrial cancer. The risk of endometrial cancer increases with duration of tamoxifen therapy and is approximately 2–3 times higher than the risk of endometrial cancer in women who have not taken the drug. There is also a slightly increased incidence of uterine sarcoma (predominantly malignant mixed Müllerian tumors). However, the clinical benefit of tamoxifen treatment of breast cancer outweighs the potential risk of endometrial neoplasms.
Common: uterine fibroids.
Uncommon: endometrial cancer.
Rare: uterine sarcoma (mainly mixed Mullerian malignant tumors).
From the reproductive system and mammary glands.
Very common: vaginal discharge, menstrual irregularities and menstrual suppression in the premenopausal period, vaginal bleeding.
Common: genital itching, increase in the size of uterine fibroids, proliferative changes in the endometrium (endometrial neoplasia, hyperplasia and polyps, rarely endometriosis).
Rare: impotence in men, cystic ovarian edema, vaginal polyps.
From the blood and lymphatic system.
Uncommon: leukopenia, transient thrombocytopenia.
Rare: agranulocytosis, neutropenia.
Rare: pancytopenia.
From the immune system.
Common: hypersensitivity reactions.
From the endocrine system.
Very common: hot flashes.
Uncommon: hypercalcemia.
Metabolic disorders.
Very common: fluid retention.
Common: increased serum triglycerides, anorexia.
Rare: severe hypertriglyceridemia, sometimes accompanied by pancreatitis.
Mental disorders.
Rare: depression.
From the nervous system.
Common: dizziness, headache, drowsiness, sensory disturbances (paresthesia, dysgeusia).
From the organs of vision.
Common: decreased visual acuity, corneal opacity, development of cataracts and retinopathy. These effects are likely to be dose-dependent and duration-dependent. They may be partially reversible upon discontinuation of tamoxifen.
Rare: optic neuropathy, optic neuritis (in isolated cases, loss of vision has been observed).
From the vascular system.
Common: flushing, ischemic cerebrovascular events, leg cramps, thrombosis. Tamoxifen therapy in combination with other cytotoxic drugs may increase the risk of thromboembolic events, including venous thromboembolism (deep vein thrombosis, microvascular thrombosis) and pulmonary embolism.
Uncommon: stroke.
Frequency unknown: thrombophlebitis.
On the part of the respiratory system, chest organs and mediastinum.
Uncommon: interstitial pneumonitis.
From the gastrointestinal tract.
Very common: nausea.
Common: vomiting, constipation, diarrhea.
Uncommon: pancreatitis.
Rare: loss of taste sensitivity, appetite disorders.
On the part of the hepatobiliary system.
Common: changes in liver enzymes, fatty liver.
Uncommon: cirrhosis, fatty hepatosis.
Rare: cholestasis, hepatitis, jaundice, necrotizing hepatitis, hepatocellular damage, hepatic failure.
Sometimes more severe liver disorders have led to fatal outcomes.
On the skin and subcutaneous tissue.
Very common: skin rashes.
Common: alopecia, increase in existing or new skin lesions.
Rare: hypertrichosis, cutaneous vasculitis, angioedema.
Rare: Isolated cases of erythema multiforme, Stevens-Johnson syndrome or bullous pemphigoid have been reported, and cases of cutaneous lupus erythematosus have also been reported.
On the part of the musculoskeletal system and connective tissues.
Common: leg cramps, myalgia.
Congenital, hereditary and genetic disorders.
Rare: chronic hematoporphyria.
General effects and local reactions.
Very common: hot flushes, partly due to the anti-estrogenic effect of tamoxifen, fatigue.
Rare: at the beginning of therapy - pain in the bones and in the area of the affected tissue in response to tamoxifen therapy.
Changes in laboratory parameters.
Changes in serum lipid profile, increased activity of liver enzymes.
Injuries, poisoning and procedural complications.
Rare: radiation reactions.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister, 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Limited Liability Company "Pharmaceutical Company "Zdorovya".
Location of the manufacturer and its business address
Ukraine, 61013, Kharkiv region, Kharkiv city, Shevchenko street, building 22.
