Instructions Tamoxifen Sandoz 20 mg film-coated tablets No. 30
Composition
active ingredient: tamoxifen citrate;
1 tablet contains 30.4 mg of tamoxifen citrate (equivalent to 20 mg of tamoxifen);
excipients: lactose monohydrate, sodium starch glycolate (type A), povidone (collidon 25), microcrystalline cellulose, magnesium stearate; shell: Opadry white containing: lactose, titanium dioxide, hydroxypropylmethylcellulose, polyethylene glycol 4000.
Dosage form
Film-coated tablets.
Main physicochemical properties: uniformly white round biconvex tablets, with a score on one side.
Pharmacotherapeutic group
Hormone antagonists and similar drugs. Antiestrogens. ATX code L02B A01.
Pharmacological properties
Pharmacodynamics.
Tamoxifen is a potent nonsteroidal estrogen antagonist. It may also have partial or full agonist properties, depending on the tissue and species. In humans, the predominant antiestrogenic effect is due to tamoxifen binding to the hormone-binding domain of the estrogen receptor and blocking the action of estradiol. Tamoxifen has no androgenic properties. On the other hand, tamoxifen may exert estrogen-like effects in various sites, such as the endometrium (see section "Adverse Reactions"), bone (reduction of bone loss in postmenopausal women) and serum lipids (reduction of LDL cholesterol). The mechanism of action in estrogen receptor-negative (ER-negative) breast cancer is not yet clear. Tamoxifen can be used regardless of menopausal status.
Pharmacokinetics.
Tamoxifen is rapidly absorbed after oral administration. 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 and the metabolite N-desmethyltamoxifen were 42 μg/L and 12 μg/L, respectively, in male volunteers. 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 that of N-desmethyltamoxifen was 481 μg/L (range 300-851 μg/L).
During tamoxifen therapy at a dose of 40 mg/day, the concentrations of tamoxifen and N-desmethyltamoxifen in tumor tissues were 5.4-11 7 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 blood plasma were 27-520 ng/mg (mean 300 ng/mg) and 210-761 ng/mg (mean 462 ng/mg), respectively. More than 99% of tamoxifen is bound to blood 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 insignificant. Tamoxifen is extensively metabolized by hydroxylation and demethylation, as well as conjugation with the participation of the cytochrome P450 system. The formation of the main metabolite N-desmethyltamoxifen is mainly catalyzed by CYP3A4. N-desmethyltamoxifen is further metabolized to endoxifen with the participation of CYP2D6. In patients with CYP2D6 deficiency (so-called "slow" metabolizers), endoxifen concentrations are approximately 75% lower than in patients with normal CYP2D6 activity.
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 - about 7 days. The half-life of N-desmethyltamoxifen is about 14 days.
Clinical response to therapy is observed at a plasma tamoxifen concentration of more than 70 μg/L.
The pharmacokinetics of tamoxifen and its main metabolites in elderly patients, patients with impaired liver function, and when taken on an empty stomach and after eating have apparently not been studied.
Indication
Adjuvant chemotherapy for breast cancer;
palliative therapy of metastatic breast cancer;
Palliative therapy of locally advanced breast cancer.
Contraindication
Hypersensitivity to tamoxifen or to other components of the drug.
Severe thrombocytopenia, leukopenia.
Severe hypercalcemia.
Concomitant use of anastrazole and tamoxifen.
Pregnancy and the breastfeeding period.
Interaction with other medicinal products and other types of interactions
When using tamoxifen in combination with other hormonal drugs containing estrogens, a decrease in the effectiveness of both drugs is possible (in particular, an unreliable contraceptive effect of the corresponding drugs).
An increased incidence of thromboembolic events has been reported with tamoxifen therapy in combination with other chemotherapy drugs.
The use of tamoxifen in combination with coumarin anticoagulants, for example, warfarin, may significantly enhance the anticoagulant effect. Patients taking coumarin anticoagulants with tamoxifen are advised to closely monitor their coagulation status, especially at the beginning of treatment.
Tamoxifen is metabolized to its active metabolite endoxifen by CYP2D6. Thus, CYP2D6 inhibitors may have a clinically significant effect on tamoxifen metabolism and may result in reduced or no efficacy of Tamoxifen Sandoz®. In addition, CYP3A4 and, to a lesser extent, CYP2C9 and CYP2C19 are also involved in tamoxifen metabolism.
The simultaneous use of tamoxifen and aromatase inhibitors during adjuvant therapy has not shown increased efficacy compared with the use of tamoxifen alone.
The main known pathway of tamoxifen metabolism in humans is demethylation by CYP3A4 enzymes. A pharmacokinetic interaction with the CYP3A4 inducer rifampicin has been reported in the literature, resulting in decreased plasma levels of tamoxifen. The clinical significance of this decrease is unknown.
Pharmacokinetic interactions with CYP2D6 inhibitors have been reported in the literature, which reduce the plasma levels of the active metabolite of tamoxifen, 4-hydroxy-N-desmethyltamoxifen (endoxifen).
Drugs that inhibit the action of cytochrome CYP2D6 reduce the concentration of endoxifen, the active metabolite of tamoxifen, by 65-75%, which leads to a decrease in the effectiveness of its therapeutic effect. In the course of separate studies, with simultaneous use of the drug with some antidepressants - selective serotonin reuptake inhibitors (SSRIs) (for example, paroxetine) - a decrease in the effectiveness of tamoxifen was noted. Therefore, if possible, the use of potent inhibitors of cytochrome CYP2D6, such as paroxetine, fluoxetine, quinidine, cinacalcet or bupropion, should be avoided.
When using anastrazole during tamoxifen treatment, no increased efficacy was observed compared to tamoxifen alone.
When tamoxifen and the aromatase inhibitor letrozole were coadministered, plasma concentrations of letrozole decreased by 37%.
Concomitant therapy with bromocriptine increases the serum concentrations of tamoxifen and its active metabolite N-desmethyltamoxifen.
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, a history of thromboembolic diseases, 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 Mullerian 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.
Before starting treatment, and every 6 months thereafter, patients should undergo a gynecological examination. If any unusual symptoms (including abnormal vaginal bleeding, menstrual irregularities, vaginal discharge, pain or pressure in the pelvic area) occur, a thorough examination should be performed immediately.
Patients taking tamoxifen for breast cancer prophylaxis should be monitored closely for signs of possible 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.
In clinical trials, cases of the development of other primary tumors, localized not in the endometrium or in the contralateral breast, have been observed after 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 damage, which may be reversible upon discontinuation of the drug.
If the patient has a history of liver disease, liver function should be carefully monitored. All patients should periodically determine the number of formed blood elements (especially platelets), liver and kidney function, and serum calcium and glucose levels. 3 In order to early detect possible metastases, it is recommended to periodically conduct X-ray examinations of the lungs and bones, as well as ultrasound of the liver.
3 It is known from published sources that patients with insufficient metabolic biotransformation rate involving cytochrome CYP2D6 have low levels of endoxifen, one of the most important active metabolites of tamoxifen. Concomitant use of drugs that inhibit the action of cytochrome CYP2D6 may lead to a decrease in the concentration of the active metabolite of endoxifen. Accordingly, if possible, the use of potent inhibitors of cytochrome CYP2D6, such as paroxetine, fluoxetine, quinidine, cinacalcet or bupropion, should be avoided during tamoxifen therapy.
Treatment with tamoxifen 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 use of tamoxifen may give positive results in doping tests.
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.
The drug contains lactose, which should be taken into account by patients with lactose and galactose intolerance.
Severe skin adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with tamoxifen treatment. Patients should be advised of the signs and symptoms of severe skin reactions and monitored closely when prescribing the drug. If signs and symptoms suggestive of these reactions occur, the drug should be discontinued immediately and alternative therapy should be considered (if necessary). If a patient develops a serious reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis while taking tamoxifen, treatment with the drug should be stopped immediately and never used again.
In patients with hereditary angioedema, tamoxifen may induce or exacerbate symptoms of angioedema.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially “sodium-free”.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding
Tamoxifen Sandoz® is contraindicated 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.
The results of reproductive studies in rats, rabbits, and monkeys indicate no teratogenic potential.
In reproductive studies in rats, conducted to monitor intrauterine development of the reproductive tract, tamoxifen produced changes similar to those seen with estradiol, ethinylestradiol, clomiphene, and diethylstilbestrol (DES). The clinical significance of these changes is unknown. Some of these changes, including vaginal adenosis, have also been observed in women exposed to DES in utero; these women have a 1 in 1,000 risk of developing clear cell carcinoma of the cervix or vagina. There is insufficient information on the use of tamoxifen during pregnancy. There have been no reports of vaginal adenosis or cervical or vaginal cancer following prenatal exposure to tamoxifen.
Before starting tamoxifen therapy, it is necessary to ensure that the patient is not pregnant. Patients of reproductive age should use effective contraceptive methods, use mechanical or other non-hormonal methods of contraception. Women should be informed of the possible risk to the fetus during and for at least 9 months after the end of treatment with Tamoxifen Sandoz®. Given the possibility of interaction, hormonal contraceptives should not be used.
Tamoxifen at a dose of 20 mg twice daily suppresses lactation in women, which is not restored even after the end of therapy. Limited data indicate that tamoxifen and its active metabolites are excreted in breast milk, where they accumulate over time, so the drug is not recommended for use during breastfeeding. A decision on whether to discontinue breastfeeding or to discontinue tamoxifen therapy should take into account the importance of the drug to the woman.
Ability to influence the speed of reactions 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.
Method of administration and doses
Usual dosage
Adjuvant therapy: 1 x 20 mg per day.
Palliative therapy: 1 x 20-40 per day.
In the case of adjuvant therapy, the recommended duration of treatment is 5 years. The benefit of longer therapy has not yet been established.
Dose adjustments due to side effects/interactions
In case of serious side effects, the dose should be reduced. In case of no improvement, treatment should be discontinued.
Special dosage instructions
Dose adjustment based on age is not necessary.
There are no dosage data in patients with hepatic or renal insufficiency.
Method of application
The film-coated tablets should always be taken at the same time of day, for example, with breakfast. The medicine can be taken before, during or after a meal.
Children.
Tamoxifen Sandoz® is not intended for use in children and adolescents.
Overdose
Symptoms of overdose.
There are no reports of acute overdose in humans. A study in patients with advanced metastatic breast cancer determined the maximum tolerated dose of tamoxifen. These patients received initial doses of >400 mg/m2. Therapy was maintained at 150 mg/m2 twice daily. Neurotoxic symptoms observed occurred within 3-5 days of initiation of therapy and resolved 2-5 days after discontinuation of tamoxifen therapy. No persistent neurological toxicity was observed. In the same study, cases of prolongation of the QT interval on the ECG were reported with tamoxifen at multiples of the standard dose (starting dose: > 250 mg/m2, maintenance dose: 80 mg/m2 twice daily).
Therapeutic measures in case of overdose.
There is no specific antidote. In case of overdose, symptomatic treatment is carried out.
Side effects
Most of the side effects listed below are reversible, often disappearing after dose reduction.
The following categories are used to indicate the frequency of adverse reactions:
Very common (≥ 1/10), common (≥ 1/100 - <1/10), uncommon (≥ 1/1000 - <1/100), isolated (≥ 1/10000 - <1/1000), rare (<1/10000), unknown (cannot be estimated from the available data).
Infections and invasions.
Bullous pemphigoid.
Benign and malignant neoplasms (including bones and polyps).
Exacerbations of disease have been reported. A small number of patients with bone metastases develop hypercalcemia at the start 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 worsen 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 the duration of tamoxifen therapy and is approximately 2-3 times greater than the risk of endometrial cancer in women who have not taken the drug. There is also a slight increase in the incidence of uterine sarcoma (predominantly malignant mixed Mullerian 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).
3 sides of the blood system and lymphatic system.
Common: transient anemia.
Uncommon: leukopenia, transient thrombocytopenia.
Rare: agranulocytosis, neutropenia.
Isolated: pancytopenia.
From the immune system.
Common: hypersensitivity reactions, angioedema.
From the endocrine system.
Very common: hot flashes.
Uncommon: hypercalcemia.
Metabolic disorders.
Very common: fluid retention.
Common: increased serum triglycerides, anorexia.
Isolated: severe hypertriglyceridemia, sometimes accompanied by pancreatitis.
3 sides of the nervous system.
Common: dizziness, headache, drowsiness, sensory disturbances (paresthesia, dysgeusia).
Mental disorders.
Rare: depression.
3 sides of the organs of vision.
Common: decreased visual acuity, corneal opacity, development of cataracts and retinopathy. These effects are likely to be dose- and duration-dependent. They may be partially reversible after discontinuation of tamoxifen.
Rare: optic neuropathy, optic neuritis (in isolated cases, loss of vision has been observed).
3 sides of the vascular system.
Common: flushing, ischemic cerebrovascular events, lower limb apoplexy, thrombosis, stroke. During therapy: tamoxifen 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.
Not known: thrombophlebitis.
From the respiratory system, chest and mediastinal organs.
Uncommon: interstitial pneumonitis.
3 sides of the gastrointestinal tract.
Very common: nausea
Common: vomiting, constipation, diarrhea.
Rare: loss of taste sensitivity, appetite disorders.
3 sides of the hepatobiliary system.
Common: changes in liver enzymes, fatty infiltration of the liver.
Uncommon: cirrhosis, fatty hepatosis.
Uncommon: cholestasis, hepatitis, jaundice, necrotizing hepatitis, hepatocellular damage,
liver failure.
Sometimes more severe liver disorders led to fatal consequences.
3 sides of the skin and subcutaneous tissues.
Very common: skin rashes (including isolated cases of erythema multiforme or bullous pemphigoid have been reported).
Common: alopecia, hypersensitivity reactions, worsening of existing or new skin lesions.
Rare: hypertrichosis, erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, cutaneous vasculitis, angioneurotic edema, toxic epidermal necrolysis.
Isolated cases of cutaneous lupus erythematosus have also been reported.
Not known: exacerbation of hereditary angioedema.
3 sides of the musculoskeletal system and connective tissues.
Common: leg cramps, myalgia.
3 sides of the reproductive system and mammary glands.
Very common: vaginal discharge, menstrual irregularities and menstrual suppression in the premenopausal period, vaginal bleeding.
Common: genital itching, uterine fibroid enlargement, endometrial proliferative disorders (endometrial neoplasia, hyperplasia and polyps, rarely endometriosis).
Uncommon: endometrial cancer.
Rare: male impotence, cystic ovarian edema, uterine sarcoma (predominantly mixed Mullerian malignancies), vaginal polyps.
Congenital hereditary and genetic disorders.
Isolated: 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 the lipid profile of blood serum, increased activity of liver enzymes.
Injury, poisoning and procedural complications
Single: radiation reactions.
Expiration date
5 years.
Storage conditions
Store in the original packaging at room temperature (15-25 °C) to protect from light. Keep out of the reach of children.
Packaging
10 film-coated tablets in a blister; 3 or 10 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Salutas Pharma GmbH.
Location of products and address of their place of business
Otto-von-Güriche-Allee 1, 39179, Barleben, Germany.
