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Indications/Uses
Tamoxifen is indicated in the treatment of breast cancer.
Dosage/Direction for Use
Posology: Breast Cancer: Adults (including older people): The dosage range is 20 to 40 mg daily, given either in divided doses twice daily or as a single dose once daily. In early disease, it is currently recommended that treatment is given for not less than 5 years. The optimal duration of Tamoxifen (TAMOXEN) therapy remains to be determined.
Pediatric population: The use of Tamoxifen (TAMOXEN) is not recommended in children, as safety and efficacy have not been established.
Method of administration: For administration by the oral route.
Pediatric population: The use of Tamoxifen (TAMOXEN) is not recommended in children, as safety and efficacy have not been established.
Method of administration: For administration by the oral route.
Overdosage
On theoretical grounds, overdosage would be expected to cause enhancement of the anti-oestrogenic side effects mentioned previously. Observations in animals show that extreme overdosage (100-200 times recommended daily dose) may produce oestrogenic effects.
There have been reports in the literature that Tamoxifen (TAMOXEN) given at several times the standard dose may be associated with prolongation of the QT interval of the ECG. There is no specific antidote to overdosage and treatment must be symptomatic.
There have been reports in the literature that Tamoxifen (TAMOXEN) given at several times the standard dose may be associated with prolongation of the QT interval of the ECG. There is no specific antidote to overdosage and treatment must be symptomatic.
Administration
May be taken with or without food.
Contraindications
Tamoxifen (TAMOXEN) should not be used in the following: Pregnancy: There have been a small number of reports of spontaneous abortions, birth defects and foetal deaths after women have taken Tamoxifen (TAMOXEN), although no causal relationship has been established.
Hypersensitivity to the active substance, or to any of the excipients.
Hypersensitivity to the active substance, or to any of the excipients.
Special Precautions
Menstruation is suppressed in a proportion of premenopausal women receiving Tamoxifen (TAMOXEN) for the treatment of breast cancer.
An increased incidence of endometrial cancer and uterine sarcoma (mostly malignant mixed Mullerian tumors) has been reported in association with Tamoxifen (TAMOXEN) treatment. The underlying mechanism is unknown, but may be related to the oestrogen-like effect of Tamoxifen (TAMOXEN). Any patients receiving or having previously received Tamoxifen (TAMOXEN), who report abnormal gynaecological symptoms, especially vaginal bleeding, should be promptly investigated.
Nonetheless, the possibility that Tamoxifen (TAMOXEN) may affect the development of endometrial pathology, including neoplasia, should be kept in mind when designing treatment regimens.
Investigations in different in vivo and in vitro systems have shown that Tamoxifen (TAMOXEN) has a genotoxic potential following hepatic activation. Gonadal tumors in mice and liver tumors in rats receiving Tamoxifen (TAMOXEN) have been reported in long-term studies. The clinical relevance of these findings has not been established.
A number of second primary tumours, occurring at sites other than the endometrium and the opposite breast, have been reported in clinical trials, following the treatment of breast cancer patients with Tamoxifen (TAMOXEN). No causal link has been established and the clinical significance of these observations remains unclear.
In delayed microsurgical breast reconstruction Tamoxifen (TAMOXEN) may increase the risk of microvascular flap complications. In an uncontrolled trial in 28 girls aged 2-10 years with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration, mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. While this finding is in line with the pharmacodynamic properties of Tamoxifen (TAMOXEN), a causal relationship has not been established.
Tamoxifen (TAMOXEN) contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
In the literature it has been shown that CYP2D6 poor metabolisers have a lowered plasma level of endoxifen, one of the most important active metabolites of Tamoxifen (TAMOXEN).
Concomitant medications that inhibit CYP2D6 may lead to reduced concentrations of the active metabolite endoxifen. Therefore, potent inhibitors of CYP2D6 (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided during Tamoxifen (TAMOXEN) treatment.
Effects on ability to drive and use machines: Tamoxifen (TAMOXEN) is unlikely to impair the ability of patients to drive or use machinery. However, fatigue has been reported with the use of Tamoxifen (TAMOXEN) and caution should be observed when driving or using machinery while such symptoms persist.
An increased incidence of endometrial cancer and uterine sarcoma (mostly malignant mixed Mullerian tumors) has been reported in association with Tamoxifen (TAMOXEN) treatment. The underlying mechanism is unknown, but may be related to the oestrogen-like effect of Tamoxifen (TAMOXEN). Any patients receiving or having previously received Tamoxifen (TAMOXEN), who report abnormal gynaecological symptoms, especially vaginal bleeding, should be promptly investigated.
Nonetheless, the possibility that Tamoxifen (TAMOXEN) may affect the development of endometrial pathology, including neoplasia, should be kept in mind when designing treatment regimens.
Investigations in different in vivo and in vitro systems have shown that Tamoxifen (TAMOXEN) has a genotoxic potential following hepatic activation. Gonadal tumors in mice and liver tumors in rats receiving Tamoxifen (TAMOXEN) have been reported in long-term studies. The clinical relevance of these findings has not been established.
A number of second primary tumours, occurring at sites other than the endometrium and the opposite breast, have been reported in clinical trials, following the treatment of breast cancer patients with Tamoxifen (TAMOXEN). No causal link has been established and the clinical significance of these observations remains unclear.
In delayed microsurgical breast reconstruction Tamoxifen (TAMOXEN) may increase the risk of microvascular flap complications. In an uncontrolled trial in 28 girls aged 2-10 years with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration, mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. While this finding is in line with the pharmacodynamic properties of Tamoxifen (TAMOXEN), a causal relationship has not been established.
Tamoxifen (TAMOXEN) contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
In the literature it has been shown that CYP2D6 poor metabolisers have a lowered plasma level of endoxifen, one of the most important active metabolites of Tamoxifen (TAMOXEN).
Concomitant medications that inhibit CYP2D6 may lead to reduced concentrations of the active metabolite endoxifen. Therefore, potent inhibitors of CYP2D6 (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided during Tamoxifen (TAMOXEN) treatment.
Effects on ability to drive and use machines: Tamoxifen (TAMOXEN) is unlikely to impair the ability of patients to drive or use machinery. However, fatigue has been reported with the use of Tamoxifen (TAMOXEN) and caution should be observed when driving or using machinery while such symptoms persist.
Use In Pregnancy & Lactation
Pregnancy: Tamoxifen (TAMOXEN) must not be administered during pregnancy. There have been a small number of reports of spontaneous abortions, birth defects and foetal deaths after women have taken Tamoxifen (TAMOXEN), although no causal relationship has been established.
Reproductive toxicology studies in rats, rabbits and monkeys have shown no teratogenic potential.
In rodent models of foetal reproductive tract development, Tamoxifen (TAMOXEN) was associated with changes similar to those caused by oestradiol, ethinylestradiol, clomiphene and diethylstilboestrol (DES). Although the clinical relevance of these changes is unknown, some of them, especially vaginal adenosis, are similar to those seen in young women who were exposed to DES in utero and who have a 1 in 1000 risk of developing clear-cell carcinoma of the vagina or cervix. Only a small number of pregnant women have been exposed to Tamoxifen (TAMOXEN). Such exposure has not been reported to cause subsequent vaginal adenosis or clear-cell carcinoma of the vagina or cervix in young women exposed in utero to Tamoxifen (TAMOXEN).
Women should be advised not to become pregnant whilst taking Tamoxifen (TAMOXEN) and should use barrier or other non-hormonal contraceptive methods if sexually active. Premenopausal patients must be carefully examined before treatment to exclude pregnancy. Women should be appraised of the potential risks to the foetus, should they become pregnant whilst taking Tamoxifen (TAMOXEN) or within two months of cessation of therapy.
Breast-feeding: It is not known if Tamoxifen (TAMOXEN) is excreted in human milk and therefore the drug is not recommended during breast-feeding. The decision either to discontinue nursing or discontinue Tamoxifen (TAMOXEN) should take into account the importance of the drug to the mother.
Reproductive toxicology studies in rats, rabbits and monkeys have shown no teratogenic potential.
In rodent models of foetal reproductive tract development, Tamoxifen (TAMOXEN) was associated with changes similar to those caused by oestradiol, ethinylestradiol, clomiphene and diethylstilboestrol (DES). Although the clinical relevance of these changes is unknown, some of them, especially vaginal adenosis, are similar to those seen in young women who were exposed to DES in utero and who have a 1 in 1000 risk of developing clear-cell carcinoma of the vagina or cervix. Only a small number of pregnant women have been exposed to Tamoxifen (TAMOXEN). Such exposure has not been reported to cause subsequent vaginal adenosis or clear-cell carcinoma of the vagina or cervix in young women exposed in utero to Tamoxifen (TAMOXEN).
Women should be advised not to become pregnant whilst taking Tamoxifen (TAMOXEN) and should use barrier or other non-hormonal contraceptive methods if sexually active. Premenopausal patients must be carefully examined before treatment to exclude pregnancy. Women should be appraised of the potential risks to the foetus, should they become pregnant whilst taking Tamoxifen (TAMOXEN) or within two months of cessation of therapy.
Breast-feeding: It is not known if Tamoxifen (TAMOXEN) is excreted in human milk and therefore the drug is not recommended during breast-feeding. The decision either to discontinue nursing or discontinue Tamoxifen (TAMOXEN) should take into account the importance of the drug to the mother.
Adverse Reactions
Tabulated list of adverse reactions: Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women patients with operable breast cancer treated for 5 years and unless specified, no account was taken of the frequency within the comparative treatment group or whether the investigator considered it to be related to study medication.
Adverse drug reactions (ADRs) can be classified as either due to the pharmacological action of the drug, e.g. hot flushes, vaginal bleeding, vaginal discharge and pruritus vulvae, or as more general ADRs e.g. nausea, fluid retention and skin rash. When such side effects are severe, it may be possible to control them by a simple reduction of dosage (within the recommended dose range) without loss of control of the disease.
This adverse drug reaction was not reported in the Tamoxifen arm (n=3094) of the previously mentioned study; however, it has been reported in other trials or from other sources. (See table.)
Adverse drug reactions (ADRs) can be classified as either due to the pharmacological action of the drug, e.g. hot flushes, vaginal bleeding, vaginal discharge and pruritus vulvae, or as more general ADRs e.g. nausea, fluid retention and skin rash. When such side effects are severe, it may be possible to control them by a simple reduction of dosage (within the recommended dose range) without loss of control of the disease.
This adverse drug reaction was not reported in the Tamoxifen arm (n=3094) of the previously mentioned study; however, it has been reported in other trials or from other sources. (See table.)
Drug Interactions
When Tamoxifen (TAMOXEN) is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration is initiated, careful monitoring of the patient is recommended.
When Tamoxifen (TAMOXEN) is used in combination with cytotoxic agents, there is increased risk of thromboembolic events occurring.
The use of Tamoxifen (TAMOXEN) in combination with anastrozole as adjuvant therapy has not shown improved efficacy compared with Tamoxifen (TAMOXEN) alone.
The known principal pathway for Tamoxifen (TAMOXEN) metabolism in humans is demethylation, catalysed by CYP3A4 enzymes. Pharmacokinetic interaction with the CYP3A4 inducing agent rifampicin, showing a reduction in Tamoxifen (TAMOXEN) in plasma levels have been reported in the literature. The relevance of this finding is not known.
Pharmacokinetic interaction with CYP2D6 inhibitors, showing a reduction in plasma level of an active Tamoxifen (TAMOXEN) metabolite, 4-hydroxy-Ndesmethyltamoxifen (endoxifen), has been reported in the literature.
Pharmacokinetic interaction with CYP2D6 inhibitors, showing a 65-75% reduction in plasma levels of one of the more active forms of the drug, i.e. endoxifen, has been reported in the literature. Reduced efficacy of Tamoxifen (TAMOXEN) has been reported with concomitant usage of some SSRI antidepressants (e.g. paroxetine) in some studies. As a reduced effect of Tamoxifen (TAMOXEN) cannot be excluded, co-administration with potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided.
When Tamoxifen (TAMOXEN) is used in combination with cytotoxic agents, there is increased risk of thromboembolic events occurring.
The use of Tamoxifen (TAMOXEN) in combination with anastrozole as adjuvant therapy has not shown improved efficacy compared with Tamoxifen (TAMOXEN) alone.
The known principal pathway for Tamoxifen (TAMOXEN) metabolism in humans is demethylation, catalysed by CYP3A4 enzymes. Pharmacokinetic interaction with the CYP3A4 inducing agent rifampicin, showing a reduction in Tamoxifen (TAMOXEN) in plasma levels have been reported in the literature. The relevance of this finding is not known.
Pharmacokinetic interaction with CYP2D6 inhibitors, showing a reduction in plasma level of an active Tamoxifen (TAMOXEN) metabolite, 4-hydroxy-Ndesmethyltamoxifen (endoxifen), has been reported in the literature.
Pharmacokinetic interaction with CYP2D6 inhibitors, showing a 65-75% reduction in plasma levels of one of the more active forms of the drug, i.e. endoxifen, has been reported in the literature. Reduced efficacy of Tamoxifen (TAMOXEN) has been reported with concomitant usage of some SSRI antidepressants (e.g. paroxetine) in some studies. As a reduced effect of Tamoxifen (TAMOXEN) cannot be excluded, co-administration with potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacotherapeutic group: Anti-estrogens. ATC Code: L02BA01.
Pharmacology: Pharmacodynamics: Tamoxifen (TAMOXEN) is a non-steroidal, triphenylethylene-based drug which displays a complex spectrum of oestrogen antagonist and oestrogen agonist-like pharmacological effects in different tissues. In breast cancer patients, at the tumour level, Tamoxifen (TAMOXEN) acts primarily as an antioestrogen, preventing oestrogen binding to the oestrogen receptor. In women with oestrogen receptor positive/unknown breast tumors, adjuvant Tamoxifen (TAMOXEN) has been shown to significantly reduce recurrence of the disease and improve 10-year survival, achieving a significantly greater effect with five years treatment than with 1 or 2 years treatment. These benefits appear to be largely irrespective of age, menopausal status, Tamoxifen (TAMOXEN) dose and additional chemotherapy.
In the clinical situation, it is recognized that Tamoxifen (TAMOXEN) leads to reduction in levels of blood total cholesterol and low density lipoproteins in postmenopausal women of the order of 10-20 %. Additionally Tamoxifen (TAMOXEN) has been reported to lead to maintenance of bone mineral density in postmenopausal women.
An uncontrolled trial was undertaken in a heterogeneous group of 28 girls aged 2 to 10 years with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration. Among the patients who reported vaginal bleeding during the pre-study period, 62% (13 out of 21 patients) reported no bleeding for a 6 month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. While this finding is in line with the pharmacodynamic properties of Tamoxifen (TAMOXEN), a causal relationship has not been established. There are no long-term safety data in children. In particular, the long term effects of Tamoxifen (TAMOXEN) on growth, puberty, and general development have not been studied.
CYP2D6 polymorphism status may be associated with variability in clinical response to Tamoxifen (TAMOXEN). The poor metaboliser status may be associated with reduced response. The consequences of the findings for the treatment of CYP2D6 poor metabolisers have not been fully elucidated.
CYP2D6 genotype: Available clinical data suggest that patients who are homozygote for non-functional CYP2D6 alleles, may experience reduced effect of Tamoxifen in the treatment of breast cancer.
The available studies have mainly been performed in postmenopausal women.
Pharmacodynamic properties: After oral administration, Nolvadex is absorbed rapidly with maximum serum concentrations attained within 4-7 hours. Steady state concentrations (about 300 ng/mL) are achieved after four weeks treatment with 40 mg daily. The drug is highly protein bound to serum albumin (>99%). Metabolism is by hydroxylation, demethylation and conjugation, giving rise to several metabolites which have a similar pharmacological profile to the parent compound and thus contribute to the therapeutic effect. Excretion occurs primarily via the faeces and an elimination half-life of approximately seven days has been calculated for the drug itself, whereas that for N-desmethyltamoxifen, the principal circulating metabolite, is 14 days.
In a clinical study where girls between 2 and 10 years with McCune Albright Syndrome (MAS) received 20 mg Tamoxifen (TAMOXEN) once a day for up to 12 months duration, there was an age-dependent decrease in clearance and an increase in exposure (AUC), (with values up to 50% higher in the youngest patients) compared with adults.
Tamoxifen (TAMOXEN) is metabolised mainly via CYP3A4 to N-desmethyl-tamoxifen, which is further metabolised by CYP2D6 to another active metabolite endoxifen. In patients who lack the enzyme CYP2D6 endoxifen concentrations are approximately 75% lower than in patients with normal CYP2D6 activity. Administration of strong CYP2D6 inhibitors reduces endoxifen circulating levels to a similar extent.
Pharmacology: Pharmacodynamics: Tamoxifen (TAMOXEN) is a non-steroidal, triphenylethylene-based drug which displays a complex spectrum of oestrogen antagonist and oestrogen agonist-like pharmacological effects in different tissues. In breast cancer patients, at the tumour level, Tamoxifen (TAMOXEN) acts primarily as an antioestrogen, preventing oestrogen binding to the oestrogen receptor. In women with oestrogen receptor positive/unknown breast tumors, adjuvant Tamoxifen (TAMOXEN) has been shown to significantly reduce recurrence of the disease and improve 10-year survival, achieving a significantly greater effect with five years treatment than with 1 or 2 years treatment. These benefits appear to be largely irrespective of age, menopausal status, Tamoxifen (TAMOXEN) dose and additional chemotherapy.
In the clinical situation, it is recognized that Tamoxifen (TAMOXEN) leads to reduction in levels of blood total cholesterol and low density lipoproteins in postmenopausal women of the order of 10-20 %. Additionally Tamoxifen (TAMOXEN) has been reported to lead to maintenance of bone mineral density in postmenopausal women.
An uncontrolled trial was undertaken in a heterogeneous group of 28 girls aged 2 to 10 years with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration. Among the patients who reported vaginal bleeding during the pre-study period, 62% (13 out of 21 patients) reported no bleeding for a 6 month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. While this finding is in line with the pharmacodynamic properties of Tamoxifen (TAMOXEN), a causal relationship has not been established. There are no long-term safety data in children. In particular, the long term effects of Tamoxifen (TAMOXEN) on growth, puberty, and general development have not been studied.
CYP2D6 polymorphism status may be associated with variability in clinical response to Tamoxifen (TAMOXEN). The poor metaboliser status may be associated with reduced response. The consequences of the findings for the treatment of CYP2D6 poor metabolisers have not been fully elucidated.
CYP2D6 genotype: Available clinical data suggest that patients who are homozygote for non-functional CYP2D6 alleles, may experience reduced effect of Tamoxifen in the treatment of breast cancer.
The available studies have mainly been performed in postmenopausal women.
Pharmacodynamic properties: After oral administration, Nolvadex is absorbed rapidly with maximum serum concentrations attained within 4-7 hours. Steady state concentrations (about 300 ng/mL) are achieved after four weeks treatment with 40 mg daily. The drug is highly protein bound to serum albumin (>99%). Metabolism is by hydroxylation, demethylation and conjugation, giving rise to several metabolites which have a similar pharmacological profile to the parent compound and thus contribute to the therapeutic effect. Excretion occurs primarily via the faeces and an elimination half-life of approximately seven days has been calculated for the drug itself, whereas that for N-desmethyltamoxifen, the principal circulating metabolite, is 14 days.
In a clinical study where girls between 2 and 10 years with McCune Albright Syndrome (MAS) received 20 mg Tamoxifen (TAMOXEN) once a day for up to 12 months duration, there was an age-dependent decrease in clearance and an increase in exposure (AUC), (with values up to 50% higher in the youngest patients) compared with adults.
Tamoxifen (TAMOXEN) is metabolised mainly via CYP3A4 to N-desmethyl-tamoxifen, which is further metabolised by CYP2D6 to another active metabolite endoxifen. In patients who lack the enzyme CYP2D6 endoxifen concentrations are approximately 75% lower than in patients with normal CYP2D6 activity. Administration of strong CYP2D6 inhibitors reduces endoxifen circulating levels to a similar extent.
MedsGo Class
Cancer Hormone Therapy
Features
Dosage
20mg
Ingredients
- Tamoxifen
Packaging
Film-Coated Tablet 1's
Generic Name
Tamoxifen Citrate
Registration Number
DRP-6772
Classification
Prescription Drug (RX)
Product Questions
Questions
