Tamoxifene

Uses

Tamoxifene is used for the treatment of breast cancer.

Tamoxifene is a praparation of Tamoxifene which is a non-steroidal, triphenylene based drug and displays a complex spectrum of oestrogen antagonist and oestrogen agonist like pharmacological effects in different tissues. In breast cancer patients, at the tumour level, Tamoxifene acts primarily as an antioestrogen, preventing oestrogen binding to the oestrogen receptor. Additionally Tamoxifene has been reported to lead to maintenance of bone mineral density in post-menopausal women.

Tamoxifene is also used to associated treatment for these conditions: Breast Cancer, Desmoid Tumors, Endometrial Cancer, Gynecomastia, Invasive Breast Cancer, Invasive Breast Carcinoma, Metastatic Breast Cancer, Ovarian Cancer, Puberty, Precocious, Ovulation induction therapy

How Tamoxifene works

Tamoxifene competitively inhibits estrogen binding to its receptor, which is critical for it's activity in breast cancer cells. Tamoxifene leads to a decrease in tumor growth factor α and insulin-like growth factor 1, and an increase in sex hormone binding globulin. The increase in sex hormon binding globulin limits the amount of freely available estradiol. These changes reduce levels of factors that stimulate tumor growth.

Tamoxifene has also been shown to induce apoptosis in estrogen receptor positive cells. This action is thought to be the result of inhibition of protein kinase C, which prevents DNA synthesis. Alternate theories for the apoptotic effect of tamoxifen comes from the approximately 3 fold increase in intracellular and mitochondrial calcium ion levels after administration or the induction of tumor growth factor β.

Dosage

Tamoxifene dosage

Adults (including elderly): The dosage range is 20 to 40 mg daily, given either in divided doses twice daily or as a single dose once daily.

Side Effects

Side effects can be classified as either due to the pharmacological action of the drug, e.g., hot flushes, vaginal bleeding, vaginal discharge, pruritus vulvae and tumour flare or as more general side effects, e.g., gastrointestinal intolerance, headache, light-headedness and occasionally fluid retention and alopecia. 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.

Skin rashes including isolated reports of erythema multiforme, Stevens Johnson syndrome and bullous pemphigoid and rare hypersensitivity reactions, including angio-oedema have been reported. A small number of patients with bony metastases have developed hypercalcaemia on initiation of therapy.

Falls in platelet count, usually only to 80,000-90,000 per/mm3 but occasionally lower, have been reported in patients taking Tamoxifene for breast cancer.

A number of cases of visual disturbances including infrequent reports of corneal changes and retinopathy have been described in patients receiving Tamoxifene therapy. An increased incidence of cataracts has been reported in association with the administration of the drug. Uterine fibroids and endometrial changes including hyperplasia and polyps have been reported. Cystic ovarian swellings have occasionally been observed in premenopausal women receiving Tamoxifene.

Leucopenia has been observed following the administration of Tamoxifene, sometimes in association with anaemia and/or thrombocytopenia. Neutropenia has been reported on rare occasions; this can sometimes be severe. There is evidence of an increased incidence of thromboembolic events including deep vein thrombosis and pulmonary embolism during Tamoxifene therapy.

Tamoxifene has been associated with changes in liver enzyme levels and on rare occasions with a spectrum of more severe liver abnormalities, including fatty liver, cholestasis and hepatitis. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of Tamoxifene.

Toxicity

High doses of tamoxifen in animals lead to respiratory difficulty and convulsions. High doses in advanced metastatic cancer patients resulted in acute neurotoxicity seen by tremor, hyperreflexia, unsteady gait, and dizziness. Patients experiencing and overdose should be given supportive treatment as no specific treatment for overdose is suggested.

Precaution

Menstruation is suppressed in a proportion of premenopausal women receiving Tamoxifene for the treatment of breast cancer. An increased incidence of endometrial cancer has seen reported in association with Tamoxifene treatment. The underlying mechanism is unknown, but may be related to the oestrogen-like effect of Tamoxifene. Any patients receiving or having previously received Tamoxifene, who report abnormal gynaecological symptoms, especially vaginal bleeding, should be promptly investigated.

A number of second primary tumors, 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 Tamoxifene. No causal link has been established and the clinical significance of these observations remains unclear.

Interaction

When Tamoxifene is used in combination with coumarin type anticoagulants, a significant increase in anticoagulant effect may occur. Where such co administration is initiated, careful monitoring of the patient is recommended. When Tamoxifene is used in combination with cytotoxic agents, there is an increased risk of thromboembolic events.

Food Interaction

• Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of tamoxifen.
• Take with a full glass of water.
• Take with or without food.

[Moderate] GENERALLY AVOID: Due to their estrogenic effect, isoflavones present in soy such as genistein and daidzein may stimulate breast tumor growth and antagonize the antiproliferative action of tamoxifen.

Supportive data are derived primarily from in vitro and animal studies.

In vitro, low concentrations of these phytoestrogens have been found to promote DNA synthesis and reverse the inhibitory effect of tamoxifen on estrogen-dependent breast cancer cell proliferation.

In contrast, high concentrations of genistein greater than 10 microM

It is not known if these high concentrations are normally achieved in humans.

Plasma concentrations below 4 microM

These concentrations are comparable to the low plasma concentrations associated with tumor stimulation reported in animals.

In a study of 155 female breast cancer survivors with substantially bothersome hot flashes, a product containing 50 mg of soy isoflavones (40% to 45% genistein; 40% to 45% daidzein; 10% to 20% glycitein) taken three times a day was found to be no more effective than placebo in reducing hot flashes.

No toxicity or recurrence of breast cancer was reported during the 9-week study period.

Green tea does not appear to have significant effects on the pharmacokinetics of tamoxifen or its primary active metabolite, endoxifen.

In a study consisting of 14 patients who have been receiving tamoxifen treatment at a stable dose of 20 mg (n=13) or 40 mg (n=1) once daily for at least 3 months, coadministration with green tea supplements twice daily for 14 days resulted in no significant differences in the pharmacokinetics of either tamoxifen or endoxifen with respect to peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) compared to administration of tamoxifen alone.

The combination was well tolerated, with all reported adverse events categorized as mild (grade 1) and none categorized as serious or severe (grade 3 or higher) during the entire study.

Although some adverse events such as headache, polyuria, gastrointestinal side effects (e.g., constipation, dyspepsia), and minor liver biochemical disturbances were reported more often during concomitant treatment with green tea, most can be attributed to the high dose of green tea used or to the caffeine in green tea.

The green tea supplements used were 1000 mg in strength and contained 150 mg of epigallocatechin-3-gallate (EGCG), the most abundant and biologically active catechin in green tea.

According to the investigators, the total daily dose of EGCG taken by study participants is equivalent to the amount contained in approximately 5 to 6 cups of regular green tea.

However, it is not known to what extent the data from this study may be applicable to other preparations of green tea such as infusions, since the bioavailability of EGCG and other catechins may vary between preparations.

MANAGEMENT: Until more information is available, patients treated with tamoxifen may consider avoiding or limiting the consumption of soy-containing products.

Consumption of green tea and green tea extracts during tamoxifen therapy appears to be safe.

Tamoxifene Drug Interaction

Major: diphenhydramine, duloxetine, escitalopramModerate: venlafaxine, venlafaxineUnknown: aspirin, calcium / vitamin d, loratadine, ubiquinone, omega-3 polyunsaturated fatty acids, pregabalin, metoprolol, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, ergocalciferol, cholecalciferol, alprazolam, cetirizine

Tamoxifene Disease Interaction

Major: DVT/pulmonary embolismModerate: endometrial dysplasia, hepatic dysfunction, myelosuppression, visual disturbances

Volume of Distribution

The volume of distribution of tamoxifen is approximately 50-60L/kg.

Elimination Route

An oral dose of 20mg reaches a C_max of 40ng/mL with a T_max of 5 hours. The metabolite N-desmethyltamoxifen reaches a C_max of 15ng/mL. 10mg of tamoxifen orally twice daily for 3 months results in a C_ss of 120ng/mL and a C_ss of 336ng/mL.

Half Life

The terminal elimination half-life of tamoxifen is 5 to 7 days, while the half-life of N-desmethyltamoxifen, the primary circulating metabolite, is approximately 14 days.

Clearance

The clearance of tamoxifen was 189mL/min in a study of six postmenopausal women.

Elimination Route

Tamoxifene is mainly eliminated in the feces. Animal studies have shown 75% of radiolabelled tamoxifen recovered in the feces, with negligible collection from urine. However, 1 human study showed 26.7% recovery in the urine and 24.7% in the feces.

Pregnancy & Breastfeeding use

Pregnancy: Tamoxifene 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 Tamoxifene, although no causal relationship has been established. Reproductive toxicology studies in rats, rabbits and monkeys have shown no teratogenic potential.

Women should be advised not to become pregnant whilst taking Tamoxifene and should use barrier or other nonhormonal contraceptive methods if sexually active. Premenopausal patients must be carefully examined before treatment to exclude pregnancy. Women should be informed of the potential risks to the foetus, if they want to become pregnant whilst taking Tamoxifene or within two months of cessation of therapy.

Lactation: It is not known if Tamoxifene is excreted in human milk and therefore the drug is not recommended during lactation. The decision to discontinue Tamoxifene should take into account in case of the importance of the drug to the lactating mother.

Contraindication

Tamoxifene must not be administered during pregnancy. Tamoxifene should not be given to patients who have experienced hypersensitivity to the product or any of its ingredients.

Storage Condition

Store between 20-25° C. Protect from light.

Innovators Monograph

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