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Tamoxifen - Information Tamoxifen - Information

GENOX

Tamoxifen citrate

Presentation

Each GENOX 10 tablet contains 10mg of Tamoxifen citrate. GENOX 10 is presented as white, round, bi-convex, 7mm tablets, imprinted "TN 10" on one side and G on the other side.

Each GENOX 20 tablet contains 20mg of Tamoxifen citrate. GENOX 20 is presented as white, round, bi-convex, 9.5mm tablets, imprinted "TN/20" on one side and G on the other side.

Uses

Actions

GENOX (tamoxifen) is a non-steroidal anti-oestrogen. In humans, GENOX acts primarily as an anti-oestrogen, inhibiting the effects of endogenous oestrogen, probably by binding with oestrogen receptors. However, clinical results have shown some benefit in oestrogen receptor negative tumours which may indicate other mechanisms of action. It is recognised that tamoxifen also displays oestrogenic-like effects on several body systems including the endometrium, bone and blood lipids.

Pharmacokinetics

After oral administration, tamoxifen is absorbed rapidly with maximum serum concentrations attained within 4 to 7 hours. Steady state concentrations (about 300 nanogram/mL) are achieved after four weeks treatment with 40mg daily. The medicine 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 medicine itself, whereas that for N-desmethyltamoxifen, the principal circulating metabolite, is 14 days.

Indications

GENOX is indicated for:

The treatment of breast cancer. The response is similar to that seen with either oestrogens or androgens but tamoxifen appears to produce less marked side effects and to be more acceptable to the patient.
The treatment of endometrial cancer.

Dosage and Administration

Adults (including Elderly):

Breast and endometrial cancer: The dosage range is 20 to 40mg daily.

Not for use in Children.

Contraindications

Pregnancy:

GENOX 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, 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 was associated with changes similar to those caused by oestradiol, ethynyloestradiol, 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. 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.

Women should be advised not to become pregnant whilst taking GENOX 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 apprised of the potential risks to the foetus, should they become pregnant whilst taking GENOX or within two months of cessation of therapy.

Warnings and Precautions

Menstruation is suppressed in a proportion of pre-menopausal women receiving tamoxifen for the treatment of breast cancer.

An increased incidence of endometrial changes, including hyperplasia, polyps and cancer, has been reported in association with tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the oestrogenic properties of tamoxifen. Any patients receiving or having previously received tamoxifen, should be asked to report promptly to their doctor the following signs and symptoms which may be suggestive of the presence of endometrial cancer:

Abnormal vaginal bleeding such as:

Bleeding between periods,

Heavier than normal bleeding,

Bleeding after menopause.

Changes in vaginal discharge.

Lower abdominal pain or pressure.

These patients should be promptly investigated.

According to one study, women who have taken unopposed oestrogen therapy, who are obese, or who are continuing to take tamoxifen after therapy for ≥ 5 years may be at greater risk for endometrial cancer and consideration should be given to closer monitoring of these groups.

No mutagenic effects have been seen.

Tamoxifen was not mutagenic in a range of in vitro and in vivo mutagenicity tests. Tamoxifen was genotoxic in some in vitro tests and in vivo genotoxicity tests in rodents. Gonadal tumours in mice and liver tumours in rats receiving tamoxifen have been reported in long-term studies. The clinical significance of these findings has not been established.

Effects on reproductive functions are expected from the anti-oestrogenic properties of the medicine. In the rat, uterine pressure effects (deformation of rib cage and altered cranial ossification patterns) have been ascribed to inhibition of the action of oestrogens on the uterus, but these simple deformations disappear after birth. In pregnant marmosets dosed during organogenesis or in the last half of pregnancy, no deformations were seen.

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. No causal link has been established and the clinical significance of these observations remains unclear.

Retinopathy and keratopathy may occur and patients should be asked to report the following symptoms of ocular damage without delay:

Blurred vision lasting more than 2 weeks.

Change in colour vision.

Patients reporting these symptoms should be referred for ophthalmological examination. The ocular damage caused by tamoxifen is characterised by a reduction in visual acuity, bilateral macular oedema and yellow ringlike deposits in the paramacular and fovea areas. If tamoxifen is withdrawn promptly the vision usually returns to normal without permanent impairment.

Lactation:

It is not known if tamoxifen is excreted in human milk and therefore the medicine is not recommended during lactation. The decision either to discontinue nursing or discontinue tamoxifen should take into account the importance of the medicine to the mother.

Effect on ability to drive or operate machinery:

There is no evidence that tamoxifen results in impairment of these activities.

Adverse Effects

During long term treatment, side effects are not as numerous or as serious with tamoxifen as with the androgens and oestrogens which are also used to treat breast cancer. Those that have been reported can be classified as either due to the anti-oestrogenic action of the medicine, e.g. hot flushes, vaginal bleeding, vaginal discharge and pruritus vulvae, or as more general side effects, e.g. gastrointestinal intolerance, tumour flare, lightheadedness, skin rash 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 without loss of control of the disease. If side effects do not respond to this measure, it may be necessary to stop the treatment. A small number of patients with bony metastases developed hypercalcaemia on initiation of therapy.

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

A number of cases of visual disturbance (including corneal changes, cataracts and retinopathy) have been described in patients receiving tamoxifen.

Uterine fibroids have been reported.

Cystic ovarian swellings have occasionally been observed in pre-menopausal women receiving tamoxifen.

Leucopenia has been observed following the administration of tamoxifen, 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 tamoxifen therapy. When tamoxifen is used in combination with cytotoxic agents, there is a further increase in the risk of thromboembolic events occurring.

Tamoxifen 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.

Interactions

When tamoxifen 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 tamoxifen is used in combination with cytotoxic agents, there is increased risk of thromboembolic events occurring.

Overdosage

On theoretical grounds an overdosage would be expected to cause an enhancement of the anti-oestrogenic side effects. Animal studies have shown that extreme overdosage (100 to 200 times the recommended daily dose) may produce oestrogenic effects. There is no specific antidote and treatment must be symptomatic.