Tamoxifen

Key points

• A substudy of the NSABP P-1 trial did not find screening women for Factor V Leiden and the prothrombin G20210A mutation useful for identifying those who may not be suitable candidates for tamoxifen.
• Tamoxifen is broken down by the cytochrome P-450 3A, 2C9 and 2D6 enzymes and inhibits the P-glycoprotein transporter.
• Tamoxifen itself has an elimination half-life of about seven days, while its main circulating metabolite, N-desmethyltamoxifen, has a half-life of about 14 days, according to its UK summary of product characteristics.

How it works

In breast cancer, tamoxifen acts primarily as an antioestrogen, preventing oestrogen from binding to the oestrogen receptor in the tumour. According to its US prescribing information, in cytosols taken from human breast adenocarcinomas, tamoxifen competes with oestradiol for the oestrogen receptor protein. In postmenopausal women, tamoxifen also reduces total cholesterol and low-density lipoprotein levels by around 10 to 20%, and it does not adversely affect bone mineral density.

Safety specific to Tamoxifen

Tamoxifen carries a boxed warning in its US prescribing information for women with ductal carcinoma in situ (DCIS) and women at high risk for breast cancer. In this risk-reduction setting, serious and life-threatening events associated with tamoxifen include uterine malignancies, stroke and pulmonary embolism, with incidence rates estimated from the NSABP P-1 trial. Uterine malignancies include both endometrial adenocarcinoma, at an incidence rate of 2.20 per 1,000 women-years on tamoxifen against 0.71 on placebo, and uterine sarcoma, at 0.17 per 1,000 women-years on tamoxifen against 0.4 on placebo. The stroke incidence rate was 1.43 per 1,000 women-years on tamoxifen against 1.00 on placebo, and the pulmonary embolism rate was 0.75 per 1,000 women-years on tamoxifen against 0.25 on placebo. Some of the strokes, pulmonary emboli and uterine malignancies were fatal. Health care providers should weigh the potential benefits against the potential risks of these serious events with women at high risk of breast cancer and women with DCIS who are considering tamoxifen to reduce their risk of developing breast cancer. In women already diagnosed with breast cancer, the benefits of tamoxifen outweigh its risks.

Beyond this risk-reduction setting, an increased incidence of uterine malignancies has also been reported in association with tamoxifen treatment generally. There is evidence of an increased incidence of thromboembolic events, including deep-vein thrombosis and pulmonary embolism, during tamoxifen therapy generally, and a 2 to 3-fold increase in the risk of venous thromboembolism has been demonstrated in healthy tamoxifen-treated women. Tamoxifen is contraindicated in women who require concomitant coumarin-type anticoagulant therapy or who have a history of deep-vein thrombosis or pulmonary embolus.

Tamoxifen has also been associated with changes in liver enzyme levels and, on rare occasions, more severe liver abnormalities including fatty liver, cholestasis, hepatitis and hepatic necrosis. Ocular disturbances, including corneal changes, a decrement in colour vision perception, retinal vein thrombosis and retinopathy, have been reported in patients receiving tamoxifen.

Tamoxifen may cause foetal harm when given to a pregnant woman, and premenopausal patients must be carefully examined before treatment, for all indications, to exclude the possibility of pregnancy.

Further reading

• TAMOXIFEN CITRATE tablet
• Nolvadex 10 mg Film-Coated Tablet