NOLVADEX

Indications

• Hormone receptor-positive breast cancer
• Adjuvant therapy following surgery for breast cancer
• Metastatic breast cancer
• Chemoprevention in women at high risk for breast cancer

Dosage

Children: Refer to BNF for Children for appropriate dosing

Adults: 20 mg daily

Mechanism of action

Tamoxifen competitively inhibits estrogen binding to its receptor, critical for its activity in breast cancer cells. This inhibition leads to a decrease in tumor growth factors and an increase in sex hormone binding globulin, reducing the levels of factors that stimulate tumor growth. Additionally, tamoxifen can induce apoptosis in estrogen receptor-positive cells through the inhibition of protein kinase C and an increase in intracellular calcium levels.

Pharmacodynamics

Tamoxifen is a nonsteroidal agent with potent antiestrogenic properties, primarily acting on estrogen receptor-positive tumors. It has a long duration of action due to its active metabolite, N-desmethyltamoxifen, which has a half-life of approximately 2 weeks. While effective, tamoxifen has a narrow therapeutic index and higher doses may lead to adverse effects, including respiratory difficulties and seizures. It is also associated with an increased risk of uterine malignancies.

Pharmacokinetics

Tamoxifen is absorbed orally and undergoes extensive hepatic metabolism, primarily through cytochrome P450 enzymes. The drug is distributed widely in body tissues, and its active metabolites contribute to its prolonged therapeutic effect. The elimination half-life varies, but the active metabolite N-desmethyltamoxifen can persist for several weeks, contributing to the drug's long-term effects.

Contra-indications

• Hypersensitivity to tamoxifen or any excipients
• Pregnancy
• History of idiopathic venous thromboembolism or genetic predisposition to thromboembolism
• Severe hepatic impairment

Adverse effects

• Alopecia
• Anaemia
• Cataract
• Cerebral ischaemia
• Constipation
• Diarrhoea
• Dizziness
• Hypertriglyceridaemia
• Myalgia
• Nausea
• Vision changes
• Increased risk of uterine malignancies
• Leucopenia
• Pancreatitis
• Thrombocytopenia

Interactions

• Tamoxifen may decrease the concentration of fosphenytoin and phenytoin
• Bupropion may decrease the efficacy of tamoxifen
• Cinacalcet may decrease the efficacy of tamoxifen
• Coumarins may increase the anticoagulant effect when used with tamoxifen
• Rifampicin may decrease exposure to tamoxifen
• Antiepileptics may increase the concentration of tamoxifen

Precautions

• Monitor for signs of thromboembolic events
• Caution in patients with hepatic impairment
• Use with caution in patients with a history of uterine malignancies

Pregnancy

Manufacturer advises to avoid use during pregnancy due to risk of fetal abnormalities and death in animal studies.

Breast-feeding

Manufacturer advises to avoid use during breastfeeding as it may be excreted in breast milk.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets
• Capsules
• Oral suspension

Mechanism of action

Tamoxifen competitively inhibits estrogen binding to its receptor, which is critical for it's activity in breast cancer cells. Tamoxifen 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. Tamoxifen 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. Tamoxifen is a nonsteroidal agent with potent antiestrogenic properties. The antiestrogen effects may be related to tamoxifen's ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen competes with estradiol for estrogen receptor protein in cytosols derived from human breast adenocarcinomas. Tamoxifen has been shown to inhibit the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. Tamoxifen appears to exert its antitumor effects by binding the estrogen receptors in this rat model. Tamoxifen may induce ovulation in anovulatory women, stimulating release of gonadotropin-releasing hormone from the hypothalamus, which in turn stimulates release of pituitary gonadotropins. In oligospermic males, tamoxifen increases serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estrogen. Tamoxifen is an antiestrogen frequently used in the treatment of breast cancer and is currently being assessed as a prophylactic for those at high risk of developing tumors. We have found that tamoxifen and its derivatives are high-affinity blockers of specific chloride channels. This blockade appears to be independent of the interaction of tamoxifen with the estrogen receptor and therefore reflects an alternative cellular target. One of the clinical side effects of tamoxifen is impaired vision and cataract. Chloride channels in the lens of the eye were shown to be essential for maintaining normal lens hydration and transmittance. These channels were blocked by tamoxifen and, in organ culture, tamoxifen led to lens opacity associated with cataracts at clinically relevant concentrations. These data suggest a molecular mechanism by which tamoxifen can cause cataract formation and have implications for the clinical use of tamoxifen and related antiestrogens.

Pharmacodynamics

Tamoxifen is a selective estrogen receptor modulator that inhibits growth and promotes apoptosis in estrogen receptor positive tumors. It has a long duration of action as the active metabolite N-desmethyltamoxifen has a half life of approximately 2 weeks. It has a narrow therapeutic index as higher doses can lead to breathing difficulty or convulsions. Tamoxifen administration is also associated with an increased incidence of uterine malignancies.