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Drug Reference

tamoxifen

selective oestrogen receptor modulator (SERM)· Brands: Nolvadex, SoltamoxPO

Mechanism of action
Tamoxifen binds competitively to oestrogen receptors (ER alpha and ER beta). In breast tissue it recruits co-repressor proteins to the receptor complex, blocking oestrogen-driven transcription of genes such as cyclin D1, which leads to G1 cell cycle arrest, reduced proliferation and apoptosis of ER-positive breast cancer cells. In other tissues it behaves as a partial agonist: it preserves bone mineral density in postmenopausal women, stimulates the endometrium, where it can cause hyperplasia, polyps and rarely carcinoma, and has oestrogen-like effects on hepatic lipid and clotting factor synthesis, which contribute to its thrombotic risk. Most antitumour activity comes from metabolites, particularly 4-hydroxytamoxifen and endoxifen, which have far greater receptor affinity than the parent drug; endoxifen formation depends on CYP2D6 activity.
Pharmacokinetics
Absorbed well after oral administration, with bioavailability approaching that of an intravenous dose, although plasma concentrations vary widely between patients. It undergoes extensive hepatic metabolism by CYP3A4/3A5, CYP2C9 and CYP2D6, first to N-desmethyltamoxifen and 4-hydroxytamoxifen, then to the active endoxifen. Around 99% is bound to plasma albumin. Elimination is biphasic: the parent drug has a half-life of roughly 5 to 7 days and N-desmethyltamoxifen about 14 days, so steady state is reached in 3 to 4 weeks. Excretion is mainly biliary and faecal as conjugates, with small amounts in urine. Potent CYP2D6 inhibitors such as paroxetine and fluoxetine reduce endoxifen exposure, and strong CYP3A4 inducers such as rifampicin, carbamazepine and phenytoin lower tamoxifen concentrations.
Indications & dosing

Adjuvant treatment of hormone receptor-positive early breast cancer in women (and men) after surgery

Standard teaching dose 20 mg daily for 5 years; some guidelines extend to 10 years in selected higher-risk patients. Duration and extension decisions vary by regional guideline and menopausal status.

  • adult · PO: 20 mg once daily · Standard teaching dose 20 mg daily for 5 years; some guidelines extend to 10 years in selected higher-risk patients. Duration and extension decisions vary by regional guideline and menopausal status.

Treatment of metastatic hormone receptor-positive breast cancer

20 mg daily is usual; 40 mg daily may be used in selected patients. Response is assessed clinically and radiologically; treatment continues while benefit persists.

  • adult · PO: 20–40 mg once daily · 20 mg daily is usual; 40 mg daily may be used in selected patients. Response is assessed clinically and radiologically; treatment continues while benefit persists.

Ductal carcinoma in situ (DCIS) after breast-conserving surgery and radiotherapy, to reduce recurrence risk

Used mainly in hormone receptor-positive DCIS where tamoxifen is preferred over an aromatase inhibitor, for example in premenopausal women.

  • adult · PO: 20 mg once daily · Used mainly in hormone receptor-positive DCIS where tamoxifen is preferred over an aromatase inhibitor, for example in premenopausal women.

Risk reduction in women at high risk of developing invasive breast cancer

Licensed for risk reduction in some regions and off-label in others. Typically given for 5 years; eligibility criteria and risk thresholds differ between formularies.

  • adult · PO: 20 mg once daily · Licensed for risk reduction in some regions and off-label in others. Typically given for 5 years; eligibility criteria and risk thresholds differ between formularies.

Reduction of contralateral breast cancer risk in women with a history of breast canceroff-label

Often a secondary benefit of adjuvant therapy rather than a separate licensed indication; listed here as a teaching example.

  • adult · PO: 20 mg once daily · Often a secondary benefit of adjuvant therapy rather than a separate licensed indication; listed here as a teaching example.

Ovulation induction in anovulatory infertility (selected patients)off-label

Off-label and largely historical; regimens vary widely (for example 20 to 100 mg daily for 5 days early in the cycle). Rarely first-line; specialist use only.

  • adult · PO: 20–100 mg once daily · Off-label and largely historical; regimens vary widely (for example 20 to 100 mg daily for 5 days early in the cycle). Rarely first-line; specialist use only.

Gynaecomastia or breast pain associated with androgen deprivation or other hormonal causesoff-label

Off-label. Doses and durations vary by protocol; prophylaxis regimens around prostate cancer treatment differ from treatment of established gynaecomastia.

  • adult · PO: 10–20 mg once daily · Off-label. Doses and durations vary by protocol; prophylaxis regimens around prostate cancer treatment differ from treatment of established gynaecomastia.

Treatment of hormone receptor-positive breast cancer in premenopausal adolescents and young women (selected cases)off-label

Breast cancer is rare in this age group; management is specialist. Adult dosing is generally used but evidence is limited and growth, bone density and fertility require monitoring.

  • pediatric · PO: 20 mg once daily · Breast cancer is rare in this age group; management is specialist. Adult dosing is generally used but evidence is limited and growth, bone density and fertility require monitoring.
Contraindications & precautions
  • Pregnancy · Tamoxifen is teratogenic. Stop treatment and seek specialist advice if pregnancy occurs.
  • Breastfeeding · Not recommended; effects on the infant are not established. Specialist advice is needed on alternative treatment.
  • Known hypersensitivity to tamoxifen or excipients · Discontinue and manage the reaction appropriately.
  • History of venous thromboembolism or known thrombophilia · Increased risk of recurrent thrombosis. Consider alternative endocrine therapy or specialist assessment; some labels list previous VTE as a contraindication.
  • Investigate any abnormal vaginal bleeding, pelvic pain or persistent discharge promptly; endometrial hyperplasia or malignancy may present this way, and biopsy may be required.
  • Assess venous thromboembolism risk before and during treatment. Advise patients to seek urgent care for unilateral leg swelling, breathlessness or chest pain, and to avoid prolonged immobility where possible.
  • Check liver function and full blood count before treatment and periodically thereafter; reduce dose or stop if severe hepatic or haematological toxicity occurs.
  • Use effective contraception during treatment and for at least two months after stopping in people of childbearing potential, because tamoxifen is teratogenic. Seek specialist advice if pregnancy occurs.
  • Ask about visual disturbance or blurred vision and refer for ophthalmological assessment; tamoxifen can cause retinopathy, corneal changes and optic neuritis.
  • Review concurrent medicines: CYP2D6 inhibitors such as paroxetine or fluoxetine may reduce formation of active metabolites, and QT-prolonging drugs increase arrhythmia risk. Evidence on CYP2D6 is mixed and practice varies by region.
Adverse effects
  • Hot flushes
  • Vaginal bleeding or dischargeserious
  • Nausea
  • Fluid retention or oedema
  • Venous thromboembolism (deep vein thrombosis or pulmonary embolism)serious
  • Endometrial hyperplasia, endometrial cancer or uterine sarcomaserious
  • Stroke or transient ischaemic attackserious
  • Ocular toxicity (retinopathy, corneal changes or optic neuritis)serious
  • Hypercalcaemia in patients with bone metastasesserious
  • Hepatic toxicity, including fatty liver and rare hepatic failureserious
Interactions
  • fluoxetinemajorAvoid the combination where possible. Consider an alternative antidepressant that does not inhibit CYP2D6, such as venlafaxine or citalopram. If fluoxetine is necessary, monitor clinical response and consider dose adjustment, but this is not generally advised.
Renal & hepatic adjustment
  • Hepatic impairment (mild): No specific dose adjustment required. Tamoxifen is extensively metabolised by the liver; monitor clinically for tolerability.
  • Hepatic impairment (moderate): No specific dose reduction is established. Use with caution and monitor for adverse effects; consider specialist advice if hepatic function deteriorates.
  • Hepatic impairment (severe): Use with caution because metabolism may be reduced and toxicity risk increased. No defined dose adjustment; specialist advice is recommended.
Monitoring, pregnancy & toxicity
  • Vaginal bleeding, discharge or pelvic pain · At each review; urgent gynaecological assessment if new or persistent.
  • Signs and symptoms of venous thromboembolism (leg swelling, pain, dyspnoea, chest pain) · At each review; advise patient to seek urgent care if symptoms occur.
  • Liver function tests · Baseline and periodically, or if symptoms of hepatotoxicity develop.
  • Visual symptoms (blurring, loss of vision, eye pain or redness) · At baseline and if new symptoms occur; refer for ophthalmological review if abnormal.
  • Pregnancy test in premenopausal women · Before starting treatment and if pregnancy is suspected.
  • Pregnancy: Tamoxifen is contraindicated in pregnancy. It may cause fetal harm, including teratogenicity and fetal loss. Women of childbearing potential should use effective non-hormonal contraception during treatment and for at least 2 months after stopping. If pregnancy occurs, stop tamoxifen and seek specialist obstetric advice.
  • Toxicity: Endometrial hyperplasia or carcinoma: abnormal vaginal bleeding, discharge or pelvic pain. · Investigate urgently with gynaecological assessment, including endometrial sampling if indicated. Discuss discontinuation of tamoxifen with the oncology team; do not stop without specialist advice.
  • Toxicity: Venous thromboembolism: unilateral leg swelling or pain, dyspnoea, chest pain or haemoptysis. · Urgent assessment and anticoagulation per local protocol. Stop tamoxifen if VTE is confirmed unless the treating team advises otherwise.
  • Toxicity: Hepatotoxicity: raised transaminases, jaundice, dark urine, abdominal pain or pruritus. · Monitor liver function. Stop tamoxifen if significant hepatic injury is suspected and manage supportively; seek specialist advice.
  • Toxicity: Ocular toxicity: visual blurring, reduced acuity, cataracts, retinopathy or optic neuropathy. · Refer for ophthalmological assessment. Consider discontinuation if significant ocular toxicity develops; discuss risks and benefits with the treating team.
Clinical notes
Given orally, commonly 20 mg once daily, for adjuvant treatment of oestrogen receptor positive early breast cancer in premenopausal and postmenopausal women, for ER-positive metastatic disease, for ductal carcinoma in situ after breast-conserving surgery and radiotherapy, and for risk reduction in women at high risk. Adjuvant treatment is conventionally given for 5 years, with extended durations considered in selected patients; duration and selection criteria vary by guideline and region. Common adverse effects are hot flushes, night sweats, vaginal discharge or dryness, fatigue and menstrual disturbance. Serious risks include venous thromboembolism, stroke, endometrial hyperplasia or carcinoma, uterine sarcoma, retinal and corneal changes, and hepatic steatosis or hepatotoxicity. Patients should seek urgent assessment for unilateral leg swelling or pain, breathlessness, chest pain, sudden visual disturbance or unexpected vaginal bleeding. Baseline and periodic review of symptoms, gynaecological history and vision is standard. Avoid in pregnancy and breastfeeding and use caution with a history of thromboembolism. Co-prescription of strong CYP2D6 inhibitors is best avoided where an alternative exists, for example venlafaxine rather than paroxetine for troublesome hot flushes.

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BNF; manufacturer Summary of Product Characteristics; NICE or local formulary guidance; specialist oncology protocol