Selective oestrogen receptor modulator (SERM)
Tamoxifen is a medicine used to treat hormone-receptor-positive breast cancer, and for prevention in high-risk women. It is taken orally, usually 20 mg a day, for 5 years.
Also known as: Nolvadex
DailyMed/FDA (NIH/NLM) — approved Tamoxifen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=509f8ba3-214d-aec8-e063-6294a90af498 ; EMC-UK (MHRA) — approved Tamoxifen SmPC: https://www.medicines.org.uk/emc/product/101398/smpc — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Fluoxetine may reduce tamoxifen's effectiveness in breast cancer by blocking the enzyme that converts it into the active form of the drug. Talk to your doctor before taking them together.
Tamoxifen is a prodrug: its conversion to endoxifen (a metabolite with ~100-fold higher affinity for the oestrogen receptor) depends on CYP2D6. Fluoxetine is a potent inhibitor of this isoenzyme; pharmacokinetic studies show a 65–75% reduction in endoxifen levels, and observational studies link the concomitant use of CYP2D6-inhibiting SSRIs to worse breast cancer outcomes. The tamoxifen SmPC (EMC-UK) recommends avoiding, whenever possible, co-administration with potent CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine, cinacalcet, bupropion). Sertraline inhibits CYP2D6 moderately and in a dose-dependent manner. If an antidepressant is needed, agents with less CYP2D6 impact should be preferred.
Potent CYP2D6 inhibitors (fluoxetine, paroxetine) reduce endoxifen (tamoxifen's active metabolite) levels by 65–75%, with possible loss of efficacy. Avoid the combination; prefer SSRIs with weaker CYP2D6 inhibition (e.g. citalopram, escitalopram, venlafaxine).
Fluoxetine inhibits CYP2D6, reducing the formation of endoxifen (the active tamoxifen metabolite).
Tamoxifen adherence and response; depressive symptoms and SSRI adverse effects.
Clinical worsening of breast cancer; serotonin syndrome (rare in this combination, but watch for tremor, agitation, hyperthermia).
Avoid the combination; if an SSRI is needed, choose one with weak CYP2D6 inhibition (citalopram, escitalopram, venlafaxine) and reassess therapy with the oncologist.
EMC-UK (MHRA) — approved Tamoxifen SmPC: https://www.medicines.org.uk/emc/product/101398/smpc ; DailyMed/FDA (NIH/NLM) — approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490 ; PubMed — https://pubmed.ncbi.nlm.nih.gov/20141708/ and https://pubmed.ncbi.nlm.nih.gov/23760858/ ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Sertraline may reduce the effectiveness of tamoxifen in breast cancer by lowering its active form. Always tell your doctor if you take both medicines.
Like other SSRIs, sertraline interferes with CYP2D6-mediated activation of tamoxifen, lowering endoxifen. The effect is smaller than with fluoxetine or paroxetine (moderate inhibition, more evident at high sertraline doses, above 100 mg/day), but the loss of efficacy is clinically relevant in a disease as sensitive to adjuvant therapy as breast cancer. The tamoxifen SmPC recommends avoiding potent CYP2D6 inhibitors and exercising caution with the others.
Sertraline inhibits CYP2D6 moderately and dose-dependently, reducing endoxifen levels. When possible, prefer an SSRI with weaker CYP2D6 inhibition; if the combination is unavoidable, monitor response.
Moderate CYP2D6 inhibition by sertraline, reducing endoxifen formation.
Tamoxifen response and adherence; signs of breast cancer recurrence.
New breast lump, bone pain, clinical worsening — oncology reassessment.
Prefer alternatives with less CYP2D6 impact (citalopram, escitalopram, venlafaxine); if sertraline is kept, use the lowest effective dose and inform the oncologist.
EMC-UK (MHRA) — approved Tamoxifen SmPC: https://www.medicines.org.uk/emc/product/101398/smpc ; DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 ; PubMed — https://pubmed.ncbi.nlm.nih.gov/20141708/ ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Taking tamoxifen with warfarin can greatly increase the anticoagulant effect and the risk of bleeding. Your doctor should check the INR more often.
The tamoxifen SmPC (EMC-UK) reports a significant increase in anticoagulant effect when combined with coumarins, and the DailyMed label contraindicates use in patients requiring concomitant coumarin anticoagulation (in the risk-reduction indication). The mechanism involves inhibition of coumarin metabolism and an additive effect on haemostasis. In adjuvant breast cancer therapy, if anticoagulation is essential, monitor INR closely after starting tamoxifen (the anticoagulant dose may need to be reduced).
Tamoxifen significantly potentiates coumarin anticoagulants; in primary prevention of breast cancer the combination is contraindicated. Monitor INR on initiation and after any dose change.
Inhibition of coumarin metabolism and additive effect on haemostasis.
Periodic INR; bleeding symptoms.
Melena, haematemesis, spontaneous bruising, bleeding — seek immediate care.
Combine only if strictly necessary; check INR 1–2 weeks after starting or changing tamoxifen and adjust the anticoagulant dose.
EMC-UK (MHRA) — approved Tamoxifen SmPC: https://www.medicines.org.uk/emc/product/101398/smpc ; DailyMed/FDA (NIH/NLM) — approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Rifampicin can markedly reduce the amount of tamoxifen in the body, lowering the effect of treatment. Talk to your doctor if you need to take rifampicin.
The approved tamoxifen label (DailyMed) documents that rifampicin, a CYP3A4 inducer, reduces tamoxifen AUC and Cmax by 86% and 55%, respectively — a loss of exposure that may compromise antitumour efficacy. The EMC-UK SmPC reinforces caution with CYP3A4 inducers. This combination arises mainly in tuberculosis or antibiotic prophylaxis; management should be multidisciplinary.
Potent CYP3A4 inducer (rifampicin) reduces tamoxifen AUC by up to 86%. Avoid the combination whenever possible; if unavoidable, consider an alternative breast cancer treatment and monitor.
CYP3A4 induction by rifampicin, accelerating tamoxifen elimination.
Treatment response and adherence; tamoxifen adverse events.
Clinical worsening; signs of disease progression.
Avoid the combination; if rifampicin is essential (tuberculosis), reassess antineoplastic therapy with the oncologist.
DailyMed/FDA (NIH/NLM) — approved Tamoxifen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=509f8ba3-214d-aec8-e063-6294a90af498 ; approved Rifampicin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b389b1a3-672f-47e3-916c-4a9c044b211b ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Do not take anastrozole and tamoxifen at the same time: there is no added benefit and the combination lowers anastrozole levels in the body.
In the ATAC trial, combining anastrozole with tamoxifen did not improve disease-free survival over anastrozole alone and reduced anastrozole exposure by about 27%. The anastrozole SmPC (EMC-UK) and the approved label state explicitly that it must not be combined with tamoxifen or oestrogen-containing therapies, as these diminish its pharmacological activity.
Co-administration of anastrozole and tamoxifen reduced anastrozole plasma concentration by 27% in the ATAC trial, with no added benefit over monotherapy. Avoid the combination (the ATAC trial showed no advantage).
Competitive effect at the oestrogen receptor and reduced anastrozole exposure.
Treatment response; bone density and lipid profile according to the agent used.
Disease progression; fractures or cardiovascular events on long-term therapy.
Use a single adjuvant hormonal agent (tamoxifen OR aromatase inhibitor), never in combination.
EMC-UK (MHRA) — approved Anastrozole SmPC: https://www.medicines.org.uk/emc/product/100971/smpc ; DailyMed/FDA (NIH/NLM) — approved Tamoxifen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=509f8ba3-214d-aec8-e063-6294a90af498 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Tamoxifen can be taken with or without food, with no relevant food interaction.
May be taken with or without food, consistently.
DailyMed/FDA (NIH/NLM) — approved Tamoxifen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=509f8ba3-214d-aec8-e063-6294a90af498
Grapefruit inhibits CYP3A4 and may raise tamoxifen concentrations; the clinical relevance is uncertain, but it is advisable to avoid it.
Avoid grapefruit juice during treatment.
DailyMed/FDA (NIH/NLM) — approved Tamoxifen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=509f8ba3-214d-aec8-e063-6294a90af498
Tamoxifen increases the risk of VTE 2–3-fold; in women with a history of deep vein thrombosis or pulmonary embolism it is contraindicated (in primary prevention) and requires careful consideration in treatment.
Assess personal and family VTE history before starting; if a prothrombotic factor is present, consider thrombophilia screening and risk-benefit; stop if VTE is suspected.
EMC-UK (MHRA) — approved Tamoxifen SmPC: https://www.medicines.org.uk/emc/product/101398/smpc ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Tamoxifen can cause liver enzyme changes, fatty liver and, rarely, severe liver injury; the risk is higher in patients with pre-existing liver disease.
Monitor liver function at baseline and periodically during treatment; stop if there is evidence of significant liver injury.
EMC-UK (MHRA) — approved Tamoxifen SmPC: https://www.medicines.org.uk/emc/product/101398/smpc
Tamoxifen is contraindicated in pregnancy; spontaneous abortions, birth defects and fetal deaths have been reported after exposure.
Do not administer in any trimester; women must use non-hormonal contraception during treatment and for up to 9 months after stopping.
Tamoxifen and its active metabolites are excreted into milk and accumulate; it is not recommended during breastfeeding.
Non-hormonal contraception (barrier) is mandatory during treatment and up to 9 months after stopping.
EMC-UK (MHRA) — approved Tamoxifen SmPC: https://www.medicines.org.uk/emc/product/101398/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Selective oestrogen receptor modulator (nonsteroidal antioestrogen) used in hormone receptor-positive breast cancer. In the NSABP P-1 prevention trial it reduced the incidence of invasive breast cancer by 44%. Benefit is greater with about 5 years of treatment.
Competes with oestradiol for binding sites in target tissues such as the breast, exerting an antioestrogenic effect; the antitumour effect results from oestrogen receptor binding.
After a single 20 mg oral dose, the mean peak plasma concentration of about 40 ng/ml occurs about 5 hours after dosing; steady state is reached in about 4 weeks (tamoxifen) and 8 weeks (N-desmethyltamoxifen). Plasma protein binding is high (about 99%).
Extensively metabolised after oral administration. N-desmethyltamoxifen is the major plasma metabolite, with biological activity similar to tamoxifen; 4-hydroxytamoxifen is a minor metabolite. It is a substrate of CYP3A, 2C9 and 2D6 and an inhibitor of P-glycoprotein. About 65% of the dose is excreted within 2 weeks, with faecal excretion as the primary route.
The terminal elimination half-life of tamoxifen is about 5 to 7 days; that of the N-desmethyltamoxifen metabolite is approximately 14 days.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
