MajorSelective serotonin reuptake inhibitor (SSRI)×Selective estrogen receptor modulator (SERM)
Updated · Methodology
Mechanism
Tamoxifen is a prodrug: CYP2D6 converts it to endoxifen, one of its most active forms. Paroxetine is a strong CYP2D6 inhibitor. The data cited in the Spanish SmPCs of both drugs show a 65–75% fall in endoxifen levels with CYP2D6 inhibitors. In some studies tamoxifen efficacy dropped with paroxetine, up to higher breast cancer relapse and mortality; other studies found no such effect, as the FDA label notes.
Symptoms
Tumour progression on imaging after 6–12 months.
Management
Avoid paroxetine during tamoxifen therapy where possible, as the Spanish SmPCs of both drugs require. The FDA label advises an antidepressant with little or no CYP2D6 inhibition. The Spanish SmPC describes venlafaxine as a relatively weak CYP2D6 inhibitor. Sertraline also inhibits CYP2D6 (mild to moderate), and escitalopram doubled desipramine and metoprolol levels in studies. Fluoxetine and bupropion are strong CYP2D6 inhibitors, like paroxetine. If depression does not respond to the switch, oncology and psychiatry agree the regimen together.
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Sources
- NCCN: NCCN Guidelines for cancer prevention and risk reduction (2024)– National Comprehensive Cancer Network, 2024
- FDA: Tamoxifen citrate tablet (Mylan Pharmaceuticals Inc.) – Prescribing Information – CYP2D6 metabolism and antidepressant interactions (2018)– FDA Nolvadex label, Clinical Pharmacology §12.3 and Drug Interactions §7; DailyMed setid 7ee3d3d2-85d1-4018-8e70-5ed8a64ae1f0
- FDA: Nolvadex (tamoxifen) prescribing information (2018)
- AEMPS: Ficha técnica Tamoxifeno Viatris 20 mg (2026)– AEMPS CIMA, Tamoxifeno Viatris 20 mg comprimidos recubiertos con película, nº registro 58110, secciones 4.4 y 4.5
- AEMPS: Ficha técnica Frosinor 20 mg (paroxetina) (2026)– AEMPS CIMA, Frosinor 20 mg comprimidos recubiertos con película, nº registro 59466, secciones 4.3, 4.4 y 4.5
- FDA: Paxil (paroxetine) prescribing information (2026)– Apotex Corp. PAXIL (paroxetine) tablets. Prescribing information, DailyMed setid ef3b5cbe-f9e1-c1ac-79da-cfe14e3a7e7e, sections 4, 5.11 and 7