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Medicines Q&As
Q&A 413.1
Tamoxifen and SSRI or SNRI antidepressants – is there an interaction?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at https://www.sps.nhs.uk/articles/about-ukmi-medicines-qas/
Date prepared: September 2016
Summary
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Tamoxifen is extensively metabolised via cytochrome P450 2D6 (CYP2D6) to active metabolites,
the most significant of which is endoxifen.
CYP2D6 is highly polymorphic, therefore capacity to metabolise tamoxifen varies according to
individual CYP2D6 genotype.
Different SSRIs/SNRIs inhibit the action of CYP2D6 to varying degrees.
Paroxetine is a potent CYP2D6 inhibitor, therefore co-prescribing with tamoxifen is not
recommended. Fluoxetine is a moderate-to-potent inhibitor, and duloxetine is a moderate inhibitor.
Preference should be given to SSRIs/SNRIs with weak inhibitory effects on CYP2D6, such as
citalopram, escitalopram, sertraline, fluvoxamine and venlafaxine.
Epidemiological data are conflicting and inconclusive with regard to the interaction between
tamoxifen and SSRIs or SNRIs.
As the mechanism of effect is biologically plausible, caution is advised when prescribing
antidepressants which are potent or moderate inhibitors of CYP2D6.
Routine pharmacogenetic testing in clinical practice for CYP2D6 alleles prior to starting tamoxifen
is not currently recommended.
Background
The selective oestrogen receptor modulator tamoxifen has been used to treat hormone receptor positive
breast cancer in the adjuvant setting for over three decades, where it has been shown to reduce annual
breast cancer mortality rate by a third and five-year recurrence by a half [1,2]. Depression and anxiety are
common co-morbidities with breast cancer. Estimates suggest 20-30% of patients taking tamoxifen are coprescribed anti-depressants either for psychiatric reasons, or off-label for tamoxifen-induced vasomotor
symptoms [1].
Tamoxifen is a prodrug that is extensively metabolised to more potent active metabolites by cytochrome
P450 isoenzymes (CYP450) in the liver [3,4]. Inhibition of these enzymes by certain antidepressants
potentially prevents formation of the active compounds, therefore negating clinical effect [3,4].
This Medicines Q&A reviews the evidence for an interaction between tamoxifen and selective serotonin
reuptake inhibitors (SSRIs)/serotonin noradrenaline reuptake inhibitors (SNRIs) resulting in reduced
tamoxifen efficacy.
Answer
Metabolism of tamoxifen
Formation of primary metabolites is catalysed by CYP2D6, with a much smaller contribution from the
CYP3A family. Active metabolites include 4-hydroxy-N-desmethyltamoxifen (endoxifen) and 4hydroxytamoxifen, both of which are 100 fold more potent anti-estrogens than the parent compound. Serum
concentrations of endoxifen are 6-10 times higher than 4-hydroxytamoxifen, therefore it is regarded as the
more clinically important metabolite for tamoxifen activity [1,4].
Medicines Q&A 413.1
Tamoxifen and SSRI or SNRI antidepressants – is there an interaction?
Available at www.sps.nhs.uk
CYP450 iso-enzymes are highly subject to genetic polymorphism, and an individual’s capacity to
metabolise tamoxifen varies according to their CYP2D6 genotype. Approximately 100 allelic variants of
CYP2D6 have been identified, presenting as four phenotypes within the population [5,6,7]:
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Poor metabolisers (PM) have two non-functional CYP2D6 alleles and so no CYP2D6 activity
Intermediate metabolisers (IM) have one functional and one deficient allele resulting in reduced
CYP2D6 activity
Extensive metabolisers (EM) have two functional alleles therefore normal CYP2D6 activity
Ultra-rapid metabolisers (UM) have multiple functional alleles, causing excess CYP2D6 activity.
Association between CYP2D6 status and clinical outcomes with tamoxifen is controversial, and trial results
are inconsistent. One review concluded that whilst CYP2D6 activity does clearly affect endoxifen levels, it is
difficult to prove this translates to reduced tamoxifen efficacy. Relevant studies are of differing design,
methodological quality and statistical power, making it difficult to combine them to enable clinically
meaningful conclusions to be drawn [8].
SSRIs/SNRIs and inhibition of CYP2D6
Different SSRIs and SNRIs inhibit CYP2D6 to varying degrees [9-19].
Of the SSRIs, paroxetine is a potent inhibitor and fluoxetine a moderate-to-potent inhibitor of CYP2D6 [913]. Citalopram, escitalopram, sertraline and fluvoxamine are weak inhibitors of CYP2D6. With regard to
SNRIs, duloxetine is a moderate inhibitor whereas venlafaxine is a weak inhibitor [11-17].
Evidence for a clinically relevant interaction between tamoxifen and SSRIs/SNRIs
Endoxifen levels have been reported to be as much as 66% lower in patients treated with tamoxifen and
concomitant paroxetine or fluoxetine than in patients treated with tamoxifen alone, essentially converting
phenotypically IM or EM individuals to PMs [13,20].
A small (n=10) prospective pharmacokinetic study examined the effect of switching patients treated for
depression or anxiety with a potent CYP2D6 inhibitor (paroxetine (n=8) or fluoxetine (n=2)) to a weak
inhibitor (escitalopram) on levels of tamoxifen and its metabolites. Nine were switched to escitalopram, one
was accidentally given citalopram. Endoxifen concentration was 3-fold higher with tamoxifen/escitalopram
or citalopram, than tamoxifen/fluoxetine or tamoxifen/paroxetine [21].
A recent meta-analysis pooled data from twelve epidemiological studies investigating the effect of
concomitant SSRIs and tamoxifen on breast cancer recurrence. Summary effect estimate of breast cancer
recurrence with tamoxifen and concomitant potent or weak CYP2D6 inhibiting SSRIs was 1.03 [95% CI
0.86 to 1.23] and 1.05 [0.91 to 1.22] respectively. Overall, the data did not suggest that taking either potent
or weak CYP2D6 inhibiting SSRIs concurrently with tamoxifen increased risk of relapse; effect of both drug
and/or gene-induced inhibition of CYP2D6 is likely to be small or at most moderate in individuals with a PM
phenotype [13].
A study of 16,887 tamoxifen-treated breast cancer survivors followed for a maximum of 14 years found no
statistically increased risk of recurrence associated with concomitant use of antidepressants (paroxetine,
fluoxetine, other SSRIs, tricyclics and other classes) with tamoxifen [22].
Mean plasma endoxifen levels were not significantly affected by venlafaxine (n=6) in one study [23].
Another reported mean plasma endoxifen concentration was slightly reduced in patients taking tamoxifen
plus venlafaxine, and substantially reduced in those taking tamoxifen plus paroxetine [24]. However more
recent data showed venlafaxine reduced endoxifen levels by 23% [p=0.004] in a patient population
predominantly comprised of UM and EM phenotypes (n=20). The authors state that whilst levels of
endoxifen were reduced by venlafaxine, the optimal level of endoxifen for prevention of recurrence remains
to be determined [25].
No direct studies involving tamoxifen and the SNRI duloxetine were identified, but as a moderate CYP2D6
inhibitor, theoretically it is expected that lower levels of endoxifen would be produced [1,12].
Guidance
MHRA, NICE and the manufacturer of tamoxifen all recommend that the potent CYP2D6 inhibitors
fluoxetine and paroxetine should not be co-prescribed with tamoxifen [26-28]. Weak inhibitors such as
Medicines Q&A 413.1
Tamoxifen and SSRI or SNRI antidepressants – is there an interaction?
Available at www.sps.nhs.uk
sertraline, escitalopram, citalopram or venlafaxine are more suitable for prescribing in this patient
population.
Routine pharmacogenetic testing in clinical practice for CYP2D6 alleles prior to initiation of tamoxifen is not
currently recommended due to uncertainty regarding type and quantity of alleles to test for, a lack of clinical
data and undetermined implementation costs [26,29].
For patients currently taking tamoxifen with an antidepressant considered a potent or moderate CYP2D6
inhibitor (paroxetine, fluoxetine, duloxetine) who wish to switch to an antidepressant that is a weak CYP2D6
inhibitor (citalopram, escitalopram, sertraline, fluvoxamine), advice can be found in the UKMi Q&A 150.5
“How do you switch between tricyclic, SSRI and related antidepressants?”
Limitations
Data for drug interactions between tamoxifen and SSRIs/SNRIs are limited; therefore further studies are
needed before definitive recommendations can be made.
References
1. Desmarais JE, Looper KJ. Interactions between tamoxifen and antidepressants via cytochrome
P450 2D6. J Clin Psychiatry 2009; 70(12): 1688–1697
2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and
hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the
randomised trials. Lancet 2005; 365: 1687–1717
3. Kelly CM, Juurlink DN, Gomes T et al. Selective serotonin reuptake inhibitors and breast cancer
mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010; 340: c693
4. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen
sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for
CYP3A and CYP2D6. J Pharmacol Exp Ther 2004; 310: 1062–1075
5. Untch M, Thomssen C. Clinical practice decisions in endocrine therapy. Cancer Investigation 2010;
28: 4–13
6. Cronin-Fenton DP, Lash TL. Clinical epidemiology and pharmacology of CYP2D6 inhibition related
to breast cancer outcomes. Expert Rev Clin Pharmacol 2011; 4(3): 363–377
7. Schroth W, Goetz MP, Hamann U et al. Association between CYP2D6 polymorphisms and
outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009
302(13): 1429–1436
8. de Vries Schultink AH, Zwart W, Linn SC et al. Effects of pharmacogenetics on the
pharmacokinetics and pharmacodynamics of tamoxifen. Clin Pharmacokinet 2015; (54): 797–810
9. Summary of Product Characteristics. Prozac 20mg hard capsules and 20mg per 5ml oral liquid. Eli
Lilly and Company Ltd. Date of last revision of text 8/2/16. Accessed via
http://www.medicines.org.uk/emc/ on 4/10/16
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suspension. GlaxoSmithKline UK. Date of last revision of text 23/10/15. Accessed via
http://www.medicines.org.uk/emc/ on 4/10/16
11. Preston CL (Ed). Stockley’s Drug Interactions. Tamoxifen + SSRIs and other CYP2D6 inhibitors
(updated 21/10/14). Electronic version. London: Pharmaceutical Press. Accessed via
http://www.medicinescomplete.com on 4/10/16
12. Flockhart DA. Drug interactions: cytochrome P450 drug interaction table. Indiana University School
of Medicine. 2007 Accessed via http://medicine.iupui.edu/clinpharm/ddis/ on 4/10/16
13. Cronin-Fenton DP, Damkier P, Lash T. Metabolism and transport of tamoxifen in relation to its
effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014; 10(1):107–122
14. Summary of Product Characteristics. Lustral 100mg tablets. Pfizer. Date of last revision of text
11/15. Accessed via http://www.medicines.org.uk/emc/ on 4/10/16
15. Summary of Product Characteristics. Cipramil tablets. Lundbeck Ltd. Date of last revision of text
29/7/15. Accessed via http://www.medicines.org.uk/emc/ on 4/10/16
16. Summary of Product Characteristics. Cipralex 5, 10 and 20mg tablets. Lundbeck Ltd. Date of last
revision of text 5/9/13. Accessed via http://www.medicines.org.uk/emc/ on 4/10/16
17. Summary of Product Characteristics. Faverin film-coated 50mg tablets. BGP Products Ltd. Date of
last revision of text 12/8/15. Accessed via http://www.medicines.org.uk/emc/ on 4/10/16
18. Summary of Product Characteristics. Efexor XL 75mg hard prolonged-release capsules. Pfizer.
Date of last revision of text 7/16. Accessed via http://www.medicines.org.uk/emc/ on 4/10/16
Medicines Q&A 413.1
Tamoxifen and SSRI or SNRI antidepressants – is there an interaction?
Available at www.sps.nhs.uk
19. Summary of Product Characteristics. Cymbalta 30mg & 60mg hard gastro-resistant capsules. Date
of last revision of text 1/1/16. Eli Lilly and Company Ltd. Accessed via
http://www.medicines.org.uk/emc/ on 4/10/16
20. Binkhorst L, Mathijssen RH, van Herk-Sukel MP et al. Unjustified prescribing of CYP2D6 inhibiting
SSRIs in women treated with tamoxifen. Breast Cancer Res Treat. 2013; 139: 923–929
21. Binkhorst L, Bannink M, de Bruijn P et al. Augmentation of endoxifen exposure in tamoxifen-treated
women following SSRI switch. Clin Pharmacokinet Oct 8 2015. [Epub ahead of print] Accessed via
http://link.springer.com/article/10.1007%2Fs40262-015-0315-x on 4/10/16
22. Haque R, Shi J, Schottinger JE et al. Tamoxifen and antidepressant drug interaction in a cohort of
16,887 breast cancer survivors. J Natl Cancer Inst 2016; 108(3): 1460-2105
23. Borges S, Desta Z, Li L et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen
metabolism: implications for optimization of breast cancer treatment. Clin Pharmacol Ther 2006; 80:
61–74
24. Jin Y, Desta Z, Stearns V et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism
during adjuvant breast cancer treatment. J Natl Cancer Inst 2005; 97: 30–9
25. Goetz MP, Suman V, Henry NL, et al. Venlafaxine inhibits the CYP2D6 mediated metabolic
activation of tamoxifen: results of a prospective multicenter study: NCT00667121. Cancer Res
2012; 72 (24 Suppl): Abstract nr PD10–08
26. MHRA UK Public Assessment Report. Tamoxifen: reduced effectiveness when used with CYP2D6
inhibitors. September 2011. Accessed via http://www.mhra.gov.uk/home/groups/spar/documents/websiteresources/con129101.pdf on 4/10/16
27. National Institute for Health and Care Excellence Clinical Guideline 80. Early and locally advanced
breast cancer. Diagnosis and treatment. Published Feb 2009. Last modified July 2014. Updated
Nov 2015. Accessed via https://www.nice.org.uk/guidance/cg81 on 12/10/16
28. Summary of Product Characteristics. Tamoxifen 20mg tablets. Aurobindo Pharma-Milpharm Ltd.
Date of last revision of text 24/6/16. Accessed via http://www.medicines.org.uk/emc/ on 4/10/16
29. Fleeman N, Martin Saborido C, Payne K et al. The clinical effectiveness and cost-effectiveness of
genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a
systematic review. Health Technology Assessment 2011; 15(33): 63–69
Quality Assurance
Prepared by
Eimear Maguire, Medicines Information Pharmacist,
North West Medicines Information Centre, 70 Pembroke Place, Liverpool, L69 3GF.
Date Prepared
September 2016.
Checked by
Nicola Bradley and Joanne McEntee, Senior Medicines Information Pharmacists,
North West Medicines Information Centre, 70 Pembroke Place, Liverpool, L69 3GF.
Date of check
September 2016
Search strategy
In-house: Textbooks, resources and databases
 Embase via NICE Evidence TAMOXIFEN/it AND [exp SEROTONIN UPTAKE INHIBITOR/ OR exp
SEROTONIN NORADRENALIN REUPTAKE INHIBITOR/]
 Medline via NICE Evidence TAMOXIFEN/ AND[exp SEROTONIN UPTAKE INHIBITOR/ OR exp
ANTIDEPRESSIVE AGENTS, SECOND-GENERATION/]
Medicines Q&A 413.1
Tamoxifen and SSRI or SNRI antidepressants – is there an interaction?
Available at www.sps.nhs.uk