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Drug Interactions between fluoxetine and tamoxifen

This report displays the potential drug interactions for the following 2 drugs:

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Major

FLUoxetine tamoxifen

Applies to: fluoxetine and tamoxifen

GENERALLY AVOID: Chronic coadministration of potent or moderate CYP450 2D6 inhibitors including certain antidepressants may reduce the effectiveness of tamoxifen. The proposed mechanism is inhibition of tamoxifen bioactivation via CYP450 2D6 to endoxifen (4-hydroxy-N-desmethyltamoxifen), the active metabolite that may be responsible for much of tamoxifen's antiestrogenic activity. This is consistent with studies that reported poorer clinical outcome (e.g., increased breast cancer recurrence; shorter relapse-free periods; lower rates of event-free survival) and decreased incidence/severity of hot flashes in patients treated with tamoxifen who have genetic polymorphisms of CYP450 2D6 resulting in reduced or absent enzyme activity. A similar relationship has been observed between endoxifen exposure and alterations in CYP450 2D6 metabolic status, whether due to CYP450 2D6 genetic variants or use of CYP450 2D6 inhibitors such as quinidine or SSRI antidepressants. In a study of 12 patients receiving tamoxifen adjuvant therapy, mean plasma concentrations of endoxifen decreased by more than 50% after four weeks of paroxetine 10 mg/day for hot flashes, and the effect was evident primarily in patients who carried the wild-type genotype for CYP450 2D6 (i.e., extensive metabolizers). In vitro, quinidine reduced the conversion to endoxifen by 79%. Potential clinical implications of this interaction were reported in a retrospective analysis of nearly 1,300 female breast cancer patients who were newly prescribed tamoxifen between 2003 and 2005 and were monitored for at least two years (mean 2.7 years). Women who used a moderate to potent CYP450 2D6 inhibitor (n=353) during tamoxifen therapy had a two-year breast cancer recurrence rate of 13.9%, compared to 7.5% for those not taking any CYP450 2D6 inhibitors (n=945). The average duration of concomitant tamoxifen and CYP450 2D6 inhibitor use was 340 days. In a subset analysis of patients taking tamoxifen with SSRI antidepressants, a breast cancer recurrence rate of 16% was reported for 213 women who used fluoxetine, paroxetine, or sertraline--SSRIs that are considered moderate to potent inhibitors of CYP450 2D6. This rate was 2.2 times higher than that for women taking tamoxifen without CYP450 2D6 inhibitors. In contrast, the breast cancer recurrence rate was 8.8% for 137 women using citalopram, escitalopram, or fluvoxamine, which was not statistically different than controls. An earlier, smaller study conducted by a group of Danish researchers also reported no reduction of tamoxifen effectiveness in association with citalopram or escitalopram use for up to five years. It is important to note that not all studies have found an association between CYP450 2D6 activity and tamoxifen clinical effects. In fact, a couple of studies even reported decreased risk of recurrence in patients treated with tamoxifen who have a common genetic variant of CYP450 2D6. Investigators suggest that the discrepancies may be due to differences in study designs, including sample size, different genetic models for the assessment of phenotypes, and stratification effects.

MANAGEMENT: Based on available data, patients treated with tamoxifen should avoid the chronic use of potent CYP450 2D6 inhibitors such as bupropion, fluoxetine, paroxetine and quinidine whenever possible, and preferably also moderate inhibitors such as adagrasib, duloxetine, and sertraline. If an antidepressant is required during treatment with tamoxifen, agents such as desvenlafaxine, fluvoxamine, milnacipran, levomilnacipran, mirtazapine, and venlafaxine may be considered, since they have mild to no effects on CYP450 2D6. Alternatively, aromatase inhibitors such as anastrozole, exemestane, and letrozole may be appropriate substitutes for tamoxifen in certain patients. In addition, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, may reduce the effectiveness of tamoxifen for at least 28 days after administration of rolapitant.

References

  1. Jordan VC "Metabolites of tamoxifen in animals and man: identification, pharmacology, and significance." Breast Cancer Res Treat 2 (1982): 123-38
  2. Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE "The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes." Br J Clin Pharmacol 34 (1992): 262-5
  3. Amchin J, Ereshefsky L, Zarycranski W, Taylor K, Albano D, Klockowski PM "Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan, a CYP2D6 probe." J Clin Pharmacol 41 (2001): 443-51
  4. Coller JK, Krebsfaenger N, Klein K, et al. "The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver." Br J Clin Pharmacol 54 (2002): 157-167
  5. Stearns V, Johnson MD, Rae JM, et al. "Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine." J Natl Cancer Inst 95 (2003): 1758-64
  6. Goetz MP, Loprinzi CL "A hot flash on tamoxifen metabolism." J Natl Cancer Inst 95 (2003): 1734-5
  7. 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):
  8. Ratliff B, Dietze EC, Bean GR, Moore C, Wanko S, Seewaldt VL "Re: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine." J Natl Cancer Inst 96 (2004): 883; author reply 884-5
  9. Ponzone R, Biglia N, Sismondi P "Re: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine." J Natl Cancer Inst 96 (2004): 883-4; author reply 884-5
  10. Lehmann D, Nelsen J, Ramanath V, Newman N, Duggan D, Smith A "Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition." J Clin Pharmacol 44 (2004): 861-5
  11. Johnson MD, Zuo H, Lee KH, et al. "Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen." Breast Cancer Res Treat 85 (2004): 151-9
  12. Jin Y, Desta Z, Stearns V, et al. "CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment." J Natl Cancer Inst 97 (2005): 30-9
  13. McCaffrey P "Genetics and drug interactions affect tamoxifen metabolism." Lancet Oncol 6 (2005): 72
  14. Rochat B "Role of cytochrome p450 activity in the fate of anticancer agents and in drug resistance : focus on tamoxifen, Paclitaxel and imatinib metabolism." Clin Pharmacokinet 44 (2005): 349-66
  15. Goetz MP, Rae JM, Suman VJ, et al. "Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes." J Clin Oncol 23 (2005): 9312-8
  16. Borges S, Desta Z, Li L, et al. "Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment." Clin Pharmacol Ther 80 (2006): 61-74
  17. Bonanni B, Macis D, Maisonneuve P, et al. "Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial." J Clin Oncol 24 (2006): 3708-9
  18. Young D "Genetics examined in tamoxifen's effectiveness: recurrence warning urged for labeling." Am J Health Syst Pharm 63 (2006): 2286, 2296
  19. Lim HS, Ju Lee H, Seok Lee K, Sook Lee E, Jang IJ, Ro J "Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer." J Clin Oncol 25 (2007): 3837-45
  20. Goetz MP, Kamal A, Ames MM "Tamoxifen Pharmacogenomics: The Role of CYP2D6 as a Predictor of Drug Response." Clin Pharmacol Ther (2007):
  21. Schroth W, Antoniadou L, Fritz P, et al. "Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes." J Clin Oncol 25 (2007): 5187-93
  22. Desta Z, Flockhart DA "Germline pharmacogenetics of tamoxifen response: have we learned enough?" J Clin Oncol 25 (2007): 5147-9
  23. Henry NL, Stearns V, Flockhart DA, Hayes DF, Riba M "Drug interactions and pharmacogenomics in the treatment of breast cancer and depression." Am J Psychiatry 165 (2008): 1251-5
  24. Gaston C, Kolesar J "Clinical Significance of CYP2D6 Polymorphisms and Tamoxifen in Women with Breast Cancer." Clin Adv Hematol Oncol 6 (2008): 825-33
  25. Dezentje VO, Guchelaar HJ, Nortier JW, van de Velde CJ, Gelderblom H "Clinical implications of CYP2D6 genotyping in tamoxifen treatment for breast cancer." Clin Cancer Res 15 (2009): 15-21
  26. Aubert RE, Yao J, Stanek EJ, et al. "Increased risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors. https://www.medcoresearch.com/community/oncology/tamoxifen" (2009):
  27. Lash TL, Pedersen L, Cronin-Fenton D, et al. "Tamoxifen's protection against breast cancer recurrence is not reduced by concurrent use of the SSRI citalopram." Br J Cancer 99 (2008): 616-21
  28. Dehal SS, Kupfer D "CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver." Cancer Res 57 (1997): 3402-6
  29. Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam EM "Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen." Drug Metab Dispos 30 (2002): 869-74
  30. Wegman P, Vainikka L, Stal O, et al. "Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients." Breast Cancer Res 7 (2005): R284-90
  31. Wegman P, Elingarami S, Carstensen J, Stal O, Nordenskjold B, Wingren S "Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer." Breast Cancer Res 9 (2007): R7
  32. Borgna JL, Rochefort H "Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues." J Biol Chem 256 (1981): 859-68
  33. Jordan VC, Collins MM, Rowsby L, Prestwich G "A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity." J Endocrinol 75 (1977): 305-16
  34. Brauch H, Murdter TE, Eichelbaum M, Schwab M "Pharmacogenomics of tamoxifen therapy." Clin Chem 55 (2009): 1770-82
  35. "Product Information. Varubi (rolapitant)." Tesaro Inc. (2015):
View all 35 references

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Drug and food interactions

Moderate

FLUoxetine food

Applies to: fluoxetine

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References

  1. Warrington SJ, Ankier SI, Turner P "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology 15 (1986): 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc. (1990):
  3. "Product Information. Fycompa (perampanel)." Eisai Inc (2012):
  4. "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc (2015):
View all 4 references

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Moderate

tamoxifen food

Applies to: tamoxifen

GENERALLY AVOID: Due to their estrogenic effect, isoflavones present in soy such as genistein and daidzein may stimulate breast tumor growth and antagonize the antiproliferative action of tamoxifen. Supportive data are derived primarily from in vitro and animal studies. In vitro, low concentrations of these phytoestrogens have been found to promote DNA synthesis and reverse the inhibitory effect of tamoxifen on estrogen-dependent breast cancer cell proliferation. In contrast, high concentrations of genistein greater than 10 microM/L have been found to enhance tamoxifen effects by inhibiting breast cancer cell growth. It is not known if these high concentrations are normally achieved in humans. Plasma concentrations below 4 microM/L have been observed in healthy volunteers given a soy diet for one month or large single doses of genistein. These concentrations are comparable to the low plasma concentrations associated with tumor stimulation reported in animals. In a study of 155 female breast cancer survivors with substantially bothersome hot flashes, a product containing 50 mg of soy isoflavones (40% to 45% genistein; 40% to 45% daidzein; 10% to 20% glycitein) taken three times a day was found to be no more effective than placebo in reducing hot flashes. No toxicity or recurrence of breast cancer was reported during the 9-week study period.

Green tea does not appear to have significant effects on the pharmacokinetics of tamoxifen or its primary active metabolite, endoxifen. In a study consisting of 14 patients who have been receiving tamoxifen treatment at a stable dose of 20 mg (n=13) or 40 mg (n=1) once daily for at least 3 months, coadministration with green tea supplements twice daily for 14 days resulted in no significant differences in the pharmacokinetics of either tamoxifen or endoxifen with respect to peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) compared to administration of tamoxifen alone. The combination was well tolerated, with all reported adverse events categorized as mild (grade 1) and none categorized as serious or severe (grade 3 or higher) during the entire study. Although some adverse events such as headache, polyuria, gastrointestinal side effects (e.g., constipation, dyspepsia), and minor liver biochemical disturbances were reported more often during concomitant treatment with green tea, most can be attributed to the high dose of green tea used or to the caffeine in green tea. The green tea supplements used were 1000 mg in strength and contained 150 mg of epigallocatechin-3-gallate (EGCG), the most abundant and biologically active catechin in green tea. According to the investigators, the total daily dose of EGCG taken by study participants is equivalent to the amount contained in approximately 5 to 6 cups of regular green tea. However, it is not known to what extent the data from this study may be applicable to other preparations of green tea such as infusions, since the bioavailability of EGCG and other catechins may vary between preparations.

MANAGEMENT: Until more information is available, patients treated with tamoxifen may consider avoiding or limiting the consumption of soy-containing products. Consumption of green tea and green tea extracts during tamoxifen therapy appears to be safe.

References

  1. Therapeutic Research Faculty "Natural Medicines Comprehensive Database. http://www.naturaldatabase.com" (2008):
  2. Braal CL, Hussaarts KGAM, Seuren L, et al. "Influence of green tea consumption on endoxifen steady-state concentration in breast cancer patients treated with tamoxifen." Breast Cancer Res Treat 184 (2020): 107-13

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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