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1 Maturitas 67 (2010) Contents lists available at ScienceDirect Maturitas journal homepage: Review Managing menopausal symptoms and depression in tamoxifen users: Implications of drug and medicinal interactions Julie Eve Desmarais a,b,, Karl J. Looper b,c a Clinical Psychophacology Unit, Allan Memorial Institute, McGill University Health Centre, 1025 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1 b Dept of Psychiatry, McGill University, Canada c Consultation-Liaison Service, Dept of Psychiatry, Sir Mortimer B. Davis Jewish General Hospital, 3755 Ch. Côte-Ste-Catherine Office A-540, Montréal, Québec, Canada H3T 1E2 article info abstract Article history: Received 26 July 2010 Received in revised form 10 August 2010 Accepted 10 August 2010 Keywords: Tamoxifen Hot flashes Menopause Depression Treatment Drug interaction or incompatibility Objective: Tamoxifen, a medication used in the treatment of breast cancer, often induces menopausal symptoms. Certain medications and natural supplements taken or prescribed to alleviate tamoxifeninduced hot flashes and depressive states in women with breast cancer interact with tamoxifen. This paper reviews potentially problematic interactions and offers treatment recommendations. Methods: Medline (1950-June 1, 2010), Embase Classic + Embase (1947-June 1, 2010) and PsycINFO (1967- June 1, 2010) were searched through Ovid. The word tamoxifen was searched with depression and then with menopaus* and symptoms, with treatment as a limit. Tamoxifen was later searched with the MeSH terms drug interaction or drug incompatibility. Results: Venlafaxine is efficacious for the treatment of hot flashes and depression and safe to use in combination with tamoxifen. Gabapentin is also efficacious in treating tamoxifen-induced hot flashes and, since it does not interact with cytochrome P450 system, is likely safe to use in patients using tamoxifen. Desvenlafaxine and pregabalin may be alternatives to venlafaxine and gabapentin, respectively, although desvenlafaxine has not yet been studied in this population. Paroxetine, fluoxetine and bupropion are strong CYP2D6 inhibitors which should be avoided in tamoxifen users. Fluvoxamine and nefazodone both inhibit CYP3A, which could potentially affect the metabolism of tamoxifen. Clonidine can be an alternative agent but may carry significant side effects. Evidence of medicinal products for the treatment of tamoxifen-induced hot flashes is equivocal at best. Conclusions: Clinicians should remain cautious about using strong inhibitors and/or inducers of cytochrome 2D6 and 3A4 concomitantly with tamoxifen. Use of natural menopausal supplements and diets rich in isoflavones should not be encouraged in tamoxifen users until more data is available. There are however safe treatments for hot flashes and depression in tamoxifen users Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction Methods Vasomotor symptoms Treatment of vasomotor symptoms Non-estrogenic hormonal therapy (Table 1) [14 19] Non-hormonal therapy Antidepressants (Table 2) [23 26] Other psychotropics (Table 3) [37 46] Other medications (Table 3) Natural supplements (Table 4) [47 53] Corresponding author at: McGill University Health Centre, Allan Memorial Institute, 1025 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. Tel.: x35575; fax: addresses: julie.desmarais@mail.mcgill.ca (J.E. Desmarais), karl.looper@mcgill.ca (K.J. Looper) /$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved. doi: /j.maturitas

2 J.E. Desmarais, K.J. Looper / Maturitas 67 (2010) Depression Safety of treatment of hot flashes and depression in tamoxifen users CYP2D6 inhibitors Cytochrome P450 3A4/5 inhibitors Phytoestrogens Conclusion and recommendations (Tables 5 and 6) Contributors Competing interest Provenance and peer review References Introduction Tamoxifen is an estrogen receptor antagonist used in the treatment and prophylaxis of breast cancer. Over the past 40 years it has decreased the mortality and recurrence of early stage estrogen receptor positive breast cancer by a third and a half, respectively [1]. Tamoxifen often induces menopausal symptoms. Medications and natural supplements are often tried to alleviate tamoxifen-induced hot flashes and depressive states in women with breast cancer. It has come to light that certain of these medications and supplements decrease the metabolism of tamoxifen and may decrease its anticancer effect. It is imperative that clinicians are aware of these interactions and the safe alternative treatments. The objective of this review is to highlight potentially problematic interactions between tamoxifen and medications or natural supplements used in the treatment of hot flashes and depression in tamoxifen users. Tamoxifen is metabolized to N-desmethyltamoxifen primarily through cytochrome 3A4/5 [2]. Tamoxifen is also metabolized to 4-hydroxytamoxifen through a number of cytochromes, including 2D6, 3A4, 2C9, 2B6 and 2C19 [2]. N-desmethyltamoxifen and 4-hydroxytamoxifen are both converted to 4-hydroxy-Ndesmethyltamoxifen (endoxifen) mainly through 2D6 and 3A4, respectively [1]. 4-Hydroxytamoxifen and endoxifen are 100 times more antiestrogenic than tamoxifen and N-desmethyltamoxifen, with endoxifen present in higher concentrations in the plasma than 4-hydroxytamoxifen [1]. Endoxifen is a stronger suppressor of cell proliferation than tamoxifen [1]. 2. Methods Medline (1950-June 1, 2010), Embase Classic + Embase (1947- June 1, 2010) and PsycINFO (1967-June 1, 2010) were searched through Ovid. The word tamoxifen was searched with depression and then with menopaus* and symptoms, with treatment as a limit. Tamoxifen was later searched with the MeSH terms drug interaction or drug incompatibility. Articles were selected if they involved medications or natural supplements used in the treatment of hot flashes and depression. In vitro and animal studies were excluded. Only articles with abstracts in English or French were retrieved. Additional articles were retrieved through the bibliographies of obtained articles. 3. Vasomotor symptoms Hormone replacement therapy (HRT) is an effective treatment for menopausal symptoms, reducing frequency of weekly hot flashes by 75% 57.7% with, with severity odd ratios of 0.13 in a systematic review [3]. HRT has however been associated with increased risk of breast cancer in healthy women [4,5] and increased risk of recurrence in breast cancer survivors [6]. There is also some evidence that it may not be as effective in women using tamoxifen [7,8]. Hot flashes occur between 20% and 40%, perhaps even up to 80%, of patients receiving tamoxifen for breast cancer [9 13]. Night sweats have been reported in up to 72% of these patients [13]. Vasomotor symptoms have been associated with anxiety, sleep difficulties, poorer emotional and social functioning as well as worse body image [13]. Hormonal therapy, antidepressants and other psychotropic medications are the most commonly medications tried to alleviate vasomotor symptoms in tamoxifen users. Studies including tamoxifen users are described below. 4. Treatment of vasomotor symptoms 4.1. Non-estrogenic hormonal therapy (Table 1) [14 19] Given concerns of breast cancer recurrence or tamoxifen failure with estrogenic therapy, trials have been conducted with nonestrogenic hormonal therapy such as megestrol acetate [14,15], depomedroxyprogesterone acetate (MPA) [16], dehydroepiandrosterone (DHEA) [17] and tibolone [18,20]. Positive results have been obtained with these medications. Megestrol acetate is however associated with a worsening of hot flashes before improvement and withdrawal menstrual bleeding after discontinuation [14]. One randomized controlled trial () reported that tibolone was associated with a significant increased risk of breast cancer recurrence at 3 years (HR 1.4) [18] Non-hormonal therapy A meta-analysis [20] of 43 double-blind, s of non-hormonal therapies for hot flashes was published in Not all studies included tamoxifen users. Authors reported mean decreases in daily hot flashes of 1.13 (95% CI, 1.70 to 0.57) when combining 7 comparisons of SSRIs and SNRIs (4 of which included tamoxifen users); of 0.95 (95% CI, 1.44 to 0.47), for the 4 trials of clonidine (2 of which included tamoxifen users); and of 2.05 (95% CI, 2.80 to 1.30) for the 2 trials of gabapentin (one of which included tamoxifen users). No significant decreases in hot flashes were observed when combining studies of red clover isoflavone extracts (none of which included tamoxifen users) and mixed results were obtained with soy isoflavone extracts (one study involved tamoxifen users). In an individual patient pooled analysis [21], 7 trials of newer antidepressants and 3 trials of gabapentin for hot flashes, all double-blind trials, were examined. Two of the 3 trials with sertraline and two of 3 trials with gabapentin did not involve patients with breast cancer or patients receiving tamoxifen. One of the 2 trials performed with paroxetine had only a minority of patients with breast cancer or taking tamoxifen. Decreases in mean hot flash score was 24% for all s combined. Additional decreases in mean hot flash score from were 33% for venlafaxine (75 mg/d), 13% to 41% for paroxetine (10 to 25 mg/d), 13% for fluoxetine (20 mg/d), 9% to18% for sertraline (50 mg/d), 3%

3 Table 1 Studies of non-estrogenic hormonal therapy for hot flashes including tamoxifen users. Medication Dose Study design Duration of treatment Megestrol acetate (MA) MPA 20 mg bid then or vice versa 20 mg qd, 40 mg qd or MPA 400 mg IM x1 vs venlafaxine 37.5 mg qd x1 week, then 75 mg qd randomized controlled crossover trial * 4 weeks each 3 months + another 3 months if treatment successful N total 97 F with breast ca hx and 66 M with prostate ca hx (80 F and 60 M included in analysis of efficacy) 288 F with breast ca (286 eligible for analysis and 244 with data at 3 months) 6 weeks 220 F (188 eligible for analysis) N on tamoxifen (%) 80 81% of F Mean reduction in frequency (hot flash per day and/or %) At 4 weeks median decreases of: 74% for F and 80% for M on MA 27% for F and 19% for M on (p < 0.001) Mean reduction in score (% unless unavailable) At 4 weeks median decreases of: 83% for F and 87% for M on MA 27% for F and 16% for M on (p < 0.001) frequency At 4 weeks: 71% of F and 79% of M on MA compared to 24% of F and 12% of M on (p < 0.001) 85% N/A N/A At 3 months, a 75% decrease in: 14% on, 65% on 20 mg and 48% on 40 mg (both doses vs p < ). Most successes maintained at 6 months 40% Similar reduction in frequencies than in scores DHEA 50 mg qd Pilot 4 weeks 28 F (22 41% 50% decrease or 4.4 flash/d (p = ) Tibolone 2.5 mg qd or 2.5 mg qd or randomized trial for risk of breast cancer recurrence Median follow-up of 3.1 years * Crossover analyses not reported because of significant carryover effects F with hx of breast ca (3098 included in intent-to-treat analysis) 70 F post-surgery for breast ca (67 analysed) 67% Significant difference in favour of tibolone at week 4 (p = 0.004), week 8(p < ), and week 12 (p < ) 100% At 3 months: no decreases from baseline for either group. At 12 months: 30% decrease or 0.6 hot flash/d with tibolone vs 30% increase or +1.1 flash/d with (p = 0.022) 79% for MPA and 55% for venlafaxine (p ) 50% decrease (p = ) hot flash score N/A N/A N/A More than 50% decrease in 53% on venlafaxine and 86% on MPA (p < ) N/A Intent-to-treat analysis: 45% Adverse effects Increase in hot flash score before decrease in some F on MA. Vaginal bleeding in 31% of F (mostly upon withdrawal of MA) No significant differences by treatment Less toxicity was reported with MPA No side effects significantly worse than baseline N/A N/A N/A HR of breast cancer recurrence of 1.40 with tibolone (95% CI ) p = Treatment-related, adverse effects: 27.7%with tibolone and 21.8% with (p = ) At 3 months hot flashes less severe with tibolone N/A N/A No differences between groups re: abnormal endometrial biopsies and vaginal bleeding. At 12 months, significant decreases in triglycerides and HDL with tibolone and in LDL with Reference Loprinzi et al. [14] Goodwin et al. [15] Loprinzi et al. [16] Barton et al. [17] Kenemans et al. [18] Kroiss et al. [19] 298 J.E. Desmarais, K.J. Looper / Maturitas 67 (2010)

4 J.E. Desmarais, K.J. Looper / Maturitas 67 (2010) for sertraline (100 mg/d) and 35% to 38% for gabapentin (900 to 2400 mg/d). In a meta-analysis of 7 trials, 4 of which included tamoxifen users, gabapentin reduced the frequency and severity of hot flashes by 20% and 30% more than [22] Antidepressants (Table 2) [23 26] Fluoxetine [26], paroxetine [27 28], sertraline [29], citalopram [24] and venlafaxine [31,33] all have evidence, including patients using tamoxifen, supporting their use in the treatment of hot flashes. A pilot study showed positive results with mirtazapine [34]. Pilot studies performed with desipramine [35] and bupropion [36] have failed to show improvements in hot flashes that would likely be significantly better than Table Other psychotropics (Table 3) [37 46] Gabapentin [37,39,40] and pregabalin [41] also have proved their efficacy in the treatment of hot flashes through s that have included tamoxifen users. A pilot study [42] suggested that levetiracetam may also be effective Table Other medications (Table 3) s support the efficacy of clonidine in the treatment of tamoxifen-induced hot flashes [43 44]. A chart study performed in women with cancer treated for hot flashes suggested that oxybutynin was effective in treating hot flashes [45]. A -controlled randomized crossover trial of vitamin E in breast cancer survivors failed to show differences between the 2 s in respect to hot flash frequency but crossover analysis however showed that vitamin E could lead to one less hot flash/d compared with [46] Natural supplements (Table 4) [47 53] Two randomized -controlled trials of black cohosh have failed to show statistically significant differences between black cohosh and [49,50]. These results contrasted with positive results from an earlier pilot study [48] and a randomized open-label study [47]. No significant differences between soy and were noted in three s [51 53] Table Depression The prevalence of major depressive disorder in women with breast cancer is estimated to fall between 10% and 25% [54]. Two large cohort studies [55,56] have not shown an increased incidence of depression amongst tamoxifen users treated for cancer, despite earlier reports of the opposite. The treatment of depression and anxiety is usually similar in cancer and non-cancer patients and often consists of antidepressants and/or psychotherapy. Unfortunately, the literature on phacological treatment of depressive disorders in patients with cancer is sparse and several existing studies have methodological flaws, heterogeneity of samples or high drop-out rates [57]. 6. Safety of treatment of hot flashes and depression in tamoxifen users As mentioned above, hormonal treatment of tamoxifen-induced hot flashes may increase the risk of recurrence of breast cancer. Another concern is the risk of treatment failure when tamoxifen is used with antidepressants, especially potent cytochrome P450 2D6 (CYP2D6) inhibitors CYP2D6 inhibitors CYP2D6 plays a key role in the metabolism of tamoxifen to endoxifen [2]. Thirty-five percent of women with advanced estrogen receptor positive breast cancer do not respond to tamoxifen and this may be due to polymorphisms in the enzymes metabolizing tamoxifen to its more active metabolites [1]. Women who are poor metabolizers at CYP2D6 may have lower plasma levels of tamoxifen and its metabolites [58 60] and/or may not respond as well to tamoxifen as extensive metabolizers [61 63]. A study demonstrated that 2D6 genotype alone is ineffective at predicting 2D6 phenotype as measured by endoxifen/n-desmethyl-tamoxifen plasma ratio. When medications that inhibit 2D6 are also taken into account, the phenotype prediction although not perfect is two-times better [64]. This may explain why some studies have not found decreased relapse-free survival [65], decreased survival [66] or increased risk of recurrence [67] in poor metabolizers. Two prospective clinical studies [68,69] have shown decreased levels of endoxifen in patients with an extensive CYP2D6 genotype taking paroxetine, a strong 2D6 inhibitor. Another prospective clinical study [59] found that the endoxifen levels of extensive metabolizers receiving paroxetine and fluoxetine, both strong 2D6 inhibitors, were lower than the levels of extensive metabolizers not on inhibitors, and comparable to that of poor metabolizers. Two of these studies [59,69] involved subjects on venlafaxine and no effect on plasma endoxifen levels were noted in these subjects. A chart review of 225 patients with breast cancer on tamoxifen showed that patients homozygous for the wild type CYP2D6 allele who were not on a CYP2D6 inhibitor had a 2-year relapse-free survival rate of 98% 92% for patients either heterozygous for allele 4 (a non functioning allele) and not on a CYP2D6 inhibitor or homozygous for the wild type allele but on a weak or moderate CYP2D6 inhibitor such as sertraline [70]. Patients homozygous for allele 4 or heterozygous for allele 4 and on a moderate or potent inhibitor or homozygous for the wild type allele but on a potent inhibitor such as paroxetine or fluoxetine had, with 68%, the worse 2-year relapse-free survival rate. A retrospective cohort study of 2430 women with breast cancer taking a SSRI (paroxetine, fluoxetine, sertraline, citalopram, or fluvoxamine) or venlafaxine in conjunction with tamoxifen was performed [71]. Women taking paroxetine for 25%, 50% and 75% longer had mortality rates 24%, 54% and 91% higher, respectively. Other antidepressants were not associated with higher mortality rates. Comparing women using paroxetine for 41% of the time they were on tamoxifen with women using paroxetine for only 1% of the time, one additional death from breast cancer within 5 years of stopping tamoxifen would occur for every 19.7 women treated. This number needed to h decreased to 6.9 when women were receiving paroxetine for the whole duration of their tamoxifen treatment. On the other hand, one case control study [72] showed no significant difference in breast cancer recurrence CYP inhibitor or substrate exposure. It did not however take genotypes into account and likely did not have adequate statistical power to show a difference if one truly existed. A retrospective cohort [73] of 1306 breast cancer patients, some of whom were receiving tamoxifen, showed no association between antidepressant use and the risk of recurrence. However, a trend was noted for estrogen receptor positive breast cancer patients on tamoxifen concomitantly receiving fluoxetine or paroxetine. A case control study [74] of 184 cases of breast cancer recurrence matched to 184 controls without recurrence did not show a reduction of the effectiveness of tamoxifen in patients also receiving citalopram. The extension [75] of this study showed that 37 of the 366 women who had ever used citalopram while using tamoxifen for estrogen receptor positive breast cancer had a recurrence of breast cancer 35 of the 366 matched controls (receiving tamoxifen for estrogen positive breast cancer but not on citalopram) for an adjusted odds ratio or 1.1 (95% CI 0.7 to 1.7). Women receiving another SSRI (fluoxetine, paroxetine or sertraline) while taking tamoxifen also did

5 Table 2 Studies of antidepressants for hot flashes in tamoxifen users. Medication Dose Study design Duration of treatment Citalopram 10 mg qd 1 week then 20 mg qd Fluoxetine Paroxetine 10 mg qd or 20 mg qd or 30 mg qd (each a ) 10 mg qd 1 week then 20 mg qd 20 mg qd then or vice versa 10 mg qd or 20 mg qd then or vice versa CR 12.5 mg, 25 mg or N total Pilot 4 weeks 24 F with hx breast ca or refusing estrogen (18 Randomized double-blind 6 weeks 254 F 196 evaluable Pilot 4 weeks 30 F with inadequate control with venlafaxine (29 started, 22 fully randomized crossover trial Randomized double-blind crossover controlled trial 4 weeks per 87 F recruited (81 started, 68 and 66 completed one and two s) 4 weeks 279 F screened (151 randomized 107 included in analysis) 6 weeks 171 F entered (165 randomized, 160 included in efficacy analysis) N on tamoxifen (%) frequency (hot flash per day and/or %) score (% unless unavailable) frequency hot flash score 44% 58% 64% N/A More than 50% decrease in 65% Between 6% and 11% in each 20% for, 46% for 10 mg, 43% for 20 mg and 50% for 30 mg (differences not significant between doses of citalopram but significant p < 0.001) 23% for, 49% for 10 mg, 50% for 20 mg and 55% for 30 mg (differences not significant between doses of citalopram but significant (p < 0.001) 19% for, 35% for 10 mg, 41% for 20 mg and 46% for 30 mg (p = 0.006) 22% for, 39% for 10 mg, 45% for 20 mg and 60% for 30 mg (p < 0.001) 52% 45% (p < 0.001) 53% (p < 0.001) N/A More than 50% decrease in 50% 56% in / fluoxetine and 53% in fluoxetine/ % At end of first : median decreases of 3.4 flash/d (42%) with fluoxetine vs 2.5 flash/d (31%) with (p = 0.54). Crossover data: median improved reduction: 1.5 flash/d (19%) with fluoxetine (p = 0.01) 40.6% for 10 mg vs 13.7% for (p = ) 51.7% for 20 mg vs 26.6% for (p = 0.002). Efficacy similar between the 2 doses 7% 3.3 flash/d with 12.5 mg, 3.2 flash/d with 25 mg and 1.8 flash/d with At end of first : median decreases of 50%with fluoxetine vs 36% with (p = 0.35). Crossover data: median improved reduction: 24% with fluoxetine (p = 0.02) 45.6% for 10 mg vs 13.7% for (p = ) 56.1% for 20 mg vs 28.8% for (p = 0.004). Efficacy similar between the 2 doses Mean -adjusted reductions: 4.7 (p = 0.007) with 12.5 mg and 3.6 (p = 0.03) with 25 mg (median reductions of 62.2% with 12.5 mg, 64.6% with 25 mg and 37.8% with ) N/A More than 50% decrease in hot flash daily activity in 42% with fluoxetine and 31% with Adverse effects 6 withdrawals due to adverse effects No significant differences between and different doses of citalopram 2 withdrawals were due to adverse effects No difference between s during first. No significant findings between treatments for individual patients N/A N/A Patients less likely to discontinue 10 mg 20 mg More than 50% of 104Fon paroxetine 60.5% of 104 F on paroxetine Adverse event reported in 58.3% with paroxetine CR and in 53.6% with Reference Barton et al. [23] Barton et al. [24] Loprinzi et al. [25] Loprinzi et al. [26] Stearns et al. [27] Stearns et al. [28] 300 J.E. Desmarais, K.J. Looper / Maturitas 67 (2010)

6 Table 2 (Continued ) Medication Dose Study design Duration of treatment Sertraline 50 mg then or vice versa randomized controlled crossover study 6 weeks each N total 62 F breast ca survivors (47 completed first, 39 completed both) Venlafaxine 12.5 mg bid Pilot 4 weeks 31 breast ca survivors or men on androgen deprivation therapy (28 evaluable of which 82% F) Mirtazapine Desipramine Buproprion 37.5 mg qd or 75 mg qd (gradually increased) or 150 mg qd (gradually increased) or XR 37.5 mg 37.5 mg twice daily vs clonidine mg twice daily 7.5 mg qhs and increased to 30 mg qhs by week 4 25 mg qd Titrated up to 100 mg by week mg qd 3d then 150 mg bid 4 weeks 229 F breast ca survivors or refusing hormonal treatment (221 started, 191 Open-label study 8 weeks 40 breast ca survivors (30 completed 4 weeks, 27 completed 8 weeks) 4 weeks 80 breast ca (64 analysed) Pilot 5 weeks 22 F provided data (16 completed) Pilot 5 weeks 26 F enrolled (23 started 14 with efficacy data) Pilot 4 weeks 7 M 14 F 20 evaluable N on tamoxifen (%) frequency (hot flash per day and/or %) 100% At 6 weeks, no significant difference from baseline Crossover analysis: 0.9 flash/d for to sertraline vs +1.5 flash/d for sertraline to (p = 0.03) score (% unless unavailable) At 6 weeks, no significant difference from baseline. Crossover analysis: 1.7 for to sertraline vs +3.4 for sertraline to (p = 0.03) 68% 2.3 flash/d (34.8%) Median reduction: 55% 69% Median decreases at week 4: 19% with, 30% with 37.5 mg, 46% with 75 mg and 58% with 150 mg (p < ) 65% Completer analysis: 39.1% at 4 weeks (p < 0.001), 53.3% at 8 weeks (p < 0.001) 70% in clonidine, 81% in venlafaxine At week 4: median decrease of 7.6 flash/d (57%) with venlafaxine vs 4.85 flash/d (37%)with clonidine (p = 0.025) 45% Median decrease of 52.5% Median decreases at week 4: 27% with, 37% with 37.5 mg, 61% for 75 mg and 61% for 150 mg (p < ) Completer analysis: 41.7% at 4 weeks (p < 0.001), 59.7% at 8 weeks (p < 0.001) At week 4: median decrease of 57% with venlafaxine and 39% with clonidine (p = 0.043) Median decrease of 59.5% frequency At end of first : 36% with sertraline vs 27% with (p = 0.7) hot flash score N/A 54% More than 50% decrease in 58% of the 25 completers N/A More than 50% decrease in 20% with, 45% with 37.5 mg, 63% with 75 mg and 55% with 150 mg More than 50% decrease: 27% at 4 weeks, 66% at 8 weeks More than 50% decrease in 55% with venlafaxine vs 36% with clonidine More than 50% decrease: 33% at 4 weeks and 70% at 8 weeks N/A N/A More than 50% decrease in 63% Adverse effects More patients reported side effects on sertraline vs (43.8% vs 25%) during first 2 withdrawals due to adverse effects Higher frequencies of mouth dryness, decreased appetite, nausea and constipation with 75 mg and 150 mg Two withdrawals due to side effects (mostly gastrointestinal) Nine withdrawals due to adverse effects. Nausea more frequently reported with venlafaxine than with clonidine Significant increases in appetite and dry mouth. 2 withdrawals due to adverse effects 30% 1.9 flash/d (23%) 31% N/A N/A 7 withdrawals due to adverse effects 46% of F 20% ( 1.3 flash/d) 23% 10% 30% 5 withdrawals due to adverse effects Reference Kimmick et al. [29] Loprinzi et al. [30] Loprinzi et al. [31] Biglia et al. [32] Loibl et al. [33] Perez et al. [34] Barton et al. [35] Perez et al. [36] J.E. Desmarais, K.J. Looper / Maturitas 67 (2010)

7 Table 3 Studies of other non-hormonal therapy for hot flashes in tamoxifen users. Medication Dose Study design Duration of treatment Gabapentin Pregabalin Leviretacetam 100 mg tid, 300 mg tid (gradually increased) or 300 mg qhs 1 week then 300 mg bid 1 week then 300 mg tid 300 mg qhs 3d then 300 mg bid 3 d then 300 mg tid + continued use of antidepressant or weaning 300 mg qhs 3d then 300 mg bid 3 d then 300 mg tid or vitamin E 800 IU per day 75 mg bid (increased gradually) or 150 mg bid (increased gradually) (results significant for both doses vs ) 500 mg qhs titrated up to 1000 mg bid by week 4 N total 8 weeks 420 F with breast ca (371 Pilot 4 weeks 23 F hx of breast ca or refusing estrogen and 1 M hx prostate ca (20 F evaluable, 16 completed) 4 weeks 118 F with inadequate control with antidepressant (113 started, 91 completed) 12 weeks 115 F with breast ca (89 started, 60 completed) 6 weeks 207 F (191 eligible 163 Pilot 4 weeks 30 F with hx of breast ca or refusing estrogen (28 started, 19 with complete data) N on tamoxifen (%) 68 75% frequency (hot flash per day and/or %) Decreases after 4 and 8 weeks: 1.98 (18%) and 2.25 (15%) flash/d with, 2.64 (28%) and 2.86 (30%) flash/d with 100 mg tid, 4 (41%) and 4.21 (44%) flash/d with 300 mg tid (significant difference from with both dosages) 70% Completer analysis: 66% 33% combined, 40% gabapentin alone 86-87% ( on tamoxifen or other hormone therapy ) 7-16% Median reductions of 54% for combined treatment vs 49% for gabapentin alone (p = 0.61) Completer analysis: 52.34%, 54.09%, 57.05% with gabapentin (p 0.05) vs 11.1%, 11.63%, 10.02% with vitamin E (not significant) for weeks 4, 8 and 12 Median decreases of 2.9 flash/d (36.3%) with, 4.6 flash/d (58.5%) with 75 mg bid and 4.9 flash/d (61.1%) with 150 mg bid (results significant for both doses vs ) 11% Completer analysis: 4.5 flash/d (53%) score (% unless unavailable) Decreases after 4 and 8 weeks: 21% and 15% with, 33% and 31% with 100 mg tid, 49% and 46% with 300 mg tid (significant difference from with higher dosage only) Completer analysis: 70% Median reductions of 56% for combined treatment vs 60% for gabapentin alone (p = 0.37) Completer analysis: 62.62%, 65.52%, 66.87% with gabapentin (p 0.005) vs 8.83%, 9.56%, 7.28% with vitamin E (not significant) at weeks 4, 8 and % with, 64.9% with 75 mg bid and 71% with 150 mg bid (results significant for both doses vs ) (p = and for respective pregabalin s vs ) Completer analysis: 57% frequency hot flash score Adverse effects N/A N/A Appetite worsened at 4 weeks with gabapentin (but not at 8 weeks) N/A Completer analysis: more than 50% decrease in 82% 4 withdrawals due to adverse effects (mainly and dizziness) N/A N/A No statistically significant differences between the 2 s More than 50% decrease in 38.5%, 50% and 57% with gabapentin (weeks 4, 8 and 12) More than 50% decrease in 52%, 70% and 66.5% (weeks 4, 8 and 12) with gabapentin 28% stopped gabapentin because of side effects (mostly dizziness and somnolence) N/A N/A More dizziness with both pregabalin doses. More cognitive difficulties with higher pregabalin dose N/A N/A 29% withdrew due to adverse effects (mainly somnolence, fatigue and dizziness) Reference Pandya et al. [37] Loprinzi et al. [38] Loprinzi [39] Biglia et al. [40] Loprinzi et al. [41] Thompson et al. [42] 302 J.E. Desmarais, K.J. Looper / Maturitas 67 (2010)

8 Table 3 (Continued ) Medication Dose Study design Duration of treatment N total N on tamoxifen (%) frequency (hot flash per day and/or %) score (% unless unavailable) frequency hot flash score Adverse effects Reference Clonidine Oxybutynin Vitamin E Transdermal patch (equivalent to oral dose of 0.1 mg per day) then or vice versa 0.1 mg/d or 90% of patients received 5 mg bid or less 800 IU qd then or vice versa Randomized double-blind crossover study 4 weeks each Chart study 2 weeks to 5 years Placebocontrolled randomized crossover trial 116 F (110 randomized, 89 provided hot flash frequency data and 86 hot flash severity data) 8 weeks 198 F postmenopausal with breast ca (194 evaluable, 149 completed) 4 weeks each 48 F and 4 M with cancer (90% had previous unsuccessful treatment for hot flashes) 125 F breast cancer survivors (120 started, 105 completed first, 104 both s) 100% Median decreases at week 5: 44% for clonidine first, 27% for first (p = 0.04). Median decreases at week 9: 26% for clonidine first, 38% for first (p = 0.2) Crossover analysis: 20% more reduction with clonidine vs (p < ) 100% 37%, 38.4% with clonidine vs 20.1%, 23.6% with at week 4 (p = 0.001) and week 8 (p = 0.006) Median decreases at week 5: 56% with clonidine first, 30% with first (p = 0.04). Median decreases at week 9: 42% with clonidine first, 47% with first (p = 0.2). Crossover analysis: 27% more reduction with clonidine vs (p = ) 42.2%, 45% with clonidine vs 23.7%, 26.4% with at week 4 (p = 0.002) and week 8 (p = 0.006) 55.8% N/A 70% of patients treated had partial or excellent response 13.5% of responders required addition of another agent 59 60% After 4 weeks: 25% for vitamin E first, 22% for first (p = 0.9). After 8 weeks: additional 0.04% for vitamin E first, 17% for first (p = 0.32). Crossover analysis: 1 flash/d with vitamin E vs (p 0.05) After 4 weeks: 28%for vitamin E first, 20% for first (p = 0.68). After 8 weeks: additional 0.03% for vitamin E first, 25% for first (p = 0.24) N/A N/A Clonidine associated with mouth dryness, constipation, itchiness under patch and drowsiness N/A N/A More difficulty sleeping with clonidine N/A N/A 12% of responders stopped medication within 4 weeks due to adverse effects N/A N/A 120 patients evaluated for toxicity did not show any. No differences in side effects between the 2 groups Goldberg et al. [43] Pandya et al. [44] Sexton et al. [45] Barton et al. [46] J.E. Desmarais, K.J. Looper / Maturitas 67 (2010)

9 Table 4 Studies of medicinal products for the treatment of hot flashes including tamoxifen users. Medication Dose Study design Duration of treatment Black cohosh Soy isoflavone extracts Tamoxifen 20 mg (usual care) ± 20 mg of cimicifuga racemosa (CR BNO 1055) bid Randomized open-label N total 12 months 136 F premenopausal breast ca survivors (90 received CR BNO 1055) Remifemin Pilot 4 weeks 23 F (21 Cimicifuga racemosa 20 mg bid then or vice versa Black cohosh one tablet bid Soy beverage containing 90 mg of isoflavones or rice beverage One tablet containing 50 mg of soy isoflavones tid then or vice versa Two soy capsules bid each containing 17.5 mg of isoflavines or randomized crossover trial (stratified for tamoxifen use) randomized crossover trial 4 weeks each 132 F randomized ( d 85 F breast ca survivors (69 completed) 12 weeks 263 F with hx breast ca screened (157 randomized, 123 completed) 4 weeks each 182 F breast ca survivors (177 started, weeks 72 F breast ca (68 N on tamoxifen (%) Mean reduction in frequency (hot flash per day and/or %) 100% At 6 months: no significant decreases from baseline in usual care group Mean reduction in score (% unless unavailable) At end of study: 73.9% and 24.4% of F with usual care and CR BNO 1055 had severe flashes, 26.1% and 28.9%, moderate flashes and 0% and 46.7% no flashes. (p < 0.01) frequency hot flash score Adverse effects N/A N/A 11 minor adverse effects reported: 7 in usual care group and4in intervention group 29% 4.1 flash/d (50%) 56% 52% More than 50% decrease in 66% 40 48% After 4 weeks: 17% with black cohosh vs 26% with (p = 0.36) 69% Overall mean decline 27%. Differences between groups not significant (p = 0.44, p = 0.86 when adjusting baseline number and tamoxifen use) 34% soy 28% 68% in each 1.8 flash/d (25%) for soy vs 2.5 flash/d (34%) for (difference not stat. significant) No significant differences between soy and After 4 weeks: 20% with black cohosh vs 27% with (p = 0.53) Difference between groups not statistically significant 5.4 (30%) with soy vs 7.5 (40%) with (difference not stat. significant) No significant differences between soy and 78% (28) N/A No significant difference in menopausal symptoms between groups N/A More than 50% decrease in 24% with black cohosh and 36% with after 4 weeks (p = 0.33) Joint pain in one patient. Symptoms at baseline less frequent at end Minimal toxicity. No differences between groups N/A N/A 16 withdrawals; 3 due to adverse events. 3 serious adverse events: one with /tamoxifen, two with black cohosh/tamoxifen. 10 minor events N/A N/A More frequent and severe gastrointestinal side effects with soy. 4 women on soy and one on had vaginal spotting 36% with vs 24% with soy (p = 0.01) More than 50% reduction in 38% with vs 35% with soy (p = 0.78) No differences with regards to diarrhea, nausea, vomiting or bloating/gas N/A N/A Mild toxicity, primarily gastrointestinal with no differences between s Reference Hernandez Munoz and Pluchino [47] Pockaj et al. [48] Pockaj et al. [49] Jacobson et al. [50] Van Patten et al. [51] Quella et al. [52] MacGregor et al. [53] 304 J.E. Desmarais, K.J. Looper / Maturitas 67 (2010)

10 J.E. Desmarais, K.J. Looper / Maturitas 67 (2010) not have an increased risk of breast cancer recurrence (adjusted OR 0.9, 95% CI 0.5 to 1.8). An abstract presented in 2009 [76] described a phacy database study in the Netherlands where 1990 breast cancer patients using tamoxifen were screened for use of CYP2D6 inhibitor during tamoxifen treatment. 215 (10.8%) of the women fit the criteria. Using concomitant CYP2D6 inhibitor was not associated with recurrence of breast cancer in this cohort. Another abstract presented in 2009 [77] described an American phacy claims database study examining 1298 women with breast cancer treated with tamoxifen with or without concomitant CYP2D6 inhibitor. Two-year breast cancer recurrence rates were higher in the group taking a 2D6 inhibitor the group not taking an inhibitor (13.9% vs 7.5% for HR 1.92, 95% CI 1.33 to 2.76, p < 0.001). A review [78] of most of the above studies and of the in vivo and in vitro measures of inhibition of CYP2D6 by antidepressants concluded that paroxetine and fluoxetine had a large effect on the metabolism of tamoxifen, that bupropion may have a similarly large effect, and that venlafaxine had minimal if any effect on tamoxifen metabolism. Mirtazapine was hypothesized to have a minimal effect, citalopram and escitalopram; mild effects, and sertraline, fluvoxamine and duloxetine; moderate effects on the metabolism of tamoxifen. The review concluded that paroxetine, fluoxetine and bupropion should be avoided in patients using tamoxifen, that venlafaxine was the preferred antidepressant in this population, with desvenlafaxine a possible alternative given that its metabolism does not involve CYP2D6. Other antidepressants were to be considered only after a thorough risk-benefit assessment Cytochrome P450 3A4/5 inhibitors Less has been written about CYP3A4/5 polymorphisms and tamoxifen response as well as on failure of tamoxifen treatment with CYP3A4/5 inhibitors. A study of 677 women with breast cancer, of whom 238 were randomized to 2 or 5 years of treatment with tamoxifen, showed that women in the 5-year tamoxifen group had a significantly improved recurrence-free survival if they were homozygous for allele 3 at CYP3A5 (HR = 0.20, 95% CI = 0.07 to 0.55, p = 0.002) [65]. Women with this genotype randomized to the 2- year group had an increased risk of recurrence, which did not attain statistical significance. In a study examining exposure to CYP inhibitors in 28 cases of breast cancer recurrences and 28 controls, only one patient was on a CYP 3A inhibitor in both groups [72]. The study was not adequately powered to find a true difference if one existed. Nefazodone is a strong inhibitor, and fluvoxamine, a moderate inhibitor of CYP3A4/5. St John s wort, a natural supplement used in the treatment of depression, is an inducer of CYP3A. Genistein, an isoflavone, inhibits several subtypes of cytochrome P450, including 2D6 and 3A4 [79]. Red clover extracts are rich in isoflavones and have been shown to inhibit 3A4. Valerian extracts, used by some patients as a mild sedative, inhibit both 2D6 and 3A4 [79]. These medications and medicinal products could all potentially affect the metabolism of tamoxifen Phytoestrogens Phytoestrogens, including isoflavones such as genistein, and lignans such as flaxseed, are found in the diet and sold as diet supplements. Many women use them to relieve symptoms of menopause. A cohort of 1954 female breast cancer survivors followed for 6.31 years were asked about their soy intake [80]. Amongst women treated with tamoxifen, a significant decrease in breast cancer recurrence was observed with increased intake of glycetin but not of daidzein or of genistein (results not significant). A 60% decrease in breast cancer recurrence was observed in postmenopausal women treated with tamoxifen and ingesting high amounts of daidzein women with the lowest daidzein intake. A cross-sectional study administered a food questionnaire to calculate the daily intake of isoflavones of 380 Asian Americans with breast cancer treated with tamoxifen [81]. No relationship between plasma levels of tamoxifen and metabolites and self-reported isoflavone intake or plasma isoflavone levels was observed. In China, a cohort of 5042 female breast cancer survivors were followed for a median duration of 3.9 years [82]. Soy food intake was inversely associated with mortality and recurrence of breast cancer. Women in the highest quartile of soy protein intake were 0.71 less likely to die (95% CI 0.54 to 0.92) and 0.68 less likely to have recurrence of their disease (95% CI, 0.54 to 0.87) compared with women in the lowest quartile of soy intake. The inverse association was present in both users and nonusers of tamoxifen. A recent review [83] of phytoestrogens for breast cancer showed conflictual evidence from in vitro and animal studies, with some studies reporting that phytoestrogens stimulated estrogensensitive breast cancer growth which may or may not be counteracted by tamoxifen others stating that phytoestrogens had growth inhibitory effects on breast cancer cells, and yet other studies showing phytoestrogens to have growth stimulation effects at low doses and growth inhibitory effects at high doses. 7. Conclusion and recommendations (Tables 5 and 6) Studies done with patients using tamoxifen have shown venlafaxine can be safely administered concomitantly with tamoxifen [59,69]. Venlafaxine is effective both for the treatment of hot flashes and depression. Desvenlafaxine, a metabolite of venlafaxine, has been studied for the treatment of hot flashes with positive results [84], but has not been studied in tamoxifen users. Desvenlafaxine is likely safe to administer with tamoxifen as it is not metabolized by the cytochrome P450 enzyme. Mirtazapine has minimal 2D6 inhibition and has preliminary evidence for treating hot flashes. Paroxetine, fluoxetine and bupropion are strong CYP2D6 inhibitors and are to be avoided in tamoxifen users. Fluvoxamine and nefazodone both inhibit CYP3A, which could potentially affect the metabolism of tamoxifen, although there is no data to support this. Other commonly used antidepressants have mild to moderate degree of CYP2D6 inhibition and their use necessitates benefit-risk assessments (Tables 5 and 6). Gabapentin does not interact with the cytochrome P450 system and is likely safe to use in patients using tamoxifen. Given evidence of its efficacy in treating hot flashes, it should be considered a first-line agent for the treatment of tamoxifen-induced hot flashes in non-depressed patients. Pregabalin also does not interact with cytochrome p450 and may be an alternative to gabapentin. Clonidine is another alternative agent but may cause dry mouth, constipation and drowsiness [43] and requires blood pressure monitoring. A recent study concluded that the efficacy of the newer antidepressants and gabapentin for hot flashes is seen within 4 weeks of initiating treatment [85]. A trial of 4 weeks is thus recommended when starting one of these medications for treating hot flashes. The evidence of medicinal products for the treatment of tamoxifen-induced hot flashes is equivocal at best. Use of natural menopausal supplements and diets rich in isoflavones should not be encouraged until more data regarding their safety and efficacy in treating menopausal and depressive symptoms in tamoxifen users is available.

11 306 J.E. Desmarais, K.J. Looper / Maturitas 67 (2010) Table 5 Psychotropics used in the treatment of hot flashes or depression and their interactions with tamoxifen. Medication Impact on tamoxifen metabolism Recommendations for treatment of tamoxifen users Gabapentin Does not inhibit cytochrome p450 Use preferentially for treatment of hot flashes if no depression Recommended dose: 300 mg tid Pregabalin Does not inhibit cytochrome p450 Alternative to gabapentin Recommended dose: 75 mg bid Venlafaxine Minimal 2D6 inhibitor Use preferentially for treatment of hot flashes if depression Recommended dose for hot flashes: 75 mg per day Desvenlafaxine Mirtazapine Minimal 2D6 inhibitor Minimal 2D6 inhibitor Alternative to venlafaxine but no studies for treatment of hot flashes in this population Only one pilot study for treatment of hot flashes. Consider use based on benefit-risk assessment Citalopram Mild 2D6 inhibitor Consider use based on benefit-risk assessment Escitalopram Mild 2D6 inhibitor No studies for treatment of hot flashes in this population. Consider use based on benefit-risk assessment Sertraline Moderate 2D6 inhibitor Consider use based on benefit-risk assessment Fluvoxamine Moderate 2D6 and 3A4 inhibitor No studies for treatment of hot flashes. Consider use for depression based on benefit-risk assessment Duloxetine Moderate 2D6 inhibitor Nefazodone Mild 2D6 inhibitor Strong 3A4 inhibitor Paroxetine Strong 2D6 inhibitor Avoid use Fluoxetine Strong 2D6 inhibitor Bupropion Strong 2D6 inhibitor Table 6 Health supplements used for the treatment of hot flashes and/or depression and their interactions with tamoxifen. Health supplements Indication Theoretical impact on tamoxifen metabolism Isoflavones Used in the treatment of menopausal symptoms Genistein (found in soy) inhibits several subtypes of cytochrome P450, including 2D6 and 3A4 Red clover extracts inhibit 3A4 Does not inhibit 2D6 and 3A4 Black cohosh Used in the treatment of menopausal symptoms Valerian Used as a mild sedative Inhibits both 2D6 and 3A4 St-John s wort Used for treatment of depression Induces CYP3A Recommendations for treatment of tamoxifen users Used cannot be recommended at this time for lack of evidence and/or concerns of interactions with tamoxifen Clinicians should remain cautious about using strong inhibitors and/or inducers of cytochrome 2D6 and 3A4 in tamoxifen users until more data is available. There are however safe treatments for hot flashes and depression in tamoxifen users. Contributors Julie Eve Desmarais contributed to literature search, drafting article, approval of article. Karl J. Looper contributed to critical revision and approval of article. Competing interest Dr Desmarais and Dr Looper report no competing interests. No financial support was received for the completion of this manuscript. Provenance and peer review Commissioned and externally peer reviewed. References [1] Mayo Clinic. The phacogenetics of tamoxifen therapy. Mayo Reference Services Communiqué 2007;32(1). [2] Brauch H, Murdter TE, Eichelbaum M, Schwab M. Phacogenomics of tamoxifen therapy. Clin Chem 2009;55(10): [3] MacLennan AH, Broadbent JL, Lester S, Moore V. Oral estrogen and combined oestrogen/progesterone therapy versus for hot flushes. Cochrane Database Syst Rev 2004 Oct 18;(4):CD [4] Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350(9084): [5] Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362(9382): [6] Holmberg L, Iversen OE, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008;100(7): [7] Sestak I, Kealy R, Edwards R, Forbes J, Cuzick J. Influence of hormone replacement therapy on tamoxifen-induced vasomotor symptoms. J Clin Oncol 2006;24(24): [8] Osborne CR, Duncan A, Sedlacek S, Paul D, Holmes F, Vukelja S, et al. The addition of hormone therapy to tamoxifen does not prevent hot flashes in women at high risk for developing breast cancer. Breast Cancer Res Treat 2009;116(3): [9] Bonneterre J, Buzdar A, Nabholtz JM, Robertson JF, Thurlimann B, von Euler M, et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer 2001;92(9): [10] Coates AS, Keshaviah A, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy

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