Maturitas
Volume 67, Issue 4 , Pages 296-308, December 2010

Managing menopausal symptoms and depression in tamoxifen users: Implications of drug and medicinal interactions

  • Julie Eve Desmarais

      Affiliations

    • Clinical Psychopharmacology Unit, Allan Memorial Institute, McGill University Health Centre, 1025 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1
    • Dept of Psychiatry, McGill University, Canada
    • Corresponding Author InformationCorresponding author at: McGill University Health Centre, Allan Memorial Institute, 1025 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. Tel.: +1 514 934 1934x35575; fax: +1 514 843 2898.
    • ,
  • Karl J. Looper

      Affiliations

    • Dept of Psychiatry, McGill University, Canada
    • 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

Received 26 July 2010; received in revised form 10 August 2010; accepted 10 August 2010. published online 27 August 2010.

Article Outline

Abstract 

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 tamoxifen-induced 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.

Keywords: Tamoxifen, Hot flashes, Menopause, Depression, Treatment, Drug interaction or incompatibility

 

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1. 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-N-desmethyltamoxifen (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].

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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.

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3. Vasomotor symptoms 

Hormone replacement therapy (HRT) is an effective treatment for menopausal symptoms, reducing frequency of weekly hot flashes by 75% compared to 57.7% with placebo, with severity odd ratios of 0.13 compared to placebo 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], [10], [11], [12], [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.

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4. Treatment of vasomotor symptoms 

4.1. Non-estrogenic hormonal therapy (Table 1) [14], [15], [16], [17], [18], [19] 

Given concerns of breast cancer recurrence or tamoxifen failure with estrogenic therapy, trials have been conducted with non-estrogenic 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 (RCT) reported that tibolone was associated with a significant increased risk of breast cancer recurrence at 3 years (HR 1.4) compared to placebo [18].

Table 1. Studies of non-estrogenic hormonal therapy for hot flashes including tamoxifen users.
MedicationDoseStudy designDuration of treatmentN totalN on tamoxifen (%)Mean reduction in frequency (hot flash per day and/or %)Mean reduction in score (% unless unavailable)% of patients with ≥50% decrease in frequency% of patients with ≥50% decrease in hot flash scoreAdverse effectsReference
Megestrol acetate (MA)20mg bid then placebo or vice versaDouble-blind randomized controlled crossover trial*4 weeks each period97 F with breast ca hx and 66 M with prostate ca hx (80 F and 60 M included in analysis of efficacy)80–81% of F depending on armAt 4 weeks median decreases of: 74% for F and 80% for M on MA compared to 27% for F and 19% for M on placebo (p<0.001)At 4 weeks median decreases of: 83% for F and 87% for M on MA compared to 27% for F and 16% for M on placebo (p<0.001)At 4 weeks: 71% of F and 79% of M on MA compared to 24% of F and 12% of M on placebo (p<0.001)N/AIncrease in hot flash score before decrease in some F on MA. Vaginal bleeding in 31% of F (mostly upon withdrawal of MA)Loprinzi et al. [14]
20mg qd, 40mg qd or placeboRCT3 months + another 3 months if treatment successful288 F with breast ca (286 eligible for analysis and 244 with data at 3 months)85%N/AN/AAt 3 months, a ≥75% decrease in: 14% on placebo, 65% on 20mg and 48% on 40mg (both doses vs placebo p<0.0001). Most successes maintained at 6 monthsN/ANo significant differences by treatment armGoodwin et al. [15]

MPAMPA 400mg IM x1 vs venlafaxine 37.5mg qd x1 week, then 75mg qdRCT6 weeks220 F (188 eligible for analysis)40%Similar reduction in frequencies than in scores79% for MPA and 55% for venlafaxine (p≤0.0001)N/AMore than 50% decrease in 53% on venlafaxine and 86% on MPA (p<0.0001)Less toxicity was reported with MPALoprinzi et al. [16]
DHEA50mg qdPilot4 weeks28 F (22 evaluable)41%50% decrease or −4.4 flash/d (p=0.0002)50% decrease (p=0.0004)N/AIntent-to-treat analysis: 45%No side effects significantly worse than baselineBarton et al. [17]

Tibolone2.5mg qd or placeboDouble-blind randomized trial for risk of breast cancer recurrenceMedian follow-up of 3.1 years3148 F with hx of breast ca (3098 included in intent-to-treat analysis)67%Significant difference in favour of tibolone at week 4 (p=0.004), week 8 (p<0.0001), and week 12 (p<0.0001)N/AN/AN/AHR of breast cancer recurrence of 1.40 with tibolone (95% CI 1.14–1.70) p=0.001. Treatment-related, adverse effects: 27.7%with tibolone and 21.8% with placebo (p=0.0002)Kenemans et al. [18]
2.5mg qd or placeboDouble-blind RCT 70 F post-surgery for breast ca (67 analysed)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 placebo (p=0.022)At 3 months hot flashes less severe with tibolone compared to placeboN/AN/ANo 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 placeboKroiss et al. [19]

*Crossover analyses not reported because of significant carryover effects.

4.2. Non-hormonal therapy 

A meta-analysis [20] of 43 double-blind, RCTs of non-hormonal therapies for hot flashes was published in 2006. 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 placebo 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 placebo arms combined. Additional decreases in mean hot flash score from placebo were 33% for venlafaxine (75mg/d), 13% to 41% for paroxetine (10 to 25mg/d), 13% for fluoxetine (20mg/d), 9% to18% for sertraline (50mg/d), 3% for sertraline (100mg/d) and 35% to 38% for gabapentin (900 to 2400mg/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 placebo [22].

4.2.1. Antidepressants (Table 2) [23], [24], [25], [26] 

Fluoxetine [26], paroxetine [27], [28], sertraline [29], citalopram [24] and venlafaxine [31], [33] all have RCT 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 placebo Table 2.

Table 2. Studies of antidepressants for hot flashes in tamoxifen users.
MedicationDoseStudy designDuration of treatmentN totalN on tamoxifen (%)Mean reduction in frequency (hot flash per day and/or %)Mean reduction in score (% unless unavailable)% of patients with ≥50% decrease in frequency% of patients with ≥50% decrease in hot flash scoreAdverse effectsReference
Citalopram10mg qd×1 week then 20mg qdPilot4 weeks24 F with hx breast ca or refusing estrogen (18 evaluable)44%58%64%N/AMore than 50% decrease in 65%6 withdrawals due to adverse effectsBarton et al. [23]
10mg qd or 20mg qd or 30mg qd (each compared to a placebo arm)Randomized double-blind6 weeks254 F 196 evaluableBetween 6% and 11% in each arm20% for placebo, 46% for 10mg, 43% for 20 mg and 50% for 30mg (differences not significant between doses of citalopram but significant compared to placebo p<0.001)23% for placebo, 49% for 10mg, 50% for 20mg and 55% for 30mg (differences not significant between doses of citalopram but significant compared to placebo (p<0.001)19% for placebo, 35% for 10mg, 41% for 20mg and 46% for 30mg (p=0.006)22% for placebo, 39% for 10mg, 45% for 20mg and 60% for 30mg (p<0.001)No significant differences between placebo and different doses of citalopramBarton et al. [24]
10mg qd×1 week then 20mg qdPilot4 weeks30 F with inadequate control with venlafaxine (29 started, 22 fully evaluable)52%45% (p<0.001)53% (p<0.001)N/AMore than 50% decrease in 50%2 withdrawals were due to adverse effectsLoprinzi et al. [25]

Fluoxetine20mg qd then placebo or vice versaDouble-blind randomized crossover trial4 weeks per period87 F recruited (81 started, 68 and 66 completed one and two periods)56% in placebo/fluoxetine and 53% in fluoxetine/placeboAt end of first period: median decreases of −3.4 flash/d (42%) with fluoxetine vs −2.5 flash/d (31%) with placebo (p=0.54). Crossover data: median improved reduction: −1.5 flash/d (19%) with fluoxetine compared to placebo (p=0.01)At end of first period: median decreases of 50%with fluoxetine vs 36% with placebo (p=0.35). Crossover data: median improved reduction: 24% with fluoxetine compared to placebo (p=0.02)N/AMore than 50% decrease in “hot flash daily activity” in 42% with fluoxetine and 31% with placeboNo difference between arms during first period. No significant findings between treatments for individual patientsLoprinzi et al. [26]

Paroxetine10mg qd or 20mg qd then placebo or vice versaRandomized double-blind crossover placebo-controlled trial4 weeks279 F screened (151 randomized 107 included in analysis)78–100% depending on arm40.6% for 10mg vs 13.7% for placebo (p=0.0006) 51.7% for 20mg vs 26.6% for placebo (p=0.002). Efficacy similar between the 2 doses45.6% for 10mg vs 13.7% for placebo (p=0.0008) 56.1% for 20mg vs 28.8% for placebo (p=0.004). Efficacy similar between the 2 dosesN/AN/APatients less likely to discontinue 10mg compared to 20mgStearns et al. [27]
CR 12.5mg, 25mg or placeboRCT6 weeks171 F entered (165 randomized, 160 included in efficacy analysis)7%−3.3 flash/d with 12.5mg, −3.2 flash/d with 25mg and −1.8 flash/d with placeboMean placebo-adjusted reductions: −4.7 (p=0.007) with 12.5mg and −3.6 (p=0.03) with 25mg (median reductions of 62.2% with 12.5mg, 64.6% with 25mg and 37.8% with placebo)More than 50% of 104 F on paroxetine60.5% of 104 F on paroxetineAdverse event reported in 58.3% with paroxetine CR and in 53.6% with placeboStearns et al. [28]

Sertraline50mg then placebo or vice versaDouble-blind randomized controlled crossover study6 weeks each period62 F breast ca survivors (47 completed first period, 39 completed both)100%At 6 weeks, no significant difference from baseline Crossover analysis: −0.9 flash/d for placebo to sertraline vs +1.5 flash/d for sertraline to placebo (p=0.03)At 6 weeks, no significant difference from baseline. Crossover analysis: −1.7 for placebo to sertraline vs +3.4 for sertraline to placebo (p=0.03)At end of first period: 36% with sertraline vs 27% with placebo (p=0.7)N/AMore patients reported side effects on sertraline vs placebo (43.8% vs 25%) during first periodKimmick et al. [29]

Venlafaxine12.5mg bidPilot4 weeks31 breast ca survivors or men on androgen deprivation therapy (28 evaluable of which 82% F)68%−2.3 flash/d (34.8%)Median reduction: 55%54%More than 50% decrease in 58% of the 25 completers2 withdrawals due to adverse effectsLoprinzi et al. [30]
37.5mg qd or 75mg qd (gradually increased) or 150mg qd (gradually increased) or placeboRCT4 weeks229 F breast ca survivors or refusing hormonal treatment (221 started, 191 evaluable)69%Median decreases at week 4: 19% with placebo, 30% with 37.5mg, 46% with 75mg and 58% with 150mg (p<0.001 compared to placebo)Median decreases at week 4: 27% with placebo, 37% with 37.5mg, 61% for 75mg and 61% for 150mg (p<0.001 compared to placebo)N/AMore than 50% decrease in 20% with placebo, 45% with 37.5mg, 63% with 75mg and 55% with 150mgHigher frequencies of mouth dryness, decreased appetite, nausea and constipation with 75mg and 150mg compared to placeboLoprinzi et al. [31]
XR 37.5mgOpen-label study8 weeks40 breast ca survivors (30 completed 4 weeks, 27 completed 8 weeks)65%Completer analysis: 39.1% at 4 weeks (p<0.001), 53.3% at 8 weeks (p<0.001)Completer analysis: 41.7% at 4 weeks (p<0.001), 59.7% at 8 weeks (p<0.001)More than 50% decrease: 27% at 4 weeks, 66% at 8 weeksMore than 50% decrease: 33% at 4 weeks and 70% at 8 weeksTwo withdrawals due to side effects (mostly gastrointestinal)Biglia et al. [32]
37.5mg twice daily vs clonidine 0.075mg twice dailyDouble-blind RCT4 weeks80 breast ca (64 analysed)70% in clonidine arm, 81% in venlafaxine armAt week 4: median decrease of 7.6 flash/d (57%) with venlafaxine vs 4.85 flash/d (37%)with clonidine (p=0.025)At week 4: median decrease of 57% with venlafaxine and 39% with clonidine (p=0.043)More than 50% decrease in 55% with venlafaxine vs 36% with clonidineN/ANine withdrawals due to adverse effects. Nausea more frequently reported with venlafaxine than with clonidineLoibl et al. [33]

Mirtazapine7.5mg qhs and increased to 30mg qhs by week 4Pilot5 weeks22 F provided data (16 completed)45%Median decrease of 52.5%Median decrease of 59.5%N/AMore than 50% decrease in 63%Significant increases in appetite and dry mouth. 2 withdrawals due to adverse effectsPerez et al. [34]
Desipramine25 mg qd Titrated up to 100mg by week 5Pilot5 weeks26 F enrolled (23 started 14 with efficacy data)30%−1.9 flash/d (23%)31%N/AN/A7 withdrawals due to adverse effectsBarton et al. [35]
Buproprion150mg qd×3d then 150mg bidPilot4 weeks7 M
14 F 20 evaluable		46% of F20% (−1.3 flash/d)23%10%30%5 withdrawals due to adverse effectsPerez et al. [36]
4.2.2. Other psychotropics (Table 3) [37], [38], [39], [40], [41], [42], [43], [44], [45], [46] 

Gabapentin [37], [39], [40] and pregabalin [41] also have proved their efficacy in the treatment of hot flashes through RCTs that have included tamoxifen users. A pilot study [42] suggested that levetiracetam may also be effective Table 3.

Table 3. Studies of other non-hormonal therapy for hot flashes in tamoxifen users.
MedicationDoseStudy designDuration of treatmentN totalN on tamoxifen (%)Mean reduction in frequency (hot flash per day and/or %)Mean reduction in score (% unless unavailable)% of patients with ≥50% decrease in frequency% of patients with ≥50% decrease in hot flash scoreAdverse effectsReference
Gabapentin100mg tid, 300mg tid (gradually increased) or placeboDouble-blind RCT8 weeks420 F with breast ca (371 evaluable)68–75% depending on armDecreases after 4 and 8 weeks: −1.98 (18%) and −2.25 (15%) flash/d with placebo, −2.64 (28%) and −2.86 (30%) flash/d with 100mg tid, −4 (41%) and −4.21 (44%) flash/d with 300mg tid (significant difference from placebo with both dosages)Decreases after 4 and 8 weeks: 21% and 15% with placebo, 33% and 31% with 100mg tid, 49% and 46% with 300mg tid (significant difference from placebo with higher dosage only)N/AN/AAppetite worsened at 4 weeks with gabapentin (but not at 8 weeks)Pandya et al. [37]
300mg qhs×1 week then 300mg bid×1 week then 300mg tidPilot4 weeks23 F hx of breast ca or refusing estrogen and 1 M hx prostate ca (20 F evaluable, 16 completed)70%Completer analysis: 66%Completer analysis: 70%N/ACompleter analysis: more than 50% decrease in 82%4 withdrawals due to adverse effects (mainly and dizziness)Loprinzi et al. [38]
300mg qhs×3d then 300mg bid×3d then 300mg tid+continued use of antidepressant or weaningRCT4 weeks118 F with inadequate control with antidepressant (113 started, 91 completed)33% combined arm, 40% gabapentin alone armMedian reductions of 54% for combined treatment vs 49% for gabapentin alone (p=0.61)Median reductions of 56% for combined treatment vs 60% for gabapentin alone (p=0.37)N/AN/ANo statistically significant differences between the 2 armsLoprinzi [39]
300mg qhs×3d then 300 mg bid×3d then 300mg tid or vitamin E 800 IU per dayRCT12 weeks115 F with breast ca (89 started, 60 completed)86-87% depending on arm (“on tamoxifen or other hormone therapy”)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 12Completer 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 12More 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 gabapentin28% stopped gabapentin because of side effects (mostly dizziness and somnolence)Biglia et al. [40]

Pregabalin75mg bid (increased gradually) or 150mg bid (increased gradually) (results significant for both doses vs placebo)Double-blind RCT6 weeks207 F (191 eligible 163 evaluable)7-16% depending on armMedian decreases of −2.9 flash/d (36.3%) with placebo, −4.6 flash/d (58.5%) with 75mg bid and −4.9 flash/d (61.1%) with 150mg bid (results significant for both doses vs placebo)50.1% with placebo, 64.9% with 75mg bid and 71% with 150mg bid (results significant for both doses vs placebo) (p=0.009 and 0.007 for respective pregabalin arms vs placebo)N/AN/AMore dizziness with both pregabalin doses. More cognitive difficulties with higher pregabalin doseLoprinzi et al. [41]
Leviretacetam500mg qhs titrated up to 1000mg bid by week 4Pilot4 weeks30 F with hx of breast ca or refusing estrogen (28 started, 19 with complete data)11%Completer analysis: −4.5 flash/d (53%)Completer analysis: 57%N/AN/A29% withdrew due to adverse effects (mainly somnolence, fatigue and dizziness)Thompson et al. [42]

ClonidineTransdermal patch (equivalent to oral dose of 0.1mg per day) then placebo or vice versaRandomized double-blind crossover study4 weeks each period116 F (110 randomized, 89 provided hot flash frequency data and 86 hot flash severity data)100%Median decreases at week 5: 44% for clonidine first, 27% for placebo first (p=0.04). Median decreases at week 9: 26% for clonidine first, 38% for placebo first (p=0.2) Crossover analysis: 20% more reduction with clonidine vs placebo (p<0.0001)Median decreases at week 5: 56% with clonidine first, 30% with placebo first (p=0.04). Median decreases at week 9: 42% with clonidine first, 47% with placebo first (p=0.2). Crossover analysis: 27% more reduction with clonidine vs placebo (p=0.0006)N/AN/AClonidine associated with mouth dryness, constipation, itchiness under patch and drowsinessGoldberg et al. [43]
0.1mg/d or placeboDouble-blind RCT8 weeks198 F postmenopausal with breast ca (194 evaluable, 149 completed)100%37%, 38.4% with clonidine vs 20.1%, 23.6% with placebo at week 4 (p=0.001) and week 8 (p=0.006)42.2%, 45% with clonidine vs 23.7%, 26.4% with placebo at week 4 (p=0.002) and week 8 (p=0.006)N/AN/AMore difficulty sleeping with clonidinePandya et al. [44]

Oxybutynin90% of patients received 5mg bid or lessChart study2 weeks to 5 years48 F and 4 M with cancer (90% had previous unsuccessful treatment for hot flashes)55.8%N/A70% of patients treated had “partial or excellent response” 13.5% of responders required addition of another agentN/AN/A12% of responders stopped medication within 4 weeks due to adverse effectsSexton et al. [45]
Vitamin E800IU qd then placebo or vice versaPlacebo-controlled randomized crossover trial4 weeks each period125 F breast cancer survivors (120 started, 105 completed first period, 104 both periods)59–60% depending on armAfter 4 weeks: 25% for vitamin E first, 22% for placebo first (p=0.9). After 8 weeks: additional 0.04% for vitamin E first, 17% for placebo first (p=0.32). Crossover analysis: −1 flash/d with vitamin E vs placebo (p≤ 0.05)After 4 weeks: 28%for vitamin E first, 20% for placebo first (p=0.68). After 8 weeks: additional 0.03% for vitamin E first, 25% for placebo first (p=0.24)N/AN/A120 patients evaluated for toxicity did not show any. No differences in side effects between the 2 groupsBarton et al. [46]
4.2.3. Other medications (Table 3) 

RCTs 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 placebo-controlled randomized crossover trial of vitamin E in breast cancer survivors failed to show differences between the 2 arms in respect to hot flash frequency but crossover analysis however showed that vitamin E could lead to one less hot flash/d compared with placebo [46].

4.2.4. Natural supplements (Table 4) [47], [48], [49], [50], [51], [52], [53] 

Two randomized placebo-controlled trials of black cohosh have failed to show statistically significant differences between black cohosh and placebo [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 placebo were noted in three RCTs [51], [52], [53] Table 4.

Table 4. Studies of medicinal products for the treatment of hot flashes including tamoxifen users.
MedicationDoseStudy designDuration of treatmentN totalN on tamoxifen (%)Mean reduction in frequency (hot flash per day and/or %)Mean reduction in score (% unless unavailable)% of patients with ≥50% decrease in frequency% of patients with ≥50% decrease in hot flash scoreAdverse effectsReference
Black cohoshTamoxifen 20mg (usual care)±20mg of cimicifuga racemosa (CR BNO 1055) bidRandomized open-label12 months136 F premenopausal breast ca survivors (90 received CR BNO 1055)100%At 6 months: no significant decreases from baseline in usual care groupAt 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)N/AN/A11 minor adverse effects reported: 7 in usual care group and 4 in intervention groupHernandez Munoz and Pluchino [47]
RemifeminPilot4 weeks23 F (21 evaluable)29%−4.1 flash/d (50%)56%52%More than 50% decrease in 66%Joint pain in one patient. Symptoms at baseline less frequent at endPockaj et al. [48]
Cimicifuga racemosa 20mg bid then placebo or vice versaDouble-blind randomized crossover trial4 weeks each period132 F randomized (116 evaluable)40–48% depending on armAfter 4 weeks: 17% with black cohosh vs 26% with placebo (p=0.36)After 4 weeks: 20% with black cohosh vs 27% with placebo (p=0.53)N/AMore than 50% decrease in 24% with black cohosh and 36% with placebo after 4 weeks (p=0.33)Minimal toxicity. No differences between groupsPockaj et al. [49]
Black cohosh one tablet bidDouble-blind RCT (stratified for tamoxifen use)60d85 F breast ca survivors (69 completed)69%Overall mean decline 27%. Differences between groups not significant (p=0.44, p=0.86 when adjusting baseline number and tamoxifen use)Difference between groups not statistically significantN/AN/A16 withdrawals; 3 due to adverse events. 3 serious adverse events: one with placebo/tamoxifen, two with black cohosh/tamoxifen. 10 minor eventsJacobson et al. [50]

Soy isoflavone extractsSoy beverage containing 90mg of isoflavones or placebo rice beverageDouble-blind RCT12 weeks263 F with hx breast ca screened (157 randomized, 123 completed)34% soy arm 28% placebo arm−1.8 flash/d (25%) for soy vs −2.5 flash/d (34%) for placebo (difference not stat. significant)−5.4 (30%) with soy vs −7.5 (40%) with placebo (difference not stat. significant)N/AN/AMore frequent and severe gastrointestinal side effects with soy. 4 women on soy and one on placebo had vaginal spottingVan Patten et al. [51]
One tablet containing 50mg of soy isoflavones tid then placebo or vice versaDouble-blind randomized crossover trial4 weeks each period182 F breast ca survivors (177 started, 155 evaluable)68% in each armNo significant differences between soy and placeboNo significant differences between soy and placebo36% with placebo vs 24% with soy (p=0.01)More than 50% reduction in 38% with placebo vs 35% with soy (p=0.78)No differences with regards to diarrhea, nausea, vomiting or bloating/gasQuella et al. [52]
Two soy capsules bid each containing 17.5mg of isoflavines or placeboDouble-blind RCT12 weeks72 F breast ca (68 evaluable)78% (28)N/ANo significant difference in menopausal symptoms between groupsN/AN/AMild toxicity, primarily gastrointestinal with no differences between armsMacGregor et al. [53]

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5. 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 pharmacological 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].

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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.

6.1. 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], [59], [60] and/or may not respond as well to tamoxifen as extensive metabolizers [61], [62], [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% compared to 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 harm 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 depending on 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 compared to 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 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 pharmacy 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 pharmacy 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 compared to 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.

6.2. 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.

6.3. 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 compared to 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 estrogen-sensitive 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.

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7. Conclusion and recommendations (Table 5, Table 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 (Table 5, Table 6).

Table 5. Psychotropics used in the treatment of hot flashes or depression and their interactions with tamoxifen.
MedicationImpact on tamoxifen metabolismRecommendations for treatment of tamoxifen users
GabapentinDoes not inhibit cytochrome p450Use preferentially for treatment of hot flashes if no depression
Direct studies with tamoxifen lackingRecommended dose: 300mg tid

PregabalinDoes not inhibit cytochrome p450Alternative to gabapentin
Direct studies with tamoxifen lackingRecommended dose: 75mg bid

VenlafaxineMinimal 2D6 inhibitorUse preferentially for treatment of hot flashes if depression
Recommended dose for hot flashes: 75mg per day

DesvenlafaxineMinimal 2D6 inhibitor
Direct studies with tamoxifen lacking		Alternative to venlafaxine but no studies for treatment of hot flashes in this population

MirtazapineMinimal 2D6 inhibitor
Direct studies with tamoxifen lacking		Only one pilot study for treatment of hot flashes. Consider use based on benefit-risk assessment

CitalopramMild 2D6 inhibitorConsider use based on benefit-risk assessment

EscitalopramMild 2D6 inhibitor
Direct studies with tamoxifen lacking		No studies for treatment of hot flashes in this population. Consider use based on benefit-risk assessment

SertralineModerate 2D6 inhibitorConsider use based on benefit-risk assessment

FluvoxamineModerate 2D6 and 3A4 inhibitorNo studies for treatment of hot flashes. Consider use for depression based on benefit-risk assessment
Direct studies with tamoxifen lacking
DuloxetineModerate 2D6 inhibitor
Direct studies with tamoxifen lacking
NefazodoneMild 2D6 inhibitor
Strong 3A4 inhibitor

ParoxetineStrong 2D6 inhibitorAvoid use
FluoxetineStrong 2D6 inhibitor
BupropionStrong 2D6 inhibitor
Table 6. Health supplements used for the treatment of hot flashes and/or depression and their interactions with tamoxifen.
Health supplementsIndicationTheoretical impact on tamoxifen metabolismRecommendations for treatment of tamoxifen users
IsoflavonesUsed in the treatment of menopausal symptomsGenistein (found in soy) inhibits several subtypes of cytochrome P450, including 2D6 and 3A4Used cannot be recommended at this time for lack of evidence and/or concerns of interactions with tamoxifen
Red clover extracts inhibit 3A4
Black cohoshUsed in the treatment of menopausal symptomsDoes not inhibit 2D6 and 3A4
ValerianUsed as a mild sedativeInhibits both 2D6 and 3A4
St-John's wortUsed for treatment of depressionInduces CYP3A

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.

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.

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Contributors 

Julie Eve Desmarais contributed to literature search, drafting article, approval of article. Karl J. Looper contributed to critical revision and approval of article.

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Competing interest 

Dr Desmarais and Dr Looper report no competing interests. No financial support was received for the completion of this manuscript.

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Provenance and peer review 

Commissioned and externally peer reviewed.

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PII: S0378-5122(10)00318-X

doi:10.1016/j.maturitas.2010.08.005

Maturitas
Volume 67, Issue 4 , Pages 296-308, December 2010

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