Background History SSRIs for VMS

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org/display/toxipedia/sel ective+serotonin+reuptake+inhibitors Anecdotal evidence of hot flash benefit in men and women with cancer Loprinzi, 199 Quella, 1999 First RCT Loprinzi, 2000 Loprinzi CL.

1 .pptx Non hormonal Pharmacologic Options: SSRIs/SNRIs/Gabapentin Susan D. Reed, MD, MPH Department of Obstetrics and Gynecology University of Washington, Seattle, WA Christopher Rasmussen, MD, InflaNATION Blog Background History SSRIs for VMS ective+serotonin+reuptake+inhibitors Anecdotal evidence of hot flash benefit in men and women with cancer Loprinzi, 199 Quella, 1999 First RCT Loprinzi, 2000 Loprinzi CL. J Clin Oncol 199;16: Quella S. J Urol 1999; 162: Loprinzi CL. Lancet 16 December 2000; 356: Disclosures MsFLASH Menopause strategies Finding Lasting Answers for Symptoms and Health. National Institute on Aging (NIA) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) The National Center for Complementary and Alternative Medicine (NCCAM) The Office of Research on Women's Health (ORWH) (U01 AG032699) Escitalopram, Venlafaxine Objective Explain the evidence supporting SSRIs, SNRIs and gabapentin for menopausal symptoms and be able to counsel patients on their efficacy and side effect profile Discuss relative safety and the probable physiologic action of these medications 1

.pptx Additional Questions SSRIs, SNRIs, Gabapentin Equally effective in women with and without breast cancer?

- onset of action -efficacy - side effects - other benefits -price Menopausal Hot Flash Control Kappa Agonist GABA? Norepinephrine? Serotonin?

Clifton D, Oakley A, 2014 Additional Questions SSRIs, SNRIs, Gabapentin Equally effective in women with and without breast cancer?

In general, doses < for depression How do nonhormonal pharmaceuticals compare with hormonal therapies?

2 .pptx Additional Questions SSRIs, SNRIs, Gabapentin Equally effective in women with and without breast cancer? What about interactions, cyp2d6, tamoxifen? How to dose? How do non-hormonal pharmaceuticals compare with hormonal therapies? - onset of action -efficacy - side effects - other benefits -price Menopausal Hot Flash Control Kappa Agonist GABA? Norepinephrine? Serotonin? Estrogen Progesterone? Clifton D, Oakley A, 2014 Additional Questions SSRIs, SNRIs, Gabapentin Equally effective in women with and without breast cancer? Yes (Bardia, 2009) Can paroxetine be used in women with breast cancer on tamoxifen? Controversial (Rae, 2012; Regan, 2012 ) Dosing? In general, doses < for depression How do nonhormonal pharmaceuticals compare with hormonal therapies? - onset of action: faster -efficacy: < standard dose estrogen formulations - side effects: some women do not tolerate - other benefits: pain, sleep, mood -price: similar Bardia A. Menopause 2009;16(3): Rae JM. J Natl Cancer Inst 2012;104: Regan M. J Natl Cancer Inst 2012;104: Efficacy, Cost, Side Effects SSRIs, SNRIs, Gabapentin part they dont tell you ssri discontinuation syndrome 2

3 .pptx ANNA BRCA1 carrier Refuses HT, sister has breast cancer Has mod HF, sleeping poorly, mild joint pain On tamoxifen for prevention On citalopram 20 mg for mood sheknows.com Her friend takes gabapentin and she wants to try this, but asks about efficacy, and in particular, benefit compared with estrogen and other nonhormonal therapies Randomized double blind placebo controlled trials: Nonhormonal R for VMS At least 1 wk baseline hot flash data (preferably 2-3 wk), >6 HF/d baseline No cross-over designs, non-depressed women 4 wk, preferably > week duration Provide data on frequency, severity Outcome - change from baseline compared with placebo Cyp2d6, SSRIs, Tamoxifen Cytochrome p450 inhibition GABA-nergic placebo controlled trials Paroxetine mesylate Paroxetine HCl Escitalopram Citalopram Venlafaxine Desvenlafaxine NO/LOW MODERATE HIGH Gabapentin IR: INCLUDE Guttuso, 2003; Pandya, 2005; Butt, 200; ECLUDE: Reddy, 2006 outcome not shown as HF frequency; Saadati, 2013 not blinded, no placebo response Gabapentin GR: INCLUDE Pinkerton, 2014 Pregabalin: INCLUDE Loprinzi, Co administration of paroxetine 10 mg/d with tamoxifen decreased plasma concentrations of endotoxifen by 64% (Stearns, 2003) CYP2D6 genotype does not appear to predict clinical benefit with adjuvant tamoxifen therapy in postmenopausal breast cancer patients, in conjunction with or without SSRIs (Rae, 2012) GABAPENTIN: Guttuso JL. Obstet Gynecol 2003;101(2):337. Pandya KJ. Lancet 2005;366(94):1.Butt DA. Menopause 200;15(2):310. Pinkerton JV. Menopause 2014;21(6): PREGABALIN: Loprinzi CL. J Clin Oncol 2010; 2(4):

.pptx Gabapentin IR 900 mg/d (300 tid) Pregabalin 150 mg/d (75 bid) www.campacademia.com VMS Frequency VMS Severity www.campacademia.com Guttuso JL. Obstet Gynecol 2003;101(2):337. Loprinzi CL.

4 .pptx Gabapentin IR 900 mg/d (300 tid) Pregabalin 150 mg/d (75 bid) VMS Frequency VMS Severity Guttuso JL. Obstet Gynecol 2003;101(2):337. Loprinzi CL. J Clin Oncol 2010; 2(4): 641. Gabapentin GR 100 mg/d (600 am, 1200 pm) mg pm Gabalin, Pregabalin Benefit: 1 2 HF/d N Duration (weeks) Frequency from BL Active vs PL HF/d BL Overall HF/d Severity VMS Frequency Gabapentin IR 300, 900 mg 347/ / vs vs vs ~ *Gabapentin GR 600, 1200, 100 mg Pregabalin 150, 300 mg 593/ vs >7 ** ~ / vs 2.9 >6 ~ VMS Severity Pinkerton JV. Menopause 2014;21(6): *Industry supported, ** Moderate to severe HF GABAPENTIN IR:. Guttuso JL. Obstet Gynecol 2003;101(2):337. Pandya KJ. Lancet 2005;366(94):1. Butt DA. Menopause 200;15(2):310. GABAPENTIN GR: Pinkerton JV. Menopause 2014;21(6): PREGABALIN: Loprinzi CL. J Clin Oncol 2010;2:641. 4

5 .pptx Approximate Price per month supply Price per month Paroxetine mesylate $165 Paroxetine HCl $25 Escitalopram $49 Citalopram $34 Venlafaxine $40 Desvenlafaxine $10 Gabapentin IR $29 Gabapentin GR $443 Pregabalin $336 accessed Sept 1, 2014 ANNA Chooses Gabapentin IR because she is worried about health care costs You prescribe 300 mg nightly for at least 3 nights and ask her to titrate to 900 mg nightly as tolerated, then if still bothered in the day take 300 mg every morning She returns in one month, sleeping better and happy with treatment, but stopped the morning dose due to drowsiness sheknows.com Oral Estradiol Comparisons SSRI/SNRI,Gabapentin faster onset than E2 Similar efficacy to low dose oral E2? Notelovitz M. Obstet Gynecol 2000; ;95(5):726. Reddy S. Obstetrics & Gynecology 2006; 10(1):41. Joffe H. JAMA Int Med, 2014;174(7):105.. ESTRADIOL c c VENLAFAINE GABAPENTIN Benefits/Side effects Tailor therapy to your patient Benefits Side effects Paroxetine Nausea, fatigue, dizzy Escitalopram Pain Nausea, sweating, dizzy Citalopram Drowsy, sweating, dizzy, sexual function Venlafaxine Pain Nausea, headache, BP, jittery Desvenlafaxine Nausea, vomiting Gabapentin IR Pain Dizzy, unsteady, drowsy Gabapentin GR Pain Dizzy, headache, drowsy Pregabalin Pain Dizzy, cognition, drowsy, blurry vision, weight gain Potential for: nausea, insomnia, dizziness, headache, dry mouth, diarrhea, bloating, constipation, insomnia, sexual dysfunction 5

6 .pptx Benefits/Side effects Tailor therapy to your patient Majority of side effects are self limiting and resolve in first 2-4 weeks Higher rate of side effects in depressed populations Side effects vary from woman to woman Close follow up and encouragement are critical for ongoing adherence A small % of women do not tolerate Placebo controlled trials with VMS benefit Paroxetine*: INCLUDE Simon, 2013; Stearns, 2003; ECLUDE Stearns, 2005, x-over design; Soares, 200, small study low baseline VMS Escitalopram: INCLUDE Freeman, 2011 Citalopram: INCLUDE Barton, 2010; ECLUDE Suvanto-Luukkonen, 2005, lacking baseline measure VMS Venlafaxine: INCLUDE Joffe, 2014; Loprinzi, 2000; ECLUDE Carpenter, 2007, x-over design; Loprinzi, 2003 < 6 HF/d, Evans, 2005, lack baseline VMS ) Desvenlafaxine*: INCLUDE Speroff, 200; Archer, 2009; Archer 2009; Pinkerton, 2013 * Industry sponsored studies MARTHA Placebo controlled trials unknown VMS benefit Having moderate hot flashes Low mood Best friend with ovarian cancer, does not want HT Interested in SSRI/SNRI, but is worried about diminished sexual function more.com Sertraline (INCLUDE: Grady, 2007; ECLUDE: Kimmick, 2006; Gordon, 2006, cross over designs) Grady: 7-day baseline HF, relatively small n=100,.9 BL HF 3.5 HF both groups at 6 wk Group differences: Placebo older, caucasian, high SES; Sertraline younger, AA, low SES Grady D. Obstet Gynecol 2007;109:23 30 Kimmick GG. Breast J 2006;12: Gordon PR. Menopause 2006;13(4):

7 .pptx Placebo controlled trials unknown VMS benefit Paroxetine CR Hot Flash Composite Score, 12.5 mg/d Fluoxetine: No trials fit my inclusion criteria ECLUDE Suvanto-Luukkonen, 2005, lacking baseline measure VMS; Loprinzi, 2002, x-over Suvanto Luukkonen E. Menopause 2005;12:1 26. Loprinzi CL. J Clin Oncol 2002;20(6):157. Error bars indicate SE. Compared with placebo, the mean reduction in the hot flash composite score for those taking 25.0 mg/d of paroxetine CR was statistically significant (P<.05 in weeks1, 2, 3, and 4; P<.001 in weeks 5 and 6); for those taking 12.5 mg/d of paroxetine CR, the mean reduction in the hot flashcomposite score was statistically significant in weeks 1, 3, and 6 (P<.05) and in week 5 (P<.001). Stearns V. JAMA. 2003;29(21): doi: /jama No placebo controlled double-blind trials Escitalopram 10 mg/d Duloxetine Fluvoxamine Quetiapine R Hot Flash per Day Intervention Post Intervention Placebo Escitalopram Week Escitalopram vs placebo (weeks 4, ) P=0.001 Freeman E, JAMA 2011;305(3):267. 7

.pptx Citalopram 10 mg/d Desvenlafaxine 100 mg/d c Speroff L. Obstet Gynecol 200; 111(1):77. Archer D. AJOG 2009;200:23. Barton D L et al. JCO 2010;2:327-323. Venlafaxine 75 mg/d Loprinzi CL.

8 .pptx Citalopram 10 mg/d Desvenlafaxine 100 mg/d c Speroff L. Obstet Gynecol 200; 111(1):77. Archer D. AJOG 2009;200:23. Barton D L et al. JCO 2010;2: Venlafaxine 75 mg/d Loprinzi CL. Lancet 2000:9247: Joffe H. JAMA Intern Med 2014 ;174(7):105. SSRI, SNRIs Benefit: 1 3 HF/d N Duration Frequency HF/d HF/dHF/dVMS **Paroxetine 7.5, 12.5CR, 25CR mg Escitalopram 10, 20 mg Citalopram 10, 20, 30 mg Venlafaxine 37.5, 75, 150 mg **Desvenlafaxine 50, 100, 150, 200 mg 160/ /614* (weeks) 6 12 from BL Active vs PL 3.3 vs vs 5.3 BL * Overall HF/d ~0.9 ~ 1.1* Severity 200/ vs ~ vs 1.4 ~ /620* 436/452* 541/567* 319/365* (n=36) vs vs vs vs vs vs * 10.* 10.6* 11.* + ~ ~ * + * Moderate Severe HF, ** Industry sponsored PAROETINE: Stearns V. JAMA. 2003;29 (21): ; Simon JA. Menopause ;20 (10):1027. ESCITALOPRAM: Freeman E. JAMA 2011;305(3):267. CITALOPRAM: Barton D. J Clin Oncol 2010;2(20):327. VENLAFAINE: Loprinzi CL, Lancet 2000;356: Joffe H. JAMA Internal Med 2014;174(7):105. DESVENLAFAINE: Speroff L. Obstet Gynecol 200;111:77; Archer DF. Am J Obstet Gynecol 2009; 200:17; Archer DF..Am J Obstet Gynecol 2009; 200:23. Pinkerton J. Menopause 2013;20(1):3 46.

9 .pptx Approximate Price per month supply Price per month Paroxetine mesylate $165 Paroxetine HCl $25 Escitalopram $49 Citalopram $34 Venlafaxine $40 Desvenlafaxine $10 Gabapentin IR $29 Gabapentin GR $443 Pregabalin $336 accessed Sept 1, 2014 Benefits/Side effects Tailor therapy to your patient Benefits Side effects Paroxetine Nausea, fatigue, dizzy Escitalopram Pain Nausea, sweating, dizzy Citalopram Drowsy, sweating, dizzy, sexual function Venlafaxine Pain Nausea, headache, BP, jittery Desvenlafaxine Nausea, vomiting Gabapentin IR Pain Dizzy, unsteady, drowsy Gabapentin GR Pain Dizzy, headache, drowsy Pregabalin Pain Dizzy, cognition, drowsy, blurry vision, weight gain All have potential for: nausea, insomnia, dizziness, headache, dry mouth, diarrhea, bloating, constipation, insomnia, sexual dysfunction MARTHA R paroxetine mesylate 7.5 mg because she wants an FDA approved product and wants the lowest dose possible She returns in wks much improved, but thinks she may be a little drowsy during the day. She was told by her girl friend that she will not be able to orgasm. How do you counsel her? more.com Placebo Controlled Trials Quality Of Life Sleep Sexual Quality of Life Function Paroxetine ASE Escitalopram FSFI Menqol Citalopram orgasm HFRDIS Venlafaxine FSFI Menqol Desvenlafaxine Greene Climacteric Gabapentin * Menqol PAROETINE: Pinkerton JV. Menopause August, 2014; Portman DJ. Menopause February, 2014; Stearns V. JAMA. 2003;29 (21): ESCITALOPRAM: LaCroix AZ. Maturitas 2012 Dec;73(4):361-. Ensrud KE. Menopause. 2012;19():4-55. Reed SD. Obstet Gynecol. 2012;119(3): CITALOPRAM: Barton D. J Clin Oncol 2010;2(20):327. VENLAFAINE: Reed SD. Obstet Gynecol 2014;124(2 ):233. Ensrud KE Sleep, 2014D. Caan B, Menopause, 2014 DESVENLAFAINE: Speroff L. Obstet Gynecol 200;111:77. GABAPENTIN: Yurchesen ME. J Womens Health 2009 Sep;1(9): *Butt DA. Menopause 200;15(2):310. 9

10 .pptx Conclusions Paroxetine, Escitalopram, Citalopram, Venlafaxine, Desvenlafaxine, Gabapentin and Pregabalin are effective for decreasing HF and in many cases, improve QOL for menopausal women The effect is modest, 50-60% decrease (~1-3 HF/d) SSRIs, SNRIs and gabapentin are effective in women with and without breast cancer Their effect may be similar to low dose oral estrogen (0.5 mg estradiol) Side effects in some women will preclude their use, though in general these R are relatively well tolerated at low doses Costs vary considerably Tailor therapy consider sleep, pain, sexual function, QOL VMS studies predominantly in white women, with exception of Escitalopram MsFLASH Collaborators Ellen Freeman, PhD Hadine Joffe, MD Lee Cohen, MD Janet Carpenter, RN, PhD Katherine Guthrie, PhD Joe Larson, MS Questions SSRIs, SNRIs and Gabapentin for Menopause 10

Non hormonal medical treatment of vasomotor symptoms

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