1. Turn down the heat! Treating hot flashes Amanda Place, PharmD, BCACP St Vincent Joshua Max Simon Primary Care Center September 2014

2. I HAVE NO ACTUAL OR POTENTIAL CONFLICT OF INTEREST IN RELATION TO THIS PROGRAM OR PRESENTATION.

3. Objectives Describe both symptoms and possible mechanisms of hot flashes Discuss benefits and risks of estrogen- containing products in the treatment of hot flashes Explain the utility of and evidence supporting non-estrogen treatment alternatives Evaluate the role of complementary and alternative medicine therapies in the treatment of hot flashes

4. What is a hot flash? Sudden sensation of heat (face, neck and chest) Skin flushing, sweating May be accompanied by anxiety, irritation Often followed by chills J Support Oncol 2006;4:315-320 Ann N Y Acad Sci 1990;592:52-86

5. Prevalence 70-80% of women will experience hot flashes Average duration: 2-5 years 15-20% of women may have ongoing hot flashes Greater severity in patients with chemical or surgical menopause, or premature menopause (<40 yrs of age) Am J Epidemiol 2000; 152:463 Am J Public Health 2006; 96: 1226 Arch Intern Med. 2008;168(8):840-846

6. Pathophysiology Exact mechanism for vasomotor flushing not yet identified Several proposed mechanisms ◦ Decrease in hormones ◦ Changes in the hypothalamus ◦ Other factors implicated  Prostaglandins  Endorphins  Neurotransmitters Acta Oncologica 2002;41:269-75Ann Pharmacother1997;31:915-7 ONF 2002;29: 33-40Ann Pharmacother2002;36:433-6

7. Contributing Factors Modifiable ◦ BMI ◦ Smoking ◦ Avoidance of triggers ◦ Exercise ◦ Depression/anxiety Difficult to modify ◦ Cause of menopause ◦ Genetics ◦ Socioeconomic factors Am J Epidemiol 2000; 152:463 Am J Public Health 2006; 96: 1226

8. Assessment Tools Patient history and recall Hot flash diary Validated tools: ◦ Hot Flash Score ◦ Greene Climacteric Score ◦ Modified Kupperman Index ◦ Utian Quality of Life Scale Menopause 2002; 9(6):402-410 J Clin Oncol 2001; 19:4280-4290 Maturitas 2012 March;71(3):213-216

9. Treatment Options Lifestyle modifications Hormonal Therapies SSRI/SNRI Gabapentin Clonidine CAM modalities Endocr Pract 2011;17 (suppl 6) Menopause 2012;19(3):257-271 Climacteric 2014;17:1-16

10. Lifestyle Modification Decrease BMI Decrease caffeine Modify or eliminate alcohol use Increase exercise Improve dietary habits Layered clothing Stress reduction/paced respirations Menopause 2004;11:11 Menopause 2012;20(2):179-184 Menopause 2012;19(7):749-759

11. Estrogen Replacement (ET) Considered most effective agent Endocr Pract 2011;17(Suppl 6) Menopause 2012;19(3):257-271 Climacteric 2014;17:1-16 AgentInitial doseHigh dose Conjugated equine estrogens (CEE) 0.3 mg1.25 mg 17 β Estradiol 0.5 mg2 mg Transdermal estradiol 0.025 mg0.1 mg Estradiol gel0.5 mg1.5 mg

12. ET Risks and Benefits BenefitsRisks Vasomotor symptomsCoronary heart disease Vaginal symptomsStroke Sexual functionVenous thromboembolism Urinary tract healthEndometrial cancer OsteoporosisBreast cancer Quality of life Effect of ET on ovarian cancer, lung cancer, mood, dementia, and mortality remain mixed. Endocr Pract 2011;17(Suppl 6) Menopause 2012;19(3):257-271 Climacteric 2014;17:1-16

13. ET Considerations Transdermal =  risk Duration of use Appropriate dose Need for progestin Choice of progestin Taper vs. stop Bioidentical ET Menopause 2010;17:946-954 Menopause 2006;13:370-376 Endocr Pract 2011;17(Suppl 6) Menopause 2012;19(3):257-271

14. Assessment question According to data from the Women’s Health Initiative, which of the following is a benefit of using estrogen to treat hot flashes? 1. Increase or maintenance of bone mass 2. Decrease in cardiovascular risk because of increase in good cholesterol 3. Decrease in the risk of endometrial cancer 4. All of the above

15. Assessment question A 50 yo female would like to start estrogen therapy for hot flashes. She has no allergies and no significant medical or surgical history. Which would be a good initial choice for her? 1. Estradiol 0.025 mg/24 hr transdermal patch once weekly 2. Estradiol 0.5 mg /norethindrone acetate 0.1 mg daily 3. CEE 0.625 mg/medroxyprogesterone 2.5 mg daily 4. Estradiol cream 0.1 mg/gm: 2 gm intravaginally once daily at bedtime

16. Bazedoxifene/CEE (Duavee) Tissue-selective estrogen complex Safety data for up to 2 years IndicationsVasomotor symptoms, prevention of postmenopausal osteoporosis Precautions/ warnings Refer to CE DoseCEE 0.45 mg and bazedoxifene 20 mg Cost≈$140 per month Lexi-Comp, Inc. (Lexi-DrugsTM ). Lexi-Comp, Inc.; Version1.13.0 Accessed July 28 th, 2014 Menopause 2009;16(6):1116-1124 Menopause 2012;19(4):479-485

17. Clinical study limitations Small sample sizes Outcomes based on patient-reported data Many studies focus on patients with breast cancer history Large placebo effect: 20-30% reductions in hot flash score/frequency Limited duration of trials

18. Menopause 2008;15:655 Non-estrogen therapies

19. Progestational agents 20-80 mg daily Megestrol acetate 400 mg depot Medroxy- progesterone acetate 10 mg daily Norethindrone acetate N Engl J Med 1994;331(6);347 J Clin Oncol 2008;26(10):1650 J Clin Oncol 2006;24(9):1409 Ann Oncol 2002;13(6):883

20. Progestational agents Adrenal suppression Clotting risk Breast cancer risk Bone loss Weight gain

21. SSRIs/SNRIs Mechanism: increases available neurotransmitters Doses differ if only treating hot flashes Serotonin syndrome risks Product selection: ◦ Drug interactions ◦ Cost ◦ Evidence ◦ Co-morbid conditions

22. Paroxetine (Brisdelle ® ) Approved 2013 Cost ~$150/month VMS frequency vs placebo Trial #1 at 4 wks ↓ 1.2 /day Trial #2 at 4 wks ↓ 1.3/day Trial #1 at 12 wks ↓ 0.9/day Trial #2 at 12 wks ↓ 1.7/day Brisdelle PI, Noven Therapeutics, LLC, Miami, FL

23. Other antidepressants DrugDaily DoseOutcomes Fluoxetine20 mg ↓ monthly hot flash score Sertraline50-100 mg ↓ weekly frequency Citalopram**20-40 mg ↓ hot flash scores Escitalopram10-20 mg ↓ daily frequency Venlafaxine37.5-75 mg ER ↓ hot flash scores Desvenlafaxine100 mg ↓ daily frequency Duloxetine60 mg ↓ VMS ** showed efficacy as an add-on to HRT as well References provided at end of presentation

24. Antidepressant safety T/F May inhibit platelet aggregation T/F May be associated with bone loss/fracture risk T/F Don’t need to be tapered when used for hot flashes T/F May decrease the efficacy of antibiotics T/F May decrease the efficacy of tamoxifen T/F May increase risk of suicidality

25. Antidepressant pearls Which one must have a wash-out? fluoxetine Which ones should be cross-tapered? paroxetine or venlafaxine Which one to choose if a patient takes clopidogrel? citalopram or venlafaxine Which one causes the MOST hypertension? venlafaxine

26. The gabas Mechanism: GABA vs. Norepinephrine Lower doses than used in neuropathic pain Drug interactions: CNS depressants Monitoring: renal function Adverse effects: drowsiness, dizziness, rash, peripheral edema, weight gain

27. J Clin Oncol 2009; 27:2831-2837 Gabapentin dose range

28. Gabapentin ER interrupted FDA declined approval in May 2013 TrialVMS change @ 4 weeks VMS change @ 12 weeks Breeze 1: 1200 mg ↓ 0.96/day↓ 0.56/day** Breeze 1: 1800 mg ↓ 1.51/day↓ 1.53/day Breeze 2: 1200 mg ↓ 1.61/day↓ 1.56/day Breeze 2: 1800 mg ↓ 1.51/day↓ 1.12/day Breeze 3: 1800 mg ↓ 1.69/day↓ 1.14/day ** not statistically significant www.clinicaltrials.govwww.clinicaltrials.gov accessed 2/13/14

29. Pregabalin Not seeking FDA approval Cost: pregabalin = gabapentin x 10 Daily doseChange in hot flash frequency 75 mg BID ↓ 1.7/day 150 mg BID ↓ 2.0/day J Clin Oncol 28:641-647

30. Gabas’ safety T/F These should not be used in pts with NYHA class 3 HF T/F These drugs should be dose adjusted for hepatic function T/F Since these agents are hepatically metabolized, they have many drug interactions T/F Dizziness/somnolence may go away over time

31. Gabas’ pearls Possible to direct switch Gabapentin dosing regimen may differ from pain dosing: ◦ 600-900 mg hs vs. 300 mg TID GabapentinPregabalin 0-900 mg per day150 mg per day 901-1500 mg per day225 mg per day 1501-2100 mg per day300 mg per day Pain Med. 2010; 11(3): 456-465

32. Clonidine Mechanism: decreases available neurotransmitters Dose range: 0.1 to 0.2 mg per day- oral or transdermal Drug interactions: antihypertensives, SNRIs Adverse effects: drowsiness, dizziness, fatigue, dry mouth, orthostatic hypotension, dermatologic reactions with transdermal form Obst Gynecol 1982;60:583-586 J Clin Oncol 1994;12:1155-158

33. Comparator Trials (Gabapentin = estrogen) >placebo Venlafaxine preferred vs gabapentin Gabapentin = gabapentin + SSRI/SNRI MPA = megestrol Fluoxetine = citalopram = placebo MPA > venlafaxine Venlafaxine > clonidine (Estradiol ≈ venlafaxine) > placebo JAMA Intern Med 2014;174(7):1058-1066 Obstet Gynecol 2006;108:41-48 J Clin Oncol 2010;28:147-5152 J Clin Oncol 2007;25:308-312 Ann Oncol 2002;13:883-888 Menopause 2005;12(1):18-26 J Clin Oncol 2006:24:1409 Ann Oncol 2007;18:689-693

34. Assessment question Which of the following drug classes have NOT shown efficacy in the treatment of hot flashes: 1. Estrogens 2. Dihydropyridine calcium channel blockers 3. α -2- δ ligands 4. Serotonin/norepinephrine reuptake inhibitors

35. Assessment question A 47 yo female with a strong family of breast cancer would like to start drug treatment for hot flashes. She takes tamoxifen 20 mg and a multivitamin daily. Blood pressure at most recent visit was 114/74 mm Hg. What would you recommend? 1. Paroxetine 7.5 mg daily 2. Estradiol 0.5 mg/norethindrone acetate 0.1 mg daily 3. Clonidine 0.1 mg/24 hr transdermal patch weekly 4. Gabapentin 300 mg in the morning and 600 mg before bedtime

36. CAM Hormonal agents Alfalfa Black Cohosh Chasteberry DHEA Dong Quai Flaxseed Hops Kudzu Licorice Panax Ginseng Red clover Soy Wild Yam

37. CAM Hormonal agents Alfalfa Black Cohosh Chasteberry DHEA Dong Quai Flaxseed Hops Kudzu Licorice Panax Ginseng Red clover Soy Wild Yam

38. CAM Treatments for Hot Flashes Likely safePossibly safe Effective Likely effective Possibly effective Flaxseed Soy foods Black Cohosh Soy extracts Insufficient evidence Chasteberry Ginkgo Vitamin E Alfalfa DHEA (short term) Hops Kudzu Licorice Valerian Possibly ineffective Evening Primrose oil Dong Quai (short term) Red Clover Wild Yam Panax Ginseng Adapted from Natural Medicines ComprehensiveDatabase-Accessed 5/17/2010

39. CAM Hormonal agents General cautions: ◦ Unknown or questionable estrogenic activity ◦ Standardization of products/preparations ◦ Consistent quality of products ◦ Lack of high quality evidence

40. Acupuncture Difficult to determine a true “placebo” group Differing disciplines of acupuncture Pt expectations Lack of understanding about physiologic effects of acupuncture Menopause 2010;17(2):228-230 Menopause 2009;16:1065-1073

41. Conclusions Choice of agent should be made with patient-specific variables as a guide. Patient expectations may impact efficacy. Different agents or combinations may need to be tried to achieve desired benefit.

42. Turn down the heat! Treating hot flashes Amanda Place, PharmD, BCACP St Vincent Joshua Max Simon Primary Care Center September 2014

43. Slide 17 References Obst Gynecol 1982;60:583-586 J Clin Oncol 1994;12:155-158 J Clin Oncol 2002;20:1578-1583 Lancet 2000;356:2059-2063 J Clin Oncol 2010;28:3278-3283 JAMA 2001;305(3):267-274 J Clin Oncol 2009;27:2831-2837 Drugs 2011;71(3):287-304 Pharmacotherapy 2009;29(11):1357-1374