Turn down the heat!

Treating hot flashes

Amanda Place, PharmD, BCACPSt Vincent Joshua Max Simon

Primary Care CenterSeptember 2014

I HAVE NO ACTUAL OR POTENTIAL

CONFLICT OF INTEREST IN RELATION TO

THIS PROGRAM OR PRESENTATION.

ObjectivesDescribe both symptoms and possible

mechanisms of hot flashesDiscuss benefits and risks of estrogen-

containing products in the treatment of hot flashes

Identify the utility of and evidence supporting non-estrogen treatment alternatives

Define the role of complementary and alternative medicine therapies in the treatment of hot flashes

What is a hot flash?Sudden sensation of heat (face, neck

and chest)Skin flushing, sweatingMay be accompanied by anxiety,

irritationOften followed by chills

J Support Oncol 2006;4:315-320Ann N Y Acad Sci 1990;592:52-86

Prevalence70-80% of women will experience hot

flashesAverage duration: 2-5 years15-20% of women may have ongoing

hot flashesGreater severity in patients with

chemical or surgical menopause, or premature menopause (<40 yrs of age)

Am J Epidemiol 2000; 152:463Am J Public Health 2006; 96: 1226

Arch Intern Med. 2008;168(8):840-846

Pathophysiology Exact mechanism for vasomotor

flushing not yet identifiedSeveral proposed mechanisms

◦Decrease in hormones◦Changes in the hypothalamus◦Other factors implicated

Prostaglandins Endorphins Neurotransmitters

Acta Oncologica 2002;41:269-75 Ann Pharmacother1997;31:915-7

ONF 2002;29: 33-40 Ann Pharmacother2002;36:433-6

Contributing FactorsModifiable

◦ BMI◦ Smoking◦ Avoidance of

triggers◦ Exercise ◦ Depression/

anxiety

Difficult to modify◦ Cause of

menopause◦ Genetics◦ Socioeconomic

factors

Am J Epidemiol 2000; 152:463Am J Public Health 2006; 96: 1226

Assessment ToolsPatient history and recallHot flash diaryValidated tools:

◦Hot Flash Score◦Greene Climacteric Score◦Modified Kupperman Index◦Utian Quality of Life Scale

Menopause 2002; 9(6):402-410J Clin Oncol 2001; 19:4280-4290

Maturitas 2012 March;71(3):213-216

Treatment Options

Lifestyle modifications

Hormonal Therapies

SSRI/SNRIGabapentinClonidine

CAM modalities

Endocr Pract 2011;17 (suppl 6)Menopause 2012;19(3):257-271

Climacteric 2014;17:1-16

Lifestyle ModificationDecrease BMIDecrease caffeineModify or eliminate alcohol useIncrease exerciseImprove dietary habitsLayered clothingStress reduction/paced respirations

Menopause 2004;11:11Menopause 2012;20(2):179-184Menopause 2012;19(7):749-759

Estrogen Replacement (ET)Considered most effective agent

Endocr Pract 2011;17(Suppl 6)Menopause 2012;19(3):257-271

Climacteric 2014;17:1-16

Agent Initial dose

High dose

Conjugated equine estrogens (CEE)

0.3 mg 1.25 mg

17βEstradiol 0.5 mg 2 mg

Transdermal estradiol

0.025 mg 0.1 mg

Estradiol gel 0.5 mg 1.5 mg

ET Risks and BenefitsBenefits Risks

Vasomotor symptoms Coronary heart disease

Vaginal symptoms Stroke

Sexual function Venous thromboembolism

Urinary tract health Endometrial cancer

Osteoporosis Breast cancer

Quality of lifeEffect 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

ET ConsiderationsTransdermal = risk Duration of useAppropriate doseNeed for progestinChoice of progestinTaper vs. stopBioidentical ET

Menopause 2010;17:946-954Menopause 2006;13:370-376

Endocr Pract 2011;17(Suppl 6)Menopause 2012;19(3):257-271

Assessment questionAccording 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

mass2. Decrease in cardiovascular risk

because of increase in good cholesterol

3. Decrease in the risk of endometrial cancer

4. All of the above

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 weekly2. Estradiol 0.5 mg /norethindrone acetate 0.1

mg daily3. CEE 0.625 mg/medroxyprogesterone 2.5 mg

daily4. Estradiol cream 0.1 mg/gm: 2 gm

intravaginally once daily at bedtime

Bazedoxifene/CEE (Duavee)Tissue-selective estrogen complex

Safety data for up to 2 years

Indications Vasomotor symptoms, prevention of postmenopausal osteoporosis

Precautions/ warnings

Refer to CE

Dose CEE 0.45 mg and bazedoxifene 20 mg

Cost ≈$140 per month

Lexi-Comp, Inc. (Lexi-DrugsTM ). Lexi-Comp, Inc.; Version1.13.0 Accessed July 28th, 2014

Menopause 2009;16(6):1116-1124Menopause 2012;19(4):479-485

Clinical study limitationsSmall sample sizesOutcomes based on patient-reported

dataMany studies focus on patients with

breast cancer historyLarge placebo effect: 20-30%

reductions in hot flash score/frequency Limited duration of trials

Menopause 2008;15:655

Non-estrogen therapies

Progestational agents

• 20-80 mg dailyMegestrol acetate

• 400 mg depotMedroxy-

progesterone acetate

• 10 mg dailyNorethindrone acetate

N Engl J Med 1994;331(6);347J Clin Oncol 2008;26(10):1650

J Clin Oncol 2006;24(9):1409Ann Oncol 2002;13(6):883

Progestational agentsAdrenal

suppression

Clotting risk

Breast cancer risk

Bone loss

Weight gain

SSRIs/SNRIsMechanism: increases available

neurotransmittersDoses differ if only treating hot flashesSerotonin syndrome risksProduct selection:

◦ Drug interactions◦ Cost◦ Evidence◦ Co-morbid conditions

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

Other antidepressantsDrug Daily

DoseOutcomes

Fluoxetine 20 mg ↓ monthly hot flash score

Sertraline 50-100 mg ↓ weekly frequency

Citalopram** 20-40 mg ↓ hot flash scores

Escitalopram 10-20 mg ↓ daily frequency

Venlafaxine 37.5-75 mg ER

↓ hot flash scores

Desvenlafaxine 100 mg ↓ daily frequency

Duloxetine 60 mg ↓ VMS** showed efficacy as an add-on to HRT as well

References provided at end of presentation

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

Antidepressant pearlsWhich one must have a wash-out?

fluoxetineWhich ones should be cross-tapered?

paroxetine or venlafaxineWhich one to choose if a patient takes

clopidogrel?citalopram or venlafaxine

Which one causes the MOST hypertension?

venlafaxine

The gabasMechanism: GABA vs. NorepinephrineLower doses than used in neuropathic

painDrug interactions: CNS depressantsMonitoring: renal functionAdverse effects: drowsiness, dizziness,

rash, peripheral edema, weight gain

J Clin Oncol 2009; 27:2831-2837

Gabapentin dose range

Gabapentin ER interrupted

FDA declined approval in May 2013Trial VMS

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.gov accessed 2/13/14

PregabalinNot seeking FDA approval

Cost: pregabalin = gabapentin x 10

Daily dose Change in hot flash frequency

75 mg BID ↓ 1.7/day

150 mg BID ↓ 2.0/day

J Clin Oncol 28:641-647

Gabas’ safetyT/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

Gabas’ pearlsPossible to direct switch

Gabapentin dosing regimen may differ from pain dosing:◦600-900 mg hs vs. 300 mg TID

Gabapentin Pregabalin0-900 mg per day 150 mg per day901-1500 mg per day 225 mg per day1501-2100 mg per day 300 mg per day

Pain Med. 2010; 11(3): 456-465

ClonidineMechanism: decreases available

neurotransmittersDose range: 0.1 to 0.2 mg per day-

oral or transdermal Drug interactions: antihypertensives,

SNRIsAdverse effects: drowsiness, dizziness,

fatigue, dry mouth, orthostatic hypotension, dermatologic reactions with transdermal form

Obst Gynecol 1982;60:583-586J Clin Oncol 1994;12:1155-158

Comparator Trials(Gabapentin = estrogen) >placeboVenlafaxine preferred vs gabapentinGabapentin = gabapentin + SSRI/SNRIMPA = megestrolFluoxetine = citalopram = placeboMPA > venlafaxineVenlafaxine > clonidine(Estradiol ≈ venlafaxine) > placebo

JAMA Intern Med 2014;174(7):1058-1066 Obstet Gynecol 2006;108:41-48J Clin Oncol 2010;28:147-5152 J Clin Oncol 2007;25:308-312Ann Oncol 2002;13:883-888 Menopause 2005;12(1):18-26

J Clin Oncol 2006:24:1409 Ann Oncol 2007;18:689-693

Assessment question

Which of the following drug classes have NOT shown efficacy in the treatment of hot flashes:1. Estrogens2. Dihydropyridine calcium

channel blockers3. α-2-δ ligands4. Serotonin/norepinephrine

reuptake inhibitors

Assessment questionA 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 daily2. Estradiol 0.5 mg/norethindrone acetate 0.1 mg

daily3. Clonidine 0.1 mg/24 hr transdermal patch

weekly4. Gabapentin 300 mg in the morning and 600 mg

before bedtime

CAM Hormonal agentsAlfalfaBlack CohoshChasteberryDHEADong QuaiFlaxseedHops

KudzuLicoricePanax GinsengRed cloverSoyWild Yam

CAM Hormonal agentsAlfalfaBlack CohoshChasteberryDHEADong QuaiFlaxseedHops

KudzuLicoricePanax GinsengRed cloverSoyWild Yam

CAM Treatments for Hot FlashesLikely safe Possibly safe

Effective

Likely effective

Possibly effective

FlaxseedSoy foods

Black CohoshSoy extracts

Insufficient evidence

ChasteberryGinkgoVitamin E

AlfalfaDHEA (short term)HopsKudzuLicoriceValerian

Possibly ineffective

Evening Primrose oil

Dong Quai (short term)Red CloverWild YamPanax GinsengAdapted from Natural Medicines

ComprehensiveDatabase-Accessed 5/17/2010

CAM Hormonal agentsGeneral cautions:

◦Unknown or questionable estrogenic activity

◦Standardization of products/preparations

◦Consistent quality of products◦Lack of high quality evidence

AcupunctureDifficult to determine a true

“placebo” groupDiffering disciplines of

acupuncturePt expectationsLack of understanding about

physiologic effects of acupuncture

Menopause 2010;17(2):228-230Menopause 2009;16:1065-1073

ConclusionsChoice 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.

Turn down the heat!

Treating hot flashes

Amanda Place, PharmD, BCACPSt Vincent Joshua Max Simon

Primary Care CenterSeptember 2014

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