Breakout Session B - 2016 Charleston APRN Conference

Women’s Health Update 2016:
A Sharmacological Review for
APRN’s
Kelly W. Jones, Pharm.D., BCPS
Associate Professor of Family Medicine
McLeod Family Medicine Center
Florence, South Carolina
kjones@mcleodhealth.org
In Memory of Dr. Sharm Steadman
Disclosure
I have no conflict of interest relating in the material covered
today
 I do not serve on any speaker bureau
 I do not have any personal grants
concerning the area of discussion today

1
More Disclaimer
I
like bow-ties. No discussion of ties in this talk
and how they could be conduits to infection.
 Just took a dose of ibuprofen to help my feet
but we will not discuss NSAID’s.
 Used “Big Sexy Hair” hairspray this morning, but
no discussion on hairspray!
 My shoe size is 10, but we will not discuss shoes
today.
Objectives
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1) Discuss the history involving use of estrogen and progesterone for
menopause.
2) Discuss the current research involving hormone therapy for the
prevention and treatment of diseases associated with menopause.
3) Compare and contrast treatment regimens for hormone therapy.
4) Describe the components of oral contraceptives, comparing
monophasic, biphasic and multiphasic products.
5) Discuss new oral contraceptives, identifying important side effects,
clinical relevance and therapeutic usefulness.
6) Discuss new products and new indications.
Recent News on Mammography
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New guidelines from the American Cancer Society
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Women 40-44 should discuss mammography with their provider and
start screening if risk or wants warrant (insurance coverage?)
Women 45 – 54 annual screening
Women older that 55 – every other year, discontinue if life expectancy
falls below 10 years (they use to recommend stopping at age 74)
Clinical breast exam for screening is not recommended at any age
JAMA 2015;314(15):1599-14
2
USPSTF Recommendation of 2009
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Biennial screening mammography for women aged 50 to 74 years.
The USPSTF recommends against routine screening mammography in
women ages 40 to 49 years. The decision to start screening
mammography should be an individual one and take patient context
into account, including the patient’s values regarding specific benefits
and harms.
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Women in their 40’s undergo excessive treatment and harm (false +,
biopsies, surgery and chemotherapy)
Hot controversy
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Excluded radiologist and oncologist
Risking lives to reduce cost
Harbinger for rationing and government-run health care
USPSTF 2016 Guidelines Ann Intern Med 2016;164(4):279-96
USPSTF Grading
3
False-Positive Results
USPSTF 2016 Guidelines Ann Intern Med 2016;164(4):279-96
What is the USPSTF?
z
z
Established in 1984
Non-governmental
y
z
z
z
y
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z
They do receive administrative support
Independent
Apolitical
The members are nonfederal experts on preventative medicine and
primary care
They weigh patient benefit and harm
They do not advise insurers
Not cost-oriented
Moral duty
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“When millions of asymptomatic women have a procedure that
benefits few, the consequences of inaccurate mammograms to
save one woman’s life is a legitimate ethical question for us to
consider.”
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JAMA 2010;303(2):162-3
For most with cancer, screening does not change the ultimate
outcome; the cancer is just as treatable or just as deadly
regardless of screening.
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Ann Intern Med 2009;151(10):738-47
4
“Take the test, not the chance” Really?
Benefit
Women age 40 to 49
NNS = 2000
For every 2000 women screened for breast cancer with mammography 1
would be spared death from breast cancer over a 10 year period.
NNS = 3400 for those in their 40’s and over 10 years (from recent 2015
JAMA editorial)
Harm
In that same 2000 women, 120 to 400 would get biopsy due to a falsepositive mammogram
2 to 10 would be overdiagnosed, resulting in tx
6
JAMA 2010;303(2):162-73
JAMA 2014;312(23):2585
Harms of Mammography
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40% can have false-positive mammogram
Overdiagnosis
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Cancers detected by mammography that were never destined to cause
symptoms or death
Because it is impossible to know who is overdiagnosed, all are treated
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Surgery, chemotherapy, radiation or some combination
Besides treatment and harm, they must live with the fear of recurrence
5
Overdiagnosis
Malmo trial
2 women are overdiagnosed for every breast cancer death avoided
BMJ 2006;332(7543):689-92
Gotzsche, et al
10 women are overdiagnosed for every breast cancer
death avoided
Cochrane 2009;4:CD001877
Overdiagnosis – Definition
Hypothetical study
Overdiagnosis
Zone
40 cases of overdiagnosis
Life Expectancy Table
JAMA 2015;314(15):1599-14
6
Breast Cancer Risk by Age
JAMA 2015;314(15):1599-14
Self-Assessment Questions-T/F
1.
2.
3.
4.
5.
6.
__ Hormone replacement therapy should be offered to most
postmenopausal women to prevent heart disease.
__ Hormone replacement therapy should be offered to most
postmenopausal women to prevent osteoporosis.
__ Hormone replacement therapy should be offered to most
postmenopausal women to prevent breast cancer.
__ Hormone replacement therapy should be offered to most
postmenopausal women to prevent vasomotor symptoms.
__ Antidepressants can be used to reduce hot flashes as an
alternative to hormones.
__ In those women who smoke, estrogen patches are the
formulation of choice.
7
Hormones for what?
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Menopause is defines retrospectively after 12 months of
amenorrhea
Usual transition begins in the mid to late forties and last 4 years
with menopause occurring at a median age of 51 years
6000 American women reach menopause every day
40% of a women’s life is spent in menopause
Smokers, low BMI, nulliparity, lower education go through
menopause 2 years earlier
Med Clin N Am 2015;99:521-34
Science side of hormones
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Women live longer than men!
Lowers cholesterol
Lowers heart disease
Increases bone mineral density and reduces osteoporosis
Improved cognition in “Nuns”
Hormones should reduce cancer, right?
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Therefore, HORMONE REPLACEMENT THERAPY
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Research
•
Yesterday
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Observational studies
Today
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•
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Evidence-based Medicine
HERS Trial
WHI Trials
WHIMS Trial
8
The WHI trial have changed things
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Top 300 drugs by total prescriptions
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rxlist.com
1995
1996
1997
1998, 1999
2000, 2001
2002
2003
2004
2005
#1
#2
#2
#1
#3
#5
#16
#31
#46
Real Benefits of HT
Hot Flashes or Flushes
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80% of women are affected
20% find the symptoms intolerable
The severity and frequency vary during the day or night.
Hot flashes last ~4 min, can last 10 min
Hot flush may or may not be associated with sweats
May have chills
Often aggravated by warm environment, stress, hot
food and beverages
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Lancet 2005;336:409-21
Med Clin N Am 2015;99:521-34
Incidence
Symptoms generally begin 2 years before
true menopause, peak one year after
menopause and diminish over next 10 yrs
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Usually transient
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30% to 50% improve over a few months
Most resolve within one year
90% have resolved by 5 years
10% can have hot flushes for many years.
Med Clin N Am 2015;99:521-34
9
New Trial
SWAN Longitudinal Database
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Longitudinal, observational trial spanning 17 years, USA trial
Sought to assess the transition from premenopause into late
postmenopause (menstrual transition)
42 to 52 year old women
13 visits from 1996 to 2013 (follow-up mean is 12.7 yrs)
Used a questionnaire at each visit
Started with 3302 cohort
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Excluded 1853
51% of these excluded women had NO visits with frequent vasomotor
symptoms (VMS)
JAMA Intern Med, published online Feb 16, 2015
SWAN Longitudinal Database
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Defined 2 groups
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Total VMS Duration (menstrual symptoms)
Post-FMP Persistence (symptom persistence after final menstrual
period)
Patients in general
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~50 years old
Multi-racial (45% white, 35% AA)
~70% married, 60% with no financial strain, 40% > college education,
54% never smoked, ~35% with BMI > 30
10
SWAN Song
Mean total VMS lasted 7.4 yrs
Those who had a defined observable final menstrual period,VMS
lasted 4.5 years
Those with premenopausal symptoms (early perimenopausal) had
VMS for the longest, median 11.8 years
Those who were postmenopausal at the onset of VMS had the
shortest duration, 3.4 years
AA had the longest duration of symptoms, 10 years
Longer duration was associated with younger age, lower education
level, greater perceived stress and anxiety, depressive symptoms
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Efficacy data in hot flashes
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Meta-analysis data reveal a reduction in vasomotor symptoms
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65% in estrogen only patients
90% in combined hormone patients
Substantial efficacy is usually seen by 4 weeks.
Low doses may take 8-12 weeks to work.
NEJM 2006;355(22):2338-47
11
Symptoms
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Vasomotor symptoms
Hot flashes
Night sweats
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Vaginal symptoms
Urinary incontinence
Trouble sleeping
Sexual dysfunction
Depression, anxiety
Labile mood
Consistent association
More Symptoms
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Memory loss
Fatigue
Headache
Joint pain
Weight gain
NEJM 2006;355(22):2338-47
Urogenital symptoms
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Symptoms include
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Vaginal dryness and atrophy
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Dyspareunia
Recurrent UTI
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Vaginal symptoms worsen with aging
Hormones help with symptoms and are best used topically, but oral
and transderm are also effective.
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HT has been shown to be more effective than Replens®
Can use when HT is contraindicated
Data does not support a reduction in UTI
12
Lifestyle Modification
Common sense
Lower room temp
Fan
Avoid hot drinks, hot or spicy foods
Smoking increases frequency
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Med Clin N Am 2015;99:521-34
Combination Regimens
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Cyclic Replacement
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Estrogen days 1-25
Progestin days 13-25
symptoms return on the 5 days off
90% have withdrawal bleeding
Continuous Estrogen with Sequential Progestin
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Estrogen daily
Progestin daily 1-14 (at least 12)
40% have withdrawal bleeding
no return of symptoms
Combination Regimens
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Continuous Combined
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Continuous Estrogen
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Estrogen daily
Low dose progestin daily
increase progestin side effects
easy, no bleeding
Estrogen daily
For those with no uterus!
NO progestin - WHY?
Modern Regimens (especially for perimenopause)
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Levonorgestrel IUD + oral estrogen
Low dose OC (10-20 mcg EE)
13
Treatment Duration
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5 years is reasonable
For vasomotor symptoms try discontinuing every 6-12 months
and only restart if necessary
Tapering does not reduce chance of hot flash recurrence
Opinion – stop drug 4-6 weeks before surgery to reduce risk of
VTE complications, especially if they are high risk for VTE
Med Clin N Am 2015;99:521-34
Continuous-combine regimens
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Prempro®, Premphase® (conjugated estrogen +
medroxyprogesterone)
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First-line agent because of data – animal source
Prempro® 0.3-1.5 mg; 0.45-1.5 mg; 0.625-2.5 mg; 0.625-5 mg all doses are ~$125 per pack
 Premphase® 0.625-5 mg dose is CE on
day 1-14, the progestin is added to day 15-28
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$100 per month
Activella®
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Soy-derived – first line plant source
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0.1 mg norethindrone/0.5 mg estradiol - $85
0.5 mg norethindrone/1 mg estradiol - $85
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generic of this dose is $75
indicated to prevent vasomotor symptoms and osteoporosis
associated with menopause
dose is one tablet daily in a calendar dial pack, 28 day
adverse effects: breast pain, headache, back pain, nausea,
increase weight
amenorrhea at 97% at 12 months
reduces cholesterol, HDL, LDL, increases TG by 12%,
significance?
14
Estrogen Side Effects
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Nausea
Dizziness
Edema
Cyclic weight gain
Bloating
Chloasma
Uterine cramping
Irritability, depression
Poor contact lens fit
Vascular type headaches
Hypertension
Headache while taking the pill
Cystic breast changes, breast tenderness, increased breast size
thrombophlebitis
cerebrovascular accident, myocardial infarction
Femhrt®
Jinteli® (Jevantique® generic)
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norethindrone acetate + EE
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1 mg/5 mcg, $50
0.5mg/2.5 mg (not sure it is still available)
Excellent for those who have estrogen side effects
indicated to prevent vasomotor symptoms and
osteoporosis associated with menopause
amenorrhea in 84% at 12 months (93% for those on
placebo), 40% in first month
increases bone mineral density 3.1% (CHART study)
endometrial hyperplasia is equal to that of placebo
dose is one tablet daily
Progesterone Side Effects
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increased appetite and weight gain (non-cyclic)
tiredness, fatigue, and weakness
depression
decreased libido
acne
loss of hair
headaches between pill packs
increased breast size (alveolar tissue)
breast tenderness
dilated leg veins
pelvic congestion syndrome
15
Ortho-Prefest®
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continuous & intermittent therapy
Excellent for those with progestin side effects
17-beta estradiol 1mg in pink tablet and 17-beta estradiol 1mg
+ norgestimate 0.09 mg in the white tablet
come in blister cards of 15 pink tablets and 15 white tablets,
alternating every
3 day dosing regimen is based on the theory that periods of unopposed
estrogen will increase estrogen and progestin sensitivity in estrogen
tissue, allowing lower doses of hormone to control symptoms
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no incidence of endometrial hyperplasia in 227 patients
amenorrhea is 51% at 12 months
$112
Conjugated estrogens/Bazedoxifene
Duavee®
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Estrogen + SERM
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Indication:
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Can use for hot flashes – has endometrial safety with no increase in
breast density or tenderness (SMART-5 trial*)
moderate to severe hot flashes of menopause
prevention of postmenopausal osteoporosis
Safety
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Same box warning as estrogens
As safe as raloxifene on endometrium**
No need for progestin to prevent endometrial hyperplasia
Endometrial risk is limited by duration of treatment
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Risk increases with 5 to 10 years of use of any estrogen therapy
* Obstet Gynecol 2013;121:959-68
**Obstet Gynecol 2005;106:1110-1
Conjugated estrogens/Bazedoxifene
Duavee®
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Safety
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Mammography and endometrial biopsy for rule-out is advised
Tolerability
Most common side effects (>5%): muscle spasm (NNH 33), nausea
(NNH 33), diarrhea (NNH 33), abdominal pain (NNH 50), dizziness
(NNH 50), dyspepsia (NNH 100), neck pain (NNH 100)
No drug interaction data
Efficacy – Clinical Trial Observations
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Women with an average of 10 hot flashes a day can expect the
frequency to be reduced to 4 per day by week 4.
Osteoporosis trials are DOE – BMD studies. The drug increases
density at the lumbar spine and hip. No fracture data
16
Conjugated estrogens/Bazedoxifene
Duavee®
Price
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~$125
Conjugated estrogen is of the equine variety
Tablets: 0.45 conjugated estrogen + 20 mg bazedoxifene
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Simplicity
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Dose is once daily
Do not use in women > 75 years
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Estrogen-only Products
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Premarin®
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0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, 1.25 mg
~$112 per month
Enjuvia®
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Oral plant conjugated estrogen
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Surelease tablet
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Blend of 10 estrogens
Main estrogen is 8,9-dehydroestrone sulfate
Slow release over several hours
0.3 mg, 0.45 mg, 0.625 mg, 1.25 mg, ~$85
Cenestin®
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a synthetic conjugated estrogen tablet
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0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, 1.25 mg, ~$120
Estrogen-only Products
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Menest® - estrogen-only
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Derived from soy bean
0.3 mg, 0.625 mg, 1.25 mg, 2.5 mg
~$40 to $50
Estropipate
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Ogen®
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Ortho-Est®
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0.75 mg, 1.5 mg, 3 mg – all ~$14 to $20
0.75 mg, 1.5 mg
$??
Estrace (estradiol)
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0.5 mg,1 mg, 2 mg – all < $10
17
Those who need higher doses?
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Heavy smokers
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Smoking increases metabolism of estrogens.
Thin smokers are even at greater risk.
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Thin patients
Patients who have had surgical menopause at an early age.
Topical Therapy
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Creams are best for short term (1-2 months), rapid relief of
urogenital/vaginal symptoms.
80% to 100% improvement in symptoms
They provide 1/4th of the systemic level achieved by oral agents.
1-2 weeks, then 3 times/weeks as maintenance.
Oral or patch therapy can be started at the same time.
Products
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Premarin Cream ($165)
Estrace cream ($165)
Vagifem (estradiol 25 mcg)
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vaginal tablet
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$240 for #18
$112 for #8
indicated for vaginal atrophy
one dose daily for 2 weeks, then one dose twice weekly
NOT indicated for vasomotor symptoms
18
Ring Products
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Estring
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Femring
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2 mg estradiol
delivers 0.0075 mg/24 hrs
$266
0.05 mg/day ($250) and 0.1 mg/day ($265)
inserted into the vaginal vault
replace every 3 months if needed
if ring is removed or falls out, rinse in warm water and re-insert
Are patches first-line?
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Smokers - smoking increases the metabolism of estrogen. The
patches bypass the liver and are not affected by smoking.
Those who cannot tolerate the GI side effects of oral
medications.
Women who have migraines.
Women with hepatobiliary disorders.
Those with fibocystic breast disease.
Those who have heavy bleeding on oral therapy
In those who have elevated triglycerides. Oral estrogen increases
triglycerides 20-25%.
Those with a history of a clotting disorder.
Patch Products
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Twice weekly patches
Estraderm® 0.05 mg (maroon package) = 0.625 mg (maroon color
tablet), $65
Estraderm® 0.1 mg (yellow package) = 1.25 mg (yellow tablet), $75
Vivelle® 0.0375 mg, 0.05 mg, 0.075 mg, 0.1 mg
Vivelle Dot® 0.025 mg, 0.0375 mg, 0.05 mg, 0.075 mg, 0.1 mg, all
are ~$95
Alora® 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg – all are ~$80
Minivelle® 0.0375 mg, 0.05 mg, 0.075 mg, 0.1 mg 0 all are ~$100
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Smallest patch is the size of a dime
19
Dosing twice weekly patches
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Baptist regimen - apply Sunday & Wednesday
rotate site - abdomen,
buttocks
bathing does NOT
affect efficacy
Patch Products
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Once weekly patches
Generic estradiol patch 0.025 mg, 0.0375 mg, 0.05 mg, 0.06
mg, 0.075 mg, 0.1 mg - all are ~$45
Menostar® - 0.014 mg ($112)
Climara® 0.025 mg, 0.0375 mg, 0.05 mg, 0.06 mg 0.075 and
0.1 mg, all are ~ $60 per month
Climara Pro® 0.045-0.015 mg/day ($128)
How to reduce skin irritation
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Apply 1% - 2.5% hydrocortisone cream, let dry and apply
patch.
Apply Maalox (antacid) with a cotton ball, let dry, wipe off
residue, then apply patch.
The patch can be moved each day to reduce irritation, there is
enough adhesive to do this without problems.
20
Unique Estrogen Cream and Gel
Topical estradiol emulsion
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Estrasorb® 4.35 mg/1.74 gm emulsion
$100 for 30 day supply
85% reduction on hot flashes
24 hour symptom control
Apply 2 packets daily to thigh
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Elestrin® (estradiol Gel 0.06%)
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low dose regimen – 0.52 mg/0.87 gm
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87 gm bottle, $100 (they do make a 26g bottle)
Estrogel® 0.06% 50 gm pump, $100
Divigel® (estradiol)
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Topical gel, #30/box - - 0.25 mg, 0.5 mg, 1 mg - $100
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Evamist® (estradiol)
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Transdermal spray for vasomotor symptoms, $100
1.5 mg estradiol per spray, use 1 to 3 sprays per day
New warning from FDA concerning exposure of estrogen to children and animals
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Ospemifine (Osphena®)
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Indication
treatment of moderate to severe dyspareunia associated with
menopause
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SERM
selective estrogen receptor modulator (agonist/antagonist)
Agonist on estrogen receptors in the vagina
Antagonist on breast tissue
Some effect on uterine tissue
non-estrogenic
tissue selective effects
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Ospemifine (Osphena®)
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Safety
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Box warning for endometrial hyperplasia and CV events
Trials did show a small increase in CV events
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DVT incidence – 1.45/1000 ospemifine vs 1.04/1000 for placebo
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Hemorrhagic stroke – 1.45/1000 ospemifine vs 0 for placebo
Cerebral thromboembolic events were higher in placebo
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Endometrial hyperplasia of 5mm was seen in 5% of patients (ARI 3.4%, NNH
30). Monitor for uterine bleeding. Add a progestin?
Metabolized primarily by CYP3A4 and CYP2C9 but CYP2C19 and other
pathways also contribute to the metabolism of ospemifene
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Therefore stop 4-6 weeks prior to a surgery with VTE risk
Concomitant administration of fluconazole not recommended
Tolerability
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Hot flush (NNH 20), vaginal discharge, muscle spasms, hyperhidrosis
UTI’s
21
Ospemifine (Osphena®)
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Efficacy
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Approval based on data from three clinical trials
two 12-week efficacy trials
one 52-week long-term safety trial
N = 1889 postmenopausal women.
In both 12-week efficacy trials, statistically significant
improvement was demonstrated compared with placebo for
vaginal pain with sexual activity, NNT 10
Ospemifene (Osphenia®)
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Price
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Cost $175/#30 film-coated tablets
Simplicity
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Dose: 60 mg once daily with food
Recommended to be taken with food; however AUC increased if
taken with high fat/high calorie meals
Should not be used in women with severe hepatic impairment
(has not been studied).
No dose adjustment of OSPHENA is required in women with
renal impairment.
Nonhormonal Therapy
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High placebo response rate - 18% to 40%
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Most trials are in women with a history of breast cancer.
Mechanism of action is unknown
There has been a link to serotonin imbalance and hot flashes.
SSRI’s and Venlafaxine (Effexor®)
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ARR 19% to 60%, NNT 2 to 5
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Fluoxetine 20 mg
Paroxetine 20mg to 40 mg
Venlafaxine 37.5 mg to 150 mg
AFP 2006;73(3):457-64
22
Paroxetine gets a new look!

Paroxetine (Brisdelle®) – low dose





Comes in mesylate form – the others are HCl (Paxil®)
First nonhormonal regimen approved by the FDA for hot flashes.
7.5 mg capsule given at bedtime
Cost : $135/mth
Trials show a difference of 1.2 hot flashes on the average per day with
paroxetine vs placebo


Those with an average of 10 hot flashes per day dropped to 6 using the
medication for 4 weeks
Main side effects: nausea (NNH 50); fatigue (NNH 50); dizziness (NNH
100)
PL document 291109
Nonhormonal Therapy for Hot Flashes

Clonidine





ARR 15% to 20%, NNT 5 to 7
Dose is 0.1 mg
Watch side effects - dry mouth, constipation, drowsiness
Patches have been used with success.
Vitamin E


800 IU per day
Reduced the number of hot flashes per day by one, but p = NS
JAMA 2006;295(17):2057-71
Nonhormonal Therapy for Hot Flashes


Other prescription agents
Bellergal - S




Gabapentin




Belladonna-ergotamine-phenobarbital
one tab three times per day
ARR 7%, NNT 14
300 mg three times a day
ARR 16%, NNT 6
Mirtazapine, report in 4 patients
Trazodone, p = NS
23
Herbal Therapy




Phytoestrogens
Some sources recommend not to
use due to the lack of safety and
efficacy data.
Not effective for vaginal symptoms
Not sure of effect on breast or endometrial cancers
Herbal Therapy



Black cohosh
Red clover isoflavones
No benefit in RCT’s


High dose black cohosh reduced hot flashes in breast cancer
tamoxifene treated patients
Has been a case of liver failure reported with black cohosh
Other complementary agents





No greater benefit than placebo
Dong quai
Evening primrose oil
Ginseng
Magnet therapy
24
Bio-identical Hormones


Brought to you by…Oprah Winfrey and Suzanne Somers
Bio-identical in structure to human hormones





Not a plant or animal source
Cannot get a patent on bio-identical structures
Usually made in compounding pharmacies
No data testing safety that I know of….
They are natural….

They may have less side effects
So where are we?



Back to the basics: treat symptoms and dis-ease more so than
disease or disease prevention.
Continuous-combined regimens have improved adherence.
We have more options to start with:




Prempro® or Activella®
Femhrt® for estrogen-sensitive patients.
Ortho-Prefest® for progestin-sensitive patients.
Use complimentary medications for symptom relief when hormones
are not used
Lancet 2005;336:409-21
25
A Reminder

Bacterial Vaginosis

Recommended regimens




Treatment recurrences



Metronidazole 500 mg bid x 7 days
Metronidazole gel 0.75%, I applicator x 5 nights ($62 at GoodRx price)
Clindamycin cream 2%, I applicator x 7 nights ($40 at GoodRx price)
Metronidazole gel twice a week for 4-6 months
Tinidazole oral followed by boric acid intravaginal 600 mg x 14d, then add gel
Trichomonas

Recommended regimen



Metronidazole or tinidazole 2 gm single dose
Most recurrence result from reexposure, use tinidazole for retreatment
4-10% resistance to metronidazole, 1% to tinidazole
Med Clin N Am 2015;99:553-74
A Quick Oral Contraceptive Review
See table
26
Estrogen Excess Side Effects















Nausea
Estrogen Deficiency: early break
Dizziness
through bleeding
Edema
Cyclic weight gain
Bloating
Chloasma
Uterine cramping
Irritability, depression
Poor contact lens fit
Vascular type headaches
Hypertension
Headache while taking the pill
Cystic breast changes, breast tenderness, increased breast size
thrombophlebitis
cerebrovascular accident, myocardial infarction
Progesterone Excess Side Effects











increased appetite and weight gain (non-cyclic)
tiredness, fatigue, and weakness
depression
Progestin Deficiency: late break
decreased libido
through bleeding
acne
loss of hair
headaches between pill packs
increased breast size (alveolar tissue)
breast tenderness
dilated leg veins
pelvic congestion syndrome
Androgen Excess Side Effects




Hirsutism
Acne
Increase libido
Increase appetite
27
Efficacy

Pearl Index





Number of pregnancies in 100 women in one year
Traditional (old) agents - <1
30-35 mcg pills – 1.5
20 mcg pills – 1.8
10 mcg pills – 2.9
MEC Criteria
Med Clin N Am 2015;99:479-503
Recent FDA Alerts! - FYI


10/27/2011
New OC’s


Drospirenone, etonogestrel (ring),
norelgestromin (patch)
Huge retrospective cohort, n = 189,210, looking into the VTE potential of
these agents



10/10,000 with these agents vs 6/10,000 with other agents vs 3/10,000 in all
nonusers
17/10,000 risk with pregnancy
Higher risk of VTE, FDA to follow up with a recommendation
28
Some Dosing Issues

Bi-cycling – 2 monophasic packs in a row
Tri-cycling – 3 monophasic packs in a row
4 monophasic packs in a row is equivalent Seasonale®

Those indicated for acne





Ortho Tri-Cyclen®
Yaz®
Estrostep®
Continuous OC’s


Median time to return of menses is 32 after stopping a
continuous OC (COC)
Return to fertility was 90 days after COC
Med Clin N Am 2015;99:479-503
New OC Agents to Consider
29
Two OC’s patent extenders approved!


Drospirenone/EE/levomefolate (Beyaz®)
Beyaz® is Yaz® with folate








24 day extended use
Safyral® is Yasmin® with folate
28 day pack for each
Both packs contain:
3 mg drospirenone, 20 mcg EE, 0.451 mg levomefolate ca
Beyaz® is 24 pills with 4 tabs of placebo containing 0.451 mg
levomefolate
Safyral® is 21 pills with 7 tabs of placebo containing 0.451 mg
levomefolate
~$116/pk
Lo Loestrin Fe

Lo Loestrin Fe and Lo Minastrin Fe (chewable)

Very confusing as they are different formulations and therefore NOT
substitutable. A generic form of Lo Loestrin Fe will come out soon but not
right yet. You may get a call!


First 10 mcg estrogen
Given for 26 days instead of 21 days or 24 days
No data to suggest it is safer
May be less effective – one extra pregnancy per 100 women-years
Caution women not to miss pills
Very low estrogen activity
Iron is only contained in the two placebo pills

Expensive ~$110.00






Don’t count on iron replacement
Newest Dosage Forms


Minastrin 24 Fe® is replacing Loestrin 24 FE®
Chewable Birth Control Pills

Lo Minastrin Fe®
Femcon Fe is the chewable version of Ovcon-35

Generess Fe, 24 day pill



Spearmint flavor
Quartette® - 84-day pill with escalating estrogen dose - $275 for 3
mths


Quadraphasic form of LoSeasonique®
EE dose varies 20 mcg 42d; 25 mcg 21d; 30 mcg 21d; 10 mcg 7d
30
Cases

Case 1


Lisa was just started on Ortho-Novum 777®. She has been nauseated
- what pill would you switch her to?
Case 2

Carol is on Yasmin® and complains of a low libido. What would you
do?
Cases

Case 3


Faith is taking Yaz® and complains of sleepiness. What would you do?
What could it be from?
Case 4

Your patient has been taking Lutera® for several months. She is in the
office today complaining of spotting. What would you do?
Some New Medications
31
The Projected Big Seller!



Kybella® (deoxycholic acid)
A cytolytic agent to reduce fat below the chin!
Up to 50 injections using 10 ml total in a single treatment


0.2 ml per injection
Use 6 treatments a month apart
“What’s the Skinny” on the Medical
Management of Obesity?
Not all are created equal!
32
Where were you in 1988?














I was at MUSC doing my fellowship in family medicine
Pan-Am 747 explodes over Scotland
Reagan was President
Life expectancy was 74 yrs
National Debt was 2 trillion
Mean income was $28,000, unemployment 5%
Cost of a stamp was 22 cents
Redskins won the super bowl against Denver
Notre Dame was NCAA National Champions
CD sales for the first time surpassed vinyl sales
TNT was started
Rain Man was the movie of choice, but The Last Emperor got best picture
We lost Roy Orbison 
JNC-4 was published that connected lifestyle to cardiovascular risk
Prevalence of Obesity
http://www.nationmaster.com/graph/hea_obe-health-obesity
History of Drug Treatments for Obesity
by date of approval/withdrawal
Drug
Serious Adverse Event
1893/1949
Thyroid Hormone
Hyperthyroidism
1933/1935
Dinitrophenol
Cataracts, neuropathy
1937/1971
Amphetamine
Addiction, psychosis
1965/1972
Aminorex
Pulmonary hypertension
1973/1997
Fenfluramine plus phentermine
Cardiac valvular insufficiency
1960/2000
Phenylpropanolamine
Hemorrhagic stroke
2006/2009
Rimonabant
Depression, suicidal ideation
1997/2010
Sibutramine
Cardiovascular Disease
•
New drugs paying the price of these failures...
Lancet, August 21, 2010. p567
33
Large Graveyard

Sibutramine (Meridia®)


Withdrawn from the US market October 2010…
FDA recommended withdrawal after publication of the SCOUT
trial:

Sibutramine Cardiovascular Outcomes Trial



Manufacturer tried to show that sibutramine could improve CV outcomes in
high-risk patients through weight loss
Enrolled 10,000+ patients > 55 years of age, overweight or obese, with history of
heart disease or type 2 DM plus one additional CV risk factor
Results



Improved weight loss (mean difference 2.4 kg)
Increased blood pressure and pulse
Increased primary outcome (nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest,
cardiovascular death) by 1.4% (NNH 71)
NEJM 2010;363(10):905-17.
NDA Withdrawn in the US

Accomplia®: Rimonabant

Endo-cannabanoid receptor blocker



Stimulation of cannabanoid type 1 receptors increases food intake
Studied in > 3000 obese and overweight patients; found 4.7 kg more weight loss vs
placebo at 12 months
Meta-analysis of 4 RCTs found increase in psychiatric events


Depressive mood, anxiety
CRESCENDO trial found increased suicide and serious psychiatric side effects (NNH
83)
When Phen-Fen Hit the Fan-Fan!

Fenfluramine and dexfenfluramine removed in 1997

Serotonin agonist

Causes valvular heart disease and pulmonary hypertension

Phenylpropanolamine (PPA)




Decongestant of old
Called Dexatrim® for weight loss
Removed in 2005
Increases cerebral hemorrhage


1 on 3,000,000
Not associated with cold use, only diet
34
The Battleground
Statement from the new
Endocrine Society guidelines



Presupposition
“The Task Force agrees with the opinion of prominent medical
societies that current scientific evidence supports the view
that obesity is a disease.”
J Clin Endocrinol Metab , 2015 published online
Naltrexone/bupropion (Contrave®)

Indication


Naltrexone


Opioid antagonist
Bupropion


Adjunct for diet and exercise to reduce weight in those obese (BMI >
30) and those overweight (BMI > 27) with one or more comorbid risk
factors – hypertension, dyslipidemia, T2DM
Dopamine and NE reuptake inhibitor
The combination affects satiety and reward
Naltrexone/bupropion (Contrave®)

Safety




Typical antidepressant issues and warnings of suicidality
Monitor BP
Seizure history?
Drug interactions – bupropion is a strong 2D6 inhibitor


Tolerability


Caution with glyburide, protease inhibitors, and lower dose of Contrave® to 1 tab
per day with clopidogrel (2B6 inhibitor)
Nausea
Selection issues – comorbidities



Smokers?
Those with sexual dysfunction?
What about those that take a chronic opioid?
35
Naltrexone/bupropion (Contrave®)

Efficacy:




In 56 week trials, the average weight loss is 9 kg vs 1.5 mg for placebo
~66% get >5% total body weight loss (intention-to-treat) vs 40% with placebo
In diabetics HbA1c change at 1 year was -0.6%
Price/Simplicity



Naltrexone/bupropion tablets 8 mg/90 mg extended release
Not a controlled substance
Dose





Week 1: 1 tab qAM
Week 2: 1 tab BID
Week 3: 2 tabs qAM and 1 tab qPM
Week 4: 2 tabs BID
Look for Saxenda 3 mg (liraglutide) injection soon!
Outcomes
Medications for Obesity
> 5% Weight Loss (Clinically
Meaningful)
Phentermine
Various, 12 weeks only, then change
Orlistat
35-73%
Lorcaserin (Belviq®)
37-47%
Phentermine + topiramate ER
(Qsymia®)
67-70%
Naltrexone + Bupropion
(Contrave®)
66%
Liraglutide (Saxenda®)
44-63%
JAMA 2014;311(1):74-86
Liraglutide (Saxenda®)
 Safety
Box warning concerning thyroid cancer
Pancreatitis
 Gallbladder disease
 Kidney problems
 Suicidal thoughts
 Tachycardia
 If the patient has not lost more than 4% of body
weight by 16 weeks, stop the medication


36
Liraglutide (Saxenda®)

Tolerability






Nausea ARI 25%, NNH 4,Vomiting NNH 8
Diarrhea ARI 11%, NNH 9
Constipation ARI 11%, NNH 9
Dyspepsia ARI 7%, NNH 14, GERD NNH 33
Fatigue ARI 3%, NNH 33
Increase lipase ARI 3%, NNH 33
Liraglutide (Saxenda®)
From package insert
Liraglutide (Saxenda®)


Efficacy
Patients without diabetes seem to have a better response than
those with diabetes




Better reduction in BP, waist circumference
Except in cholesterol levels
TC, LDL went down a few points, TG went down the most
Response was seen within 2 weeks
37
Liraglutide (Saxenda®)


Price?
Simplicity





Injection daily
Prefilled, multi-dose pen 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, 3 mg
Start 0.6 mg and increase each increment weekly
You can watch training module on www.saxenda.com
Use on abdomen, thigh, upper arm
kjones@mcleodhealth.org
38