Women s Health Update 2016: A Sharmacological Review for APRN s

Transcription

1 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

2 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 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 New guidelines from the American Cancer Society Women should discuss mammography with their provider and start screening if risk or wants warrant (insurance coverage?) Women 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):

3 USPSTF Recommendation of 2009 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. Women in their 40 s undergo excessive treatment and harm (false +, biopsies, surgery and chemotherapy) Hot controversy 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): USPSTF Grading 3

4 False-Positive Results USPSTF 2016 Guidelines Ann Intern Med 2016;164(4): What is the USPSTF? z Established in 1984 z Non-governmental y They do receive administrative support z Independent z Apolitical z The members are nonfederal experts on preventative medicine and primary care y They weigh patient benefit and harm z They do not advise insurers z Not cost-oriented Moral duty 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. 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. Ann Intern Med 2009;151(10):

5 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): JAMA 2014;312(23):2585 Harms of Mammography 40% can have false-positive mammogram Overdiagnosis 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 Surgery, chemotherapy, radiation or some combination Besides treatment and harm, they must live with the fear of recurrence 5

6 Overdiagnosis Malmo trial 2 women are overdiagnosed for every breast cancer death avoided BMJ 2006;332(7543): Gotzsche, et al 10 women are overdiagnosed for every breast cancer death avoided Cochrane 2009;4:CD Overdiagnosis Definition Hypothetical study Overdiagnosis Zone 40 cases of overdiagnosis Life Expectancy Table JAMA 2015;314(15):

7 Breast Cancer Risk by Age JAMA 2015;314(15): Self-Assessment Questions-T/F 1. Hormone replacement therapy should be offered to most postmenopausal women to prevent heart disease. 2. Hormone replacement therapy should be offered to most postmenopausal women to prevent osteoporosis. 3. Hormone replacement therapy should be offered to most postmenopausal women to prevent breast cancer. 4. Hormone replacement therapy should be offered to most postmenopausal women to prevent vasomotor symptoms. 5. Antidepressants can be used to reduce hot flashes as an alternative to hormones. 6. In those women who smoke, estrogen patches are the formulation of choice. 7

8 Hormones for what? 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: Science side of hormones 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? Therefore, HORMONE REPLACEMENT THERAPY Research Yesterday Observational studies Today Evidence-based Medicine HERS Trial WHI Trials WHIMS Trial 8

9 The WHI trial have changed things Top 300 drugs by total prescriptions rxlist.com 1995 # # #2 1998, 1999 #1 2000, 2001 # # # # #46 Real Benefits of HT Hot Flashes or Flushes 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 Med Clin N Am 2015;99: Lancet 2005;336: Incidence Symptoms generally begin 2 years before true menopause, peak one year after menopause and diminish over next 10 yrs Usually transient 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:

10 New Trial SWAN Longitudinal Database 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 Excluded % of these excluded women had NO visits with frequent vasomotor symptoms (VMS) JAMA Intern Med, published online Feb 16, 2015 SWAN Longitudinal Database Defined 2 groups Total VMS Duration (menstrual symptoms) Post-FMP Persistence (symptom persistence after final menstrual period) Patients in general ~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

11 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 Efficacy data in hot flashes Meta-analysis data reveal a reduction in vasomotor symptoms 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):

12 Symptoms Vasomotor symptoms Hot flashes Night sweats Vaginal symptoms Urinary incontinence Trouble sleeping Sexual dysfunction Depression, anxiety Labile mood Consistent association More Symptoms Memory loss Fatigue Headache Joint pain Weight gain NEJM 2006;355(22): Urogenital symptoms Symptoms include Vaginal dryness and atrophy HT has been shown to be more effective than Replens Dyspareunia Recurrent UTI Vaginal symptoms worsen with aging Hormones help with symptoms and are best used topically, but oral and transderm are also effective. Can use when HT is contraindicated Data does not support a reduction in UTI 12

13 Lifestyle Modification Common sense Lower room temp Fan Avoid hot drinks, hot or spicy foods Smoking increases frequency Med Clin N Am 2015;99: Combination Regimens Cyclic Replacement Estrogen days 1-25 Progestin days symptoms return on the 5 days off 90% have withdrawal bleeding Continuous Estrogen with Sequential Progestin Estrogen daily Progestin daily 1-14 (at least 12) 40% have withdrawal bleeding no return of symptoms Combination Regimens Continuous Combined Estrogen daily Low dose progestin daily increase progestin side effects easy, no bleeding Continuous Estrogen Estrogen daily For those with no uterus! NO progestin - WHY? Modern Regimens (especially for perimenopause) Levonorgestrel IUD + oral estrogen Low dose OC (10-20 mcg EE) 13

14 Treatment Duration 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: Continuous-combine regimens Prempro, Premphase (conjugated estrogen + medroxyprogesterone) First-line agent because of data animal source Prempro mg; mg; mg; mg - all doses are ~$125 per pack Premphase mg dose is CE on day 1-14, the progestin is added to day $100 per month Activella Soy-derived first line plant source 0.1 mg norethindrone/0.5 mg estradiol - $ mg norethindrone/1 mg estradiol - $85 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

15 Estrogen Side Effects 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) norethindrone acetate + EE 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 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

16 Ortho-Prefest 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 no incidence of endometrial hyperplasia in 227 patients amenorrhea is 51% at 12 months $112 Conjugated estrogens/bazedoxifene Duavee Estrogen + SERM Can use for hot flashes has endometrial safety with no increase in breast density or tenderness (SMART-5 trial*) Indication: moderate to severe hot flashes of menopause prevention of postmenopausal osteoporosis Safety 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 Risk increases with 5 to 10 years of use of any estrogen therapy * Obstet Gynecol 2013;121: **Obstet Gynecol 2005;106: Conjugated estrogens/bazedoxifene Duavee Safety 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 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

17 Conjugated estrogens/bazedoxifene Duavee Price ~$125 Conjugated estrogen is of the equine variety Tablets: 0.45 conjugated estrogen + 20 mg bazedoxifene Simplicity Dose is once daily Do not use in women > 75 years Estrogen-only Products Premarin 0.3 mg, 0.45 mg, mg, 0.9 mg, 1.25 mg ~$112 per month Enjuvia Oral plant conjugated estrogen Blend of 10 estrogens Main estrogen is 8,9-dehydroestrone sulfate Surelease tablet Slow release over several hours 0.3 mg, 0.45 mg, mg, 1.25 mg, ~$85 Cenestin a synthetic conjugated estrogen tablet 0.3 mg, 0.45 mg, mg, 0.9 mg, 1.25 mg, ~$120 Estrogen-only Products Menest - estrogen-only Derived from soy bean 0.3 mg, mg, 1.25 mg, 2.5 mg ~$40 to $50 Estropipate Ogen 0.75 mg, 1.5 mg, 3 mg all ~$14 to $20 Ortho-Est 0.75 mg, 1.5 mg $?? Estrace (estradiol) 0.5 mg,1 mg, 2 mg all < $10 17

18 Those who need higher doses? Heavy smokers Smoking increases metabolism of estrogens. Thin smokers are even at greater risk. Thin patients Patients who have had surgical menopause at an early age. Topical Therapy 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 Premarin Cream ($165) Estrace cream ($165) Vagifem (estradiol 25 mcg) vaginal tablet $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

19 Ring Products Estring 2 mg estradiol delivers mg/24 hrs $266 Femring 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? 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 Twice weekly patches Estraderm 0.05 mg (maroon package) = mg (maroon color tablet), $65 Estraderm 0.1 mg (yellow package) = 1.25 mg (yellow tablet), $75 Vivelle mg, 0.05 mg, mg, 0.1 mg Vivelle Dot mg, mg, 0.05 mg, mg, 0.1 mg, all are ~$95 Alora mg, 0.05 mg, mg, 0.1 mg all are ~$80 Minivelle mg, 0.05 mg, mg, 0.1 mg 0 all are ~$100 Smallest patch is the size of a dime 19

20 Dosing twice weekly patches Baptist regimen - apply Sunday & Wednesday rotate site - abdomen, buttocks bathing does NOT affect efficacy Patch Products Once weekly patches Generic estradiol patch mg, mg, 0.05 mg, 0.06 mg, mg, 0.1 mg - all are ~$45 Menostar mg ($112) Climara mg, mg, 0.05 mg, 0.06 mg and 0.1 mg, all are ~ $60 per month Climara Pro mg/day ($128) How to reduce skin irritation 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

21 Unique Estrogen Cream and Gel Topical estradiol emulsion 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 Elestrin (estradiol Gel 0.06%) low dose regimen 0.52 mg/0.87 gm Estrogel 0.06% 50 gm pump, $ gm bottle, $100 (they do make a 26g bottle) Divigel (estradiol) Topical gel, #30/box mg, 0.5 mg, 1 mg - $100 Evamist (estradiol) Transdermal spray for vasomotor symptoms, $ mg estradiol per spray, use 1 to 3 sprays per day New warning from FDA concerning exposure of estrogen to children and animals Ospemifine (Osphena ) Indication treatment of moderate to severe dyspareunia associated with menopause 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 Ospemifine (Osphena ) Safety Box warning for endometrial hyperplasia and CV events Trials did show a small increase in CV events DVT incidence 1.45/1000 ospemifine vs 1.04/1000 for placebo Therefore stop 4-6 weeks prior to a surgery with VTE risk Hemorrhagic stroke 1.45/1000 ospemifine vs 0 for placebo Cerebral thromboembolic events were higher in placebo 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 Concomitant administration of fluconazole not recommended Tolerability Hot flush (NNH 20), vaginal discharge, muscle spasms, hyperhidrosis UTI s 21

22 Ospemifine (Osphena ) Efficacy 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 ) Price Cost $175/#30 film-coated tablets Simplicity 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 High placebo response rate - 18% to 40% 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 ) ARR 19% to 60%, NNT 2 to 5 Fluoxetine 20 mg Paroxetine 20mg to 40 mg Venlafaxine 37.5 mg to 150 mg AFP 2006;73(3):

23 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 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): Nonhormonal Therapy for Hot Flashes Other prescription agents Bellergal - S Belladonna-ergotamine-phenobarbital one tab three times per day ARR 7%, NNT 14 Gabapentin 300 mg three times a day ARR 16%, NNT 6 Mirtazapine, report in 4 patients Trazodone, p = NS 23

24 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

25 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:

26 A Reminder Bacterial Vaginosis Recommended regimens 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) Treatment recurrences 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: A Quick Oral Contraceptive Review See table 26

27 Estrogen Excess Side Effects Nausea Dizziness Estrogen Deficiency: early break 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 decreased libido acne loss of hair headaches between pill packs increased breast size (alveolar tissue) breast tenderness dilated leg veins pelvic congestion syndrome Progestin Deficiency: late break through bleeding Androgen Excess Side Effects Hirsutism Acne Increase libido Increase appetite 27

28 Efficacy Pearl Index Number of pregnancies in 100 women in one year Traditional (old) agents - < mcg pills mcg pills mcg pills 2.9 MEC Criteria Med Clin N Am 2015;99: 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

29 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: New OC Agents to Consider 29

30 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, mg levomefolate ca Beyaz is 24 pills with 4 tabs of placebo containing mg levomefolate Safyral is 21 pills with 7 tabs of placebo containing mg levomefolate ~$116/pk Lo Loestrin Fe Lo Loestrin Fe and Lo Minastrin Fe (chewable) Very confusing as they are different formulations and therefore NOT substitutable. A generic form of Lo Loestrin Fe will come out soon but not right yet. You may get a call! First 10 mcg estrogen Given for 26 days instead of 21 days or 24 days No data to suggest it is safer May be less effective one extra pregnancy per 100 women-years Caution women not to miss pills Very low estrogen activity Iron is only contained in the two placebo pills Don t count on iron replacement Expensive ~$ 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 Spearmint flavor Generess Fe, 24 day pill 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

31 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

32 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

33 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 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, p567 33

34 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): 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

35 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 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 Naltrexone Opioid antagonist Bupropion 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 Caution with glyburide, protease inhibitors, and lower dose of Contrave to 1 tab per day with clopidogrel (2B6 inhibitor) Tolerability Nausea Selection issues comorbidities Smokers? Those with sexual dysfunction? What about those that take a chronic opioid? 35

36 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 Phentermine > 5% Weight Loss (Clinically Meaningful) Various, 12 weeks only, then change Orlistat 35-73% Lorcaserin (Belviq ) 37-47% Phentermine + topiramate ER (Qsymia ) Naltrexone + Bupropion (Contrave ) 67-70% 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

37 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

38 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 Use on abdomen, thigh, upper arm kjones@mcleodhealth.org 38