7/29/2018 DISCLOSURE OF RELEVANT RELATIONSHIPS WITH INDUSTRY

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1 Update on Hormonal Therapy for Acne Bethanee J. Schlosser, MD, PhD Depts. of Dermatology and OB/GYN Northwestern University Chicago, IL July 29, 2018 DISCLOSURE OF RELEVANT RELATIONSHIPS WITH INDUSTRY Bethanee J. Schlosser, MD, PhD F033: Acne Guideline Update on Hormonal Therapy Author: UpToDate, Decision Support in Medicine Advisory Board: Allergan, UCB, Beiersdorf Speaker: Allergan Off-label use of medication will be discussed. Hormonal Therapy for Acne Anti-Androgens (receptor) Progestins Cyproterone acetate Spironolactone Flutamide Androgen Inhibitors (synthesis) Estrogen Progestins D Thiboutot et al. J Am Acad Dermatol 2009; 60: S1. When to Consider Hormonal Therapy Hyperandrogenism Late-onset or persistent (>25yo) Prominence of acne at lower face, neck Perimenstrual flare Comedonal acne with seborrhea Resistant to conventional therapies Alternative to repeat isotretinoin Strength of Evidence for Hormonal Therapy Recommendation Combined oral contraceptives Strength of Recommendation Level of Evidence Spironolactone B II, III A/I = Recommendation based on consistent and good-quality patient-oriented evidence A B/II = Recommendation based on inconsistent or limited quality patient-oriented evidence C/III = Recommendation based on consensus, opinion, case studies or disease-oriented evidence Zaenglein AL et al. J Am Acad Dermatol 2016; 74: 945. I 1

2 Combined Oral Contraceptives Ethinyl estradiol 1960s: µg per pill 2010s: 10-30µg per pill Progestin androgenicity varies Overall net effect is anti-androgenic due to estrogen impact Reduce androgens via: Reduces GnRH pulsatility LH production Sex hormone binding globulin synthesis Androgenic Index of Progestins 4 th Generation 3 rd Generation 2 nd Generation 1 st Generation Drospirenone Desogestrel Norethindrone Norgestrel Cyproterone acetate Norgestimate Norethindrone acetate Medroxyprogesterone acetate Gestodene Desogestrel Ethynodiol diacetate Levonorgestrel FDA Indication for Combined OCP Use in Acne Moderate inflammatory acne At least 15 years old Has achieved menarche Desires contraception Plans to take OCP for at least 6 months Has failed to respond to topical anti-acne medications Migraine w/ focal neurologic sx, w/o aura if 35yr Biliary tract disease Major surgery with prolonged immobilization History of cholestasis related to OCP use Migraine w/ focal neurologic sx, w/o aura if 35yr Biliary tract disease Major surgery with prolonged immobilization History of cholestasis related to OCP use Migraine w/ focal neurologic sx, w/o aura if 35yr Biliary tract disease Major surgery with prolonged immobilization History of cholestasis related to OCP use 2

3 Migraine w/ focal neurologic sx, w/o aura if 35yr Biliary tract disease Major surgery with prolonged immobilization History of cholestasis related to OCP use OCPs and Health Screening Pelvic examination and Pap smear are not required for initiation of hormonal contraception in most women 1 Pelvic examination is not necessary prior to initiating oral contraceptives in teenagers 2 History (PMH, family, social) Blood pressure measurement test 1 Frangos JE et al. J Am Acad Dermatol 2008; 58: ACOG Oral contraceptives for adolescents: benefits and safety; Moderate facial acne Inflammatory 20mcg EE/3mg DSP (n= 266) vs placebo (n=268) Noninflammatory Moderate inflammatory truncal acne, 18-45yo Noninflammatory Total % reduction greater for treatment group across all lesion types (p<0.0001) OR clear/almost clear = 4.31 At least 3 cycles of use prior to judging efficacy Inflammatory Total 20mcg EE/3mg DSP 24/4 regimen (n= 16) vs placebo (n=14) % reduction greater for treatment group across all lesion types, mean DLQI score Significant reductions seen as early as week 12 (3 cycles) W Koltun et al. Contraception 2008; 77: 249. Palli MB et al. J Drugs Dermatol 2013; 12: 633. Meta-Analysis: Combined OCPs for Acne 24 randomized trials 9 compared combined OCP vs placebo 17 compared different OCPs 1 compared combined OCP (EE/CYP) vs oral antibiotic (MCN) Meta-Analysis: Combined OCPs vs Oral Antibiotics 32 RCT met criteria (of 226 total pubs) At least 6 months of data Acne lesions counts, excluded PCOS, etc. Combined OCPs outperformed placebo No consistent differences in acne reduction between different combined OCPs Arowojolu AO et al. The Cochrane Database of Systematic Reviews 2012; CD Koo EB et al. J Am Acad Dermatol 2014; 71:

4 Meta-Analysis: Combined OCPs vs Oral Antibiotics Koo EB et al. J Am Acad Dermatol 2014; 71: 450. Major surgery with prolonged immobilization Biliary tract disease Migraine w/ focal neurologic sx, w/o aura if 35yr History of cholestasis related to OCP use OCPs and VTE: What We Know Higher estrogen doses increase risk 2-fold increase: 50mcg vs 30mcg 1 VTE incidence is higher in OCPs users 40-49yo vs younger users VTE risk is higher in first 6-12 months of use Normalizes by 3 rd month after discontinuation Tobacco use increases risk 1 Bloemenkamp KWM et al. Arch Intern Med 2000; 160:49. Gomes MPV and Deitcher SR. Arch Intern Med 2004; 164: Combined OCP Progestins: Meta-Analysis 26 studies reviewed All combined OCP use increases risk of VTE vs non-use RR 3.5 (95% CI ) Dose of ethinyl estradiol, individual progestin 30-35µg EES + desogestrel, drospirenone, gestodene, or CYPA had RR 50-80% higher than OCP containing levonorgestrel de Bastos M et al. The Cochrane Database of Systematic Reviews 2014; CD VTE Risk in Women: Annual Incidence of VTE years 1-5/10,000 Combined OCP use 3-9/10,000 DSP, desogestrel, CYP use 10-15/10, /10,000 Postpartum ( 12 wks) 40-65/10,000 The American College of Obstetricians and Gynecologists Committee opinion US Food and Drug Administration website. Combined OCP and VTE American Society for Reproductive Medicine There is fair evidence that preparations of COCs with drospirenone or third-generation progestins have only a slightly higher risk of VTE compared with those containing norethindrone or levonorgestrel. (Grade B) In the patient in whom combined hormonal contraception is appropriate, it is reasonable to use any currently available preparation. Practice Committee of the American Society of Reproductive Medicine. Fertil Steril 2017; 107: 43. 4

5 Combined OCPs: Noncontraceptive Health Benefits Spironolactone Aldosterone antagonist diuresis Competitive inhibition at the androgen receptor High doses androgen synthesis via P450 inhibition Inhibits 5α-reductase hepatic SHBG synthesis Not approved by FDA for dermatologic indications Maguire K Westhoff C. Am J Obstet Gynecol 2011; 205: S4. Spironolactone for Acne: Level of Evidence Cochrane review for acne and/or hirsutism Only 1 study addressed acne as outcome No evidence for effectiveness for the treatment of acne vulgaris Hybrid systematic review of 10 RCT, 21 case series All at high risk of bias, quality of evidence was low/very low Crossover trial demonstrated superiority of spironolactone 200mg/day vs placebo for inflammatory acne Limited quality evidence to support use at 100mg/day Spironolactone: Level of Evidence "Despite the lack of published data, relying on available evidence, experience, and expert opinion, the work group supports the use of spironolactone in the management of acne in select women. Brown J et al. Cochrane Database Syst Rev 2009: CD Layton AM et al. Am J Clin Dermatol 2017; 18:169. Zaenglein AL, Pathy AL, Schlosser BJ et al. J Am Acad Dermatol 2016; 74:945. When to Consider Spironolactone Specifically Patients on combined OCP but inadequate control of acne Patients with contraindications to combined OCP Patients with hypercoagulability states Patients with LAR hormonal contraceptive devices and acne Patients on progestin-only oral contraceptive pill, nursing Patients unable to take/access/afford other acne medications Cost of Medications Spironolactone 50mg $0.58 per pill ($0.32) Spironolactone 25mg $0.30 per pill Doxycycline monohydrate 100mg $1.04 per pill ($0.74) Doxycycline hyclate 100mg $1.67 per pill ($0.84) Minocycline 100mg $2.87 per pill ($2.81) Isotretinoin 40mg $9.47 per pill ($5.23) Data obtained from Pharmacychecker.com for zipcode on July 28,

6 Spironolactone: Contraindications Renal insufficiency Hyperkalemia ACEIs, ARBs, KCl, NSAIDs Category C Feminization of male fetus Abnormal uterine bleeding (evaluate first) **Banned substance for NCAA, Olympics, etc. Sato K et al. Aesth Plast Surg 2006; 30: 689. Spironolactone for Acne 116 Asian females 64 completed 20wks 53% excellent response 47% good response Spironolactone for Acne: Combination Therapy 85 adult women 79% failed oral antibiotic 14% failed isotretinoin mg/day Mean duration = 10 months Spironolactone: Predicting Who Will Benefit Retrospective analysis of 70 adult F with facial acne Spironolactone dose 150mg/day Mean age: 31.3yr Prior acne treatment: 56% isotretinoin, 76% OCP Remission: non-inflammatory, 2 inflammatory lesions JC Shaw. J Am Acad Dermatol 2000; 43: 498. Isvy-Joubert A et al. Eur J Dermatol 2017; 27:393. Spironolactone: Predicting Who Will Benefit Positive predictors Negative predictor: 1 st /2 nd generation OCP: OR 2.77 [ ], p = Spironolactone: Adverse Effects Adverse Effect Frequency Diuretic effect 29% Menstrual irregularities (any) 22% Spotting 12% Change in flow ( / ) 6% /4% Breast tenderness 17% Breast enlargement 4% Fatigue 15% Headache 13% Dizziness 12% Lightheadedness 11% Isvy-Joubert A et al. Eur J Dermatol 2017; 27:393. JC Shaw and LE White. J Cutan Surg and Med 2002; 6:

7 Serum K: To Monitor or Not? Retrospective study, healthy women, 18-45yr Mean age = 27.5yr and 26.2yr Baseline [K] = 0.76% +Spironolactone [K] = 0.72% (13/1802) Dose, duration of spironolactone Plovanich M et al. JAMA Dermatol 2015; 151: 941. Monitoring Guidelines Renal function, electrolytes Older patients (>40-45yo?) History of renal or cardiac disease Concomitants medications which may influence renal function or serum [K] Higher doses of spironolactone (200mg/day) ROS: thirst, weakness, lethargy, muscle cramps, dizziness, HR, urination Contraception, pregnancy testing Spironolactone: Black Box Warning WARNING Aldactone has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). Aldactone should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided. 25 to 150 times usual human dose (by weight) Breast adenomas Hepatocellular adenomas Benign adenomas of testes Benign uterine endometrial stromal polyps Thyroid follicular cell adenomas, carcinomas Spironolactone: Breast Cancer 506 person-years (70.6mos) 7 abnormal mammograms no breast carcinoma person-years (3yrs follow-up) no cases of breast carcinoma women x 3-7yrs 9 cases reported, age-specific rate of 8.3 cases 3 5 case control studies no evidence for causality 4 1 Shaw JC, White LE. J Cutan Surg and Med 2002; 6: Danielson DA et al. Am J Epidemiol 1982; 116: Friedman GD, Ury HK. J Natl Cancer Inst 1980; 65: Barker DJP. J Drug Dev 1987; 1: 22. Spironolactone and Malignancies in Women Retrospective cohort study of Danish national prescription drug registry 2.3 million women, 20yo, million womanyears Biggar RJ A et al. Cancer Epidem 2013; 37:

8 Spironolactone: In My Clinical Practice Starting dose: 50mg to 100mg Drospirenone 3mg = 25mg spironolactone Once daily dosing until 100mg po BID BID dosing may minimize adverse effects Better bioavailability if taken with food Assess initial impact in 2 to 3 months Dose increase by 25mg or 50mg depending on response Once well-controlled for 6 months, consider taper Treating Acne with Hormonal Therapy Take a thorough history, select patients appropriately No significant differences between different formulations of combined OCPs for acne treatment Spironolactone has distinct differences compared to OCPs. Utility extends beyond females with hormonal acne or those with hyperandrogenemism Dermatology Foundation SHAPING THE FUTURE OF DERMATOLOGY 8