hormonal therapies in dermatology s001 - … · bayer dermatology*+# biopharmx ......

James Q. Del Rosso, DO

Adjunct Clinical Professor (Dermatology)

Touro University Nevada

Henderson, Nevada

Lakes Dermatology

Del Rosso Dermatology Research Center

Las Vegas, Nevada

HORMONAL

THERAPIES

IN

DERMATOLOGY

Disclosures

Aclaris*#

Allergan*+#

Anacor*+

Aqua/Almirall*+

Bayer Dermatology*+#

BioPharmX*#

Celgene*+

Cutanea#

Dermira*

Ferndale*+

Foamix#

Galderma*+#

Genentech+#

LeoPharma*+#

Novartis*+

Novan*#

Valeant*+#

Pharmaderm*+

Promius*+

Sebacia*#

SunPharma*+#

Unilever*+

Consultant*/ Speaker+ / Researcher#

(Updated as of 6-10-16)

Objectives of the Presentation

Provide an overview of the role of hormonal therapies in the management of common dermatologic disorders

Review specific therapies used to treat common disorders such as acne vulgaris and alopecia in men and women FINASTERIDE / DUTASTERIDE

ORAL CONTRACEPTIVES

SPIRONOLACTONE

Outline the use of each agent regarding dosing, monitoring of clinical response and potential adverse effects, and adjustments in therapy based on individual response

Acknowledgements

Jason M. Hirshburg MD, PhD, Petra A. Kelsey BS, Chelsea A. Therrien BS, A. Carlo Gavino MD1, Jason S. Reichenberg MD. Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review. J Clin Aesthet Dermatol. 2016.

Harper JC. The Use of Oral Contraceptives for Management of Acne Vulgaris. Dermatol Clin. 2016;34:159-165

Kim GK, Del Rosso JQ. Oral spironolactone in post-teenage female patients with acne vulgaris: practical considerations for the clinician based on current data and clinical experience. J Clin Aesthet Dermatol. 2012;5(31):37-50

Oral 5-alpha Reductase Inhibitors (5ARIs) Management of Androgenetic Alopecia (AgA)

Androgenetic alopecia (AgA)1,2

Affects >75% of males and ~50% of females by end of the 7th decade

Pattern differences based on gender

Finasteride / Dutasteride 2-4

Oral 5-alpha reductase inhibitors (5ARIs) Reduce testosterone formation

Finasteride inhibits Type 2 5AR receptors

Dutasteride inhibits Type 1 and Type 2 5AR receptors (greater potency)

Finasteride FDA-approved for treatment of AgA in men

Use of 5AR inhibitors increasing in women in selected cases

Used to prevent progession of hair loss and promote hair regrowth

1 Sperling LC et al, Alopecias. In: Bolognia J, Jorizzo J, Rapini R, editors. Dermatology. 3rd ed. Vol. 1. Philadelphia: Elsevier; 2013.p.1093-114.

2 Harcha WG, Martinez JB, Tsai T, Katsuoka K, Kawashima M, Tsuboi R, et al. A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of

dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia. J Am Acad Dermatol. 2014;70(3):489-498.

3 Aggarwal S, et al. An overview on 5α-reductase inhibitiors. Steroids. 2010;75:109-153.

4 Clark RV, et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab.

2004;89:2179-2184.

Oral 5-alpha Reductase Inhibitors Emerging Concerns About Adverse Events: Fact or Fiction

Does Use of Finasteride Increase Risk of Prostate Cancer?1-3

Finasteride and dutasteride used to treat benigh prostatic hypertrophy Assocation of androgen dependency and prostate cancer ?? AAD Task force to address concern with position statement

Prostate Cancer Prevention Trial (PCPT)2,4

2003: 18,800 subjects ~ Finasteride vs Placebo – followed x 7 years 25% relative risk increase of Prostate Cancer in Placebo arm

27% greater risk of high grade prostate cancer in Finasteride arm

2013: Initial PCPT group at 18 years follow-up Prostate Cancer in 10.5% in Finasteride arm vs 14.9% in Placebo arm

High Grade Prostate Cancer in 3.5% Finasteride arm vs 3.0% in Placebo arm

1 Traish AM, et al. Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know? Rev Endocr Metab Disord. 2015;16:177-198.

2 Thompson IM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215-224.

3 Feldman BJ, et al. The development of androgen-independent prostate cancer. Nature Rev Cancer. 2001;1:34-45.

4 Thompson IM, et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med. 2013;603-610.

Oral 5-alpha Reductase Inhibitors (5ARIs) Emerging Concerns About Adverse Events: Fact or Fiction

Does Use of Oral 5ARIs Increase Risk of Prostate Cancer?1,2

Controversial Topic ~ Some Opposing Data Findings in Literature Reports showing no statistical difference in prostate cancer grade with use

of finasteride

Dustasteride vs Placebo trail (N=6729 males); potential suggestion of risk ?

Theories On Potential Increase in Higher Prostate Cancer Grade3-7

Direct Induction Theory

Detection Bias Theory

Summary (1) No increased incidence (2) Possible increased risk of higher grade (3) No negative impact on overall survival rate

1 Preston MA, et al. 5α-reductase inhibitors and risk of high-grade or lethal prostate cancer. JAMA Int Med. 2014;174:1301-1307.

2 Lacy JM et al. A tale of two trials: the impact of 5α-reductase inhibition on prostate cancer (review). Oncology letters. 2014;8:1391-1396.

3 Andriole GL, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362:1192-1202.

4 Kosaka T, et al. Potent increased risk of the initiation of DNA replication in human prostate cancer with the use of 5α-reductase inhibitors. Am J Clin Exp Urol. 2014;12:136-144.

5 Hirano D, et al. Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy. Eur Urol. 2004;45:586-592.

6 Ehdaie B, Touijer KA. 5-alpha reductase inhibitiors in prostate cancer: from clinical trials to clinical practice. Eur Urol. 2013; 63:788-791.

7 Lucia MS, et al. Finasteride and high-grade prostate cancer in the prostate cancer prevention trial. J Natl Cancer Inst. 2007; 99(18):1375-1383.


Does Finasteride Cause Depression/Psychiatric Side Effects?1-3

Depression not initially listed in approved product labeling with Finasteride for AgA (1 mg daily) or for BPH (5 mg daily) Anecdotal and published reports of depression subsequently added to product

labeling for AgA product (1 mg daily)

Collection of studies correlating depressive symptoms with use of finasteride in some patients Potential increase in depressive symptoms in past users of finasteride – possible

association with concurrent sexual dysfunction

Summary No definitive direct link with depression / Depressive symptoms may occur in some treated with 5ARIs / More data on reversibility of mood-related changes are needed

1 Altomare G, et al. Depression circumstantially related to the administration of finasteride for androgenetic alopecia. J Dermatol. 2002;29:665–669.

2 Rahimi-Ardabili B, et al. Finasteride induced depression: a prospective study. BMC Clinical Pharmacology. 2006;7(6):7.

3 Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012;73(9):1220-1223.


Does Use of Oral Finasteride Cause Sexual Side Effects (SSEs)? Reported to occur in 0.9% - 38% ~ most common adverse effects1-4

ERECTILE DYSFUNCTION: Finasteride – 3.4% - 15.8% vs Placebo 1.7% - 6.3%

EJACULATORY DISTURBANCE: Finasteride – 0.9% - 5.7% vs Placebo 0.5% - 1.7%

LOSS OF LIBIDO: Finasteride – 2.36% - 10.0% vs Placebo 1.2% - 6.3%

Incidence of SSEs inceased vs placebo and not dose-dependent (1 mg = 5 mg)

Rates similar with dutasteride

Spontaneous Improvement/Resolution vs Persistence5-6

PLESS* reported 22% initial rate Improved over 2-4 months Baseline

Averages: Start after 1.8 years + Last 5.4 months after stopping use

*Proscar Long Term Efficacy and Safety Study

1 Traish AM, et al. Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know? Rev Endocr Metab Disord. 2015;16:177-198.

2 Jason M. Hirshburg MD, et al. Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review. JCAD. 2016.

3 Gormley GJ, et al. The effect of finasteride in men with benign prostatic hyperplasia. The finasteride study group. N Engl J Med. 1992;327:1185-1191.

4 Roehrborn CG, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434-441.

5 Stoner E. Three-year safety and efficacy data on the use of finasteride in the treatment of benign prostatic hyperplasia. Urology. 1994;43:284-292.

6 Ali AK, et al. Persistent sexual dysfunction and suicidal ideation in young men treated with low-dose finasteride: A pharmacovigilance study. Pharmacotherapy. 2015;35:687-695.

Oral 5-alpha Reductase Inhibitors Use in Androgenetic Alopecia (AgA) in Women

Major concern is exposure of male fetus in pregnant women1-5

Abnormal development of male genitalia

Contraindicated in pregnancy ~ consider exclusion pre-treatment

Limited data on side effects ~ small studies and case reports Decreased libido, breast tenderness, menstrual changes, and cephalgia reported

Some case reports and small series show lack of side effects

Long term data very limited

137 women (age range 41-60 yrs) ~ Side Effects Finasteride 1 mg = Placebo

1 McClellan KJ, et al. Finasteride a review of its use in male pattern hair loss. Drugs. 1999;57:111-126.

2 Stout SM et al. Finasteride treatment of hair loss in women. The annals of pharmacotherapy. 2010;44:1097.

3 Falsetti L, et al. Treatment of hirsutism by finasteride and flutamide in women with polycystic ovary syndrome. Gynecol Endocrinol. 1997;11:251-157.

4 Lumachi F et al. Use of cyproterone acetate, finasteride, and spironolactone to treat idiopathic hirsutism. Fertility and Sterility. 2003;79:942-946.

5 Jason M. Hirshburg MD, et al. Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review. JCAD. 2016.

Combination Oral Contraceptives (COCs) General Overview

Combination of ethinyl estradiol (EE) and a progestin1,2

EE dose range: 10 ug – 50 ug ~ variation is estrogenic potency Marked variability among progestins used in different COCs

First and second generation progestins ~ derived from testosterone May interact with progesterone, estrogen, and androgen receptors

NORETHINDRONE, NORETHINDRONE ACETATE, LEVONORGESTREL

Third generation progestins ~ derived from testosterone Modified to induce LESS androgenic activity

NORGESTIMATE, DESOGESTREL, GESTODENE

Fourth generation progestins Bind only to progesterone receptor NO angrogenic effects

DROSPERINONE ~ derivative of 17-alpha spironolactone

1 Harper JC. The Use of Oral Contraceptives for Management of Acne Vulgaris. Dermatol Clin. 2016;34:159-165

2 Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. 2012;(7):CD004425.

• NET INCREASE IN SEX HORMONE BINDING GLOBULIN (SHBG)

• NET DECREASE IN FREE TESTOSTERONE

Combination Oral Contraceptives (COCs)Use for Treatment of Acne Vulgaris (AV)1-4

Modes of action for Acne Vulgaris (AV) Suppress ovarian production of androgens and ovulation

EE increases hepatic synthesis of SHBG decreases free testosterone

Inhibition of 5-AR by some progestins

Efficacy for treatment of AV Most COCs not FDA-approved for AV

Can be used with or without hyperandrogenism (clinical and/or lab)

Multiple studies showing efficacy for facial AV ~ allow 3 cycles for onset

Data showing efficacy for moderate truncal AV ~ 24 week study

Comparative data limited among COCs for AV


2 Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. 2012;(7):CD004425.

3 Sitruk-Ware R, et al. Phrmacology of different progestogens: the special case of drosperinone. Climacteric. 2005;8(Suppl 3):4-12.

4 Palli MB, et al. A single center, randomized, double-blind, parallel-group study to examine thec safety and efficacy of 3 mg dosperinone /0.02 mg ethinyl estradiol compared with

placebo in the treatment of moderate truncal acne vulgaris. J Drugs Dermatol. 2013;12(6):633-637.

Combination Oral Contraceptives (COCs)Use for Treatment of Acne Vulgaris (AV)1-5

“Bonus” Noncontraceptive Benefits of COCs Normalize menstrual cycle, reduce anemia

Reduce risks of endometrial, ovarian, and colorectal cancer

Decrease symptoms of premenstrual dysmorphic disorder

When to use COCs for treatment of AV Consideration in women with AV and no contraindications to COCs

Important to review potential risks and contraindications

Useful especially in women who also desire contraception


2 The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med. 1987;316:650-655.

3 Burkman R, et al. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol. 2004;190:S5-S22.

4 Lopez LM, et al. Oral contraceptives containing drosperinone for premenstrual syndrome. Cochrane Database Syst Rev. 2012;(2):CD006586.

5 Frangos JE, et al. Acne and oral contraceptives: update on women’s health screening guidelines. J Am Acad Dermatol. 2008;58:781-786.

Combination Oral Contraceptives (COCs)Potential Risks and Contraindications1-5


2 Frangos JE, et al. Acne and oral contraceptives: update on women’s health screening guidelines. J Am Acad Dermatol. 2008;58:781-786.

CARDIOVASCULAR RISKS Increased risk of Venous Thromboembolism (VTE) Affected by dose of EE and progestin use Risk may be increased with drosperinone Overall 3-9 vs 1-5 events/10,000 woman years in COC

users vs non-users/not pregnant Increased risk >age 35; phlebitis history; postpartum,

immobilization, some GI diseases, others

CANCER RISKS Possible slight increase in breast cancer but not if at

10+ years after stopping COC use Cervical cancer increase correlated with duration of COC

use - 2-fold higher after 5 years of use + no increased risk if at 10+ years after stopping COC use

BONE RISKS Risk of inadequate bone mass if EE <30ug especially if

started within 3 years of menarche + used >2 years

??? Spironolactone ???Approach to Monitoring of Serum Potassium Levels

• Plovanich M, Weng QY. Mostaghimi A. Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne. JAMA Dermatol. 2015;151(9):941-944.

• 974 healthy adult women with acne

• 1165 young healthy women on or off spironolactone

• 13 ABNORMAL K+ VALUES / 1802 MEASUREMENTS

• 6/13 normalized with repeat testing

• The rate of hyperkalemia in healthy young women taking spironolactone (0.72%) for acne is equivalent to the baseline rate of hyperkalemia in this population (0.76%).

• Routine potassium monitoring is unecessary for healthy women taking spironolactone for acne.


• Plovanich M, Weng QY. Mostaghimi A. Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne. JAMA Dermatol. 2015;151(9):941-944.

• 974 healthy adult women with acne

• 1165 young healthy women on or off spironolactone

• 13 ABNORMAL K+ VALUES / 1802 MEASUREMENTS

• 6/13 normalized with repeat testing

• The rate of hyperkalemia in healthy young women taking spironolactone (0.72%) for acne is equivalent to the baseline rate of hyperkalemia in this population (0.76%).

• Routine potassium monitoring MAY BE unnecessary for healthy women taking spironolactone for acne.


POPULATION-BASED

DATA


NOT LIKELY

TO MATTER

TO THIRD PARTY

PAYOR

VERY LIKELY TO

MATTER TO THE

DOCTOR

AND PATIENT

hormonal therapies in dermatology s001 - … · bayer dermatology*+# biopharmx ......

Documents