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, Idiopathic: Approach to Management & Treatment Chart www.RxFiles.ca Mar 2012

IDIOPATHIC HIRSUTISM *Drug‐related hirsuitism – possible causes: aripiprazole, bupropion, carbamazepine, clonazepam, corticosteroids, cyclosporine, dantrolene, , eszopiclone, fluoxetine, interferon alfa, , lamotrigine, leuprolide, olanzapine, paroxetine, pregabalin, progestins, selegilene, Consider any drug‐related causes , testosterones, trazodone, venlafaxine, zonisamide Initiate lifestyle modifications (weight loss) Consider cosmetic procedure options* *Cosmetic Procedures are a cornerstone of care. Examples include medical laser surgery, shaving, plucking, bleaching, waxing, chemical treatment, Seeking fertility Not seeking fertility electrolysis and intense pulsed light.

Delay drug Moderate to severe Mild hirsutism treatment until hirsutism delivery

1. Topical eflornithine (8 week trial) OCP containing: Contraindication

(monotherapy or as an • Cyproterone to OCP adjunct to any • Drospirenone technique) • Neutral progestin 2. OCP containing: (desogestral, norgestimate) (with secure • Cyproterone PLUS antiandrogen contraception): • Drospirenone • • Spironolactone • Neutral progestin • or cyproterone • Finasteride (desogestrel, norgestimate) •

• seldom used due to hepatotoxicity Unsatisfactory result (@6‐12months)

Metformin, while beneficial in PCOS, is not effective for idiopathic hirsutism • Add oral agent to topical eflornithine (for facial hair only) 1. Escobar-Morreale HF, Carmina E, Dewailly D, Gambineri A, Kelestimur F, Moghetti P, et al. Epidemiology, diagnosis and management of • Add spironolactone, finasteride or hirsutism: a consensus statement by the Excess and Polycystic Ovary Syndrome Society. Human Reproductive Update 2011; 0:1-25. 2. Ferriman-Gallwey Evaluation of Hirsutism. Available at: http://www.hirsutism.com/hirsutism-biology/ferriman-gallwey-score.shtml (accessed: cyproterone to OCP December 6, 2011). OCP=oral contraceptive pill 3. Harrison S, Somani N, Bergfeld W. Update on the management of hirsutism. Cleveland Clinic J Med 2010;77(6): 338-98. 4. Bode D, Seehusen DA, Baird D. Hirsutism in women. Am Fam Physician. 2012 Feb 15;85(4):373-80. PCOS=polycystic ovary syndrome 5. www.RxFiles.ca ; 5) www.hirsutism.com;

1,2,3,4,5,6,7,8 HIRSUTISM, IDIOPATHIC: Tx Jill Hall BScPharm, PharmD Candidate, Margaret Jin Pharm D www.RxFiles.ca Mar 2012 Class / Ingredient Mechanism of Action Place in therapy Efficacy Contra‐ Major Adverse Effects Dose / Cost indication (30 days) Eflornithine 13.9% • Irreversible inhibitor of As monotherapy, for mild cases of • Improvement noted at 8+ weeks; , BF Rash, burning/tingling, Topical, twice daily cream decarboxylase facial hirsutism or as adjunct with effect reverses 8 wks after eythema (≥ 8 hrs apart) VANIQA (critical to cell growth & other therapies (complements discontinuation9,10,11 Potential systemic toxicity $70 (30g tube) anti‐androgen/laser/IPL which with widespread application Upper lip:

differentiation within hair • TOPICAL As monotherapy, successful follicle) work on terminal hairs) treatment ~30% (slows rate of hair may last 3‐5 mo CCI st • Slows rate of growth of Considered 1 line in post‐ growth)11 Lower face: terminal and vellus hairs menopausal women • Improves time to effect with laser may last 4‐6 wks therapy (up to 95% successful treatment)9 EE + drospirenone • Suppress ovarian Generalized hirsutism, for • Improvement noted at 3 months; Breast cancer Irregular vaginal bleeding 1 tablet daily YASMIN, YAZ androgen synthesis women not seeking fertility. maximum effect at 9‐12 months Smoking Risk of VTE, though rare, ↑ (brand specific) EE + desogestrel (suppress LH secretion) All OCPs may help due to (especially if age with age & possibly choice $17‐23 MARVELON, • Yasmin: ↓FGS 65‐70% at 6 months, 13 14 ORTHO‐CEPT, LINESSA • ↑SHBG, thus estrogen’s effect on SHBG 80% at 12 months , > 35 yr) of OCP 12 EE + norgestimate ↓free testosterone See RxFiles chart for other low • Marvelon: ↓FGS 40% at 6 months, Cardiovascular o Baseline: ~ 5/10,000 Option: Extended TRI‐CYCLEN, CYCLEN, androgen OCP options 35% at 12 months15 disease o OCP: ~8‐9/10,000 dosing regimens TRI‐CYLEN LO, st Considered 1 line option • Tri‐Cyclen: no specific evidence Uncontrolled HTN (up to 14/10,000) (bi‐ or tri‐ cycling of

OCPs o Possible ↑ risk with YASMIN, active OCPs) YAZ16 EE + cyproterone • See above Mild hirsutism, severe acne • Diane‐35: ↓FGS 55% at 6 months, Liver tumours Irregular vaginal bleeding $29 DIANE‐35, CYESTRA‐35 14 also see above In general, anti‐: 80% at 12 months VTE (EE 35 mcg + *not approved for 2 may be ↑ compared to CPA 2 mg) contraception in • ↓FGS 20‐40% at 6 months, maximal effect at 9‐12 months o some other OCP16 Canada; approved • superior to placebo, metformin18,23 in other countries. o Also see below (CPA) • 17 Spironolactone • may cause male pseudohermaphroditism in fetus • Superior to metformin, flutamide Lack of Irregular menstrual bleeding Initial: 25mg po BID ALDACTONE • Competitive inhibitor of Moderate‐severe hirsutism • Combination of spironolactone + contraception unless OCP co‐administered, x1wk st androgen receptor & 5α‐ Considered 1 line anti‐androgen OCP superior to OCP alone, Pregnancy, BF breast tenderness, ↓libido, 50‐100mg po BID reductase activity flutamide18,19 Liver or renal hypotension, hyperkalemia • ↑SHBG levels failure (? check K+ in 3‐7d); {risk of pseudo- $17‐25 (100mg tab) hermaphroditism in k fetus if used in pregnancy} • ↓testosterone synthesis $54‐100 (25mg tab) Cyproterone • Competitive inhibitor of Moderate‐severe hirsutism • No difference in efficacy between 2 Lack of Hepatitis/liver failure 25‐100mg daily nd acetate androgen receptor & 5α‐ Considered 2 line anti‐androgen mg and 100 mg doses20 contraception Fluid retention/edema HTN (Day 1‐10 or 5‐15 ANDROCUR reductase activity • Subjectively improves hirsutism and Pregnancy, BF Irregular menstrual bleeding of cycle) • Suppresses LH secretion provides a ‘good clinical response’ in unless OCP through progestational 60‐80% of patients20 co‐administered $9‐33 (50mg tab) • Decreased libido

androgens activity Similar efficacy to spironolactone, ‐ finasteride, GnRH analogs; less 20 Anti effective than flutamide Finasteride • Inhibits type II 5α‐ Moderate‐severe hirsutism • No difference in efficacy between 2.5 Lack of 5mg po daily PROSCAR reductase which Considered 2nd line anti‐androgen mg and 5 mg1 contraception $35 (5mg tab) (Propecia) metabolizes testosterone • Combination of finasteride + OCP Pregnancy, BF to DHT (in follicle) superior to OCP alone18 Flutamide • Non‐steroidal competitive Severe hirsutism • No difference in efficacy between Lack of Hepatotoxicity 250mg po daily EUFLEX inhibitor of androgen Considered 3rd line anti‐androgen 125 mg and 375 mg 22 contraception Breast tenderness, receptor binding (due to risk for hepatotoxicity21) Pregnancy, BF menstrual irregularities $52 (250mg tab) Liver disease Class / Ingredient Mechanism of Action Place in therapy Efficacy Contra‐ Major Adverse Effects Dose / Cost indication (30 days) Prednisone • Suppresses adrenal Classic & Nonclassic congenital • Less effective compared to OCPs or Uncontrolled Changes typical of Cushing 5‐7.5mg po daily (Glucocorticoid) function adrenal hyperplasia (NCCAH) anti‐androgens1 diabetes, syndrome (wt gain, bone Obesity loss), adrenal atrophy $8 (5mg tab) • Adrenal For patients with Cushing’s • Similar efficacy to CPA 2‐50mg20 Hepatic Gynecomastia, dry skin, 200mg po daily NIZORAL syndrome while waiting definite dysfunction hepatotoxicity, $69 (200mg tab)

therapy Pregnancy, BF adrenocortical suppression Leuprolide • Potent inhibitor of ovarian Severe hyperandrogenism of • Similar efficacy to CPA 2‐50mg, but Pregnancy, BF Osteoporosis 3.75‐7.5mg acetate depot steroidogenesis by ovarian origin that does not more adverse effects20 Osteoporosis Reversable induced monthly IM, with Agents (GnRH analog) suppressing LH & FSH respond to other drugs menopause 25‐50ug LUPRON DEPOT transdermal Other $445$415 + $24‐30 Metformin • improves insulin Used in polycystic ovary • Small benefit compared to placebo23 Renal failure Gastrointestinal upset 500‐2000mg/day (given 250‐1000mg BID) GLUCOPHAGE sensitivity syndrome (PCOS). • Inferior to OC or anti‐androgen (minimize by starting low 23 Not effective for idiopathic therapy for idiopathic hirsutism dose 250mg daily, then titrate) $21‐33 (500mg hirsutism tab) BF=breast feeding CCI=cell cycle inhibitor CPA=cyproterone acetate DHT=dihydrotestosterone EE=ethinyl estradiol FGS=Ferriman‐Gallwey Score FSH= follicle stimulating hormone GH=growth hormone GnRH=gonadotropin releasing hormone HTN=hypertension LH= luteinizing hormone OCP=oral contraceptive pill SHBG=sex hormone binding globulin VTE=venous thromboembolism

Thanks to everyone who helped with the development and review of this chart. Dr. D. Jubin and Dr. K. Insley (FM, Bella Sante MD and Laser Clinic, Saskatoon), Dr. D. Lichtenwald (Dermatol., Saskatoon), Dr. T. Arnason (U of S. Endocrin.), Dr. M. Markovski (FM, U of S. Regina), Dr. T. Laubscher (FM, U of S. Saskatoon). J Hall, M Jin, L Regier. DISCLAIMER: The content of this newsletter represents the research, experience and opinions of the authors and not those of the Board or Administration of Saskatoon Health Region (SHR). Neither the authors nor Saskatoon Health Region nor any other party who has been involved in the preparation or publication of this work warrants or represents that the information contained herein is accurate or complete, and they are not responsible for any errors or omissions or for the result obtained from

the use of such information. Any use of the newsletter will imply acknowledgment of this disclaimer and release any responsibility of SHR, its employees, servants or agents. Readers are encouraged to confirm the information contained herein with other sources. Additional information and references online at www.RxFiles.ca Copyright 2012 – RxFiles, Saskatoon Health Region (SHR) www.RxFiles.ca

References for Hirsutism, Idiopathic ‐ Tables & Figures (RxFiles.ca) http://www.rxfiles.ca/rxfiles/uploads/documents/members/Hirsutism‐Treatment‐Figure‐Drug‐Chart.pdf

17 Brown J, Farquhar C, Lee O, Toomath R, Jepson RG. Spironolactone versus placebo or in combination with steroids for hirsutism and/or 1 Escobar-Morreale HF, Carmina E, Dewailly D, Gambineri A, Kelestimur F, et al. Epidemiology, diagnosis and management of acne. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD000194. DOI: 10.1002/14651858.CD000194.pub2. hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Human Reproduction 18 Swiglo BA, Cosma M, Flynn DN, Kurtz DM, Labella ML, Mullan RJ, Erwin PJ, Montori VM. Clinical review: for the treatment Update Advanced Access published November 6, 2011 of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J Clin Endocrinol Metab 2008b;93:1153–1160. 2 Rosenfield, RL. Hirsutism. N Engl J Med 2005;353:2578-88 19 Karakurt F. Comparison of the Clinical Efficacy of Flutamide and Spironolactone plus Ethinyloestradiol/Cyproterone Acetate in the 3 e-CPS, Toronto, ON: Canadian Pharmacists Association. www-e-therapeutics-ca (accessed 2011 November) Treatment of Hirsutism: a Randomised Controlled Study. Adv Ther. 2008;25(4):321–328. 4 DRUGDEX System. Greenwood Village, CO: Thomson Micromedex. www.thomsonhc.com (accessed 2011 November) 20 van der Spuy ZM, Le Roux PA, Matjila MJ. Cyproterone acetate for hirsutism. Cochrane Database of Systematic Reviews 2003, Issue 4. 5 Kumar R, St John J, Devendra D. 10-MinuteConsultation: Hirsutism. BMJ 2009;339:b3090 doi: 10.1136/bmj.b3090 Art. No.: CD001125. DOI: 10.1002/14651858.CD001125. 6 Sathyapalan T, Atkin SL.. Rational Testing: Investigating hirsutism. BMJ 2009;338:912 doi:10.1136/bmj.b912 21 Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J et al. Acute and fulminant hepatitis induced by flutamide: Case series 7 Koulouri O, Conway GS. Clinical Review: Management of hirsutism. BMJ 2009;338:b847 doi:10.1136/bmj.b847 report and review of the literature. Ann Hepatology 2011;10(1):93-98. 8 Harrison S, Somani N, Bergfeld W. Update on the management of hirsutism. Cleveland Clinic J Med 2010;77(6): 338-98. 22 Calaf J, Lopez E, Millet A, Alcaniz J, Fortuny A, Vidal O, Callejo J, Escobar-Jimenez F, Torres E, Espinos JJ. Long-term efficacy and 9 Hamzavi I, Tan E, Shapiro J, Lui H. A randomized bilateral vehicle-controlled study of eflornithine cream combined with laser tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: a 12-month, double-blind, parallel . J treatment versus laser treatment alone for facial hirsutism in women. J Am Acad Dermatol 2007;57:54-9. Clin Endocrinol Metab 2007;92:3446–3452. 10 Smith SR, Piacquadio DJ, Beger B, Littler C. Eflornithine Cream Combined with Laser Therapy in the Management of Unwanted 23 Cosma M, Swiglo BA, Flynn DN, Kurtz DM, LaBella ML, Mullan RJ, et al. Insulin Sensitizers for the Treatment of Hirsutism: A Systematic Facial Hair Growth in Women: A Randomized Trial. Dermatol Surg 2006;32:1237–1243. Review and Metaanalyses of Randomized Controlled Trials. J Clin Endocrinol Metab 2008;93:1135–1142. 11 Wolf JE, Shander D, Huber F, Jackson J, Lin CS, Mathes BM et al. Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCl 13.9% cream in the treatment of women with facial hair. Int J Dermat 2007;46:94 –98. RxFiles provides objective, comparative, evidence informed drug information 12 Regier L, Downey S. Contraceptive, Combination Hormonal Products – Prescription. RxFiles drug comparison charts. 8th ed. Saskatoon, SK: RxFiles; 2011. Available from: http://www.rxfiles.ca/rxfiles/uploads/documents/members/CHT-OCs-Color.pdf for drug therapy decision making. One hallmark of the program is the (accessed 2011 December) academic detailing service or “office visit discussions” provided for 13 Batukan C, Muderris II. Efficacy of a new oral contraceptive containing drospirenone and ethinyl estradiol in the long-term treatment of hirsutism. Fertil Steril 2006;85:436–40. physicians/others in Saskatchewan, Canada. A second hallmark that has 14 Batukan C, Muderris II, Ozcelik B, Ozturk A. Comparison of two oral contraceptives containing either drospirenone or cyproterone evolved is the RxFiles Drug Therapy Charts book. For more information on acetate in the treatment of hirsutism. Gyne Endocrin 2007;23(1):38–44. 15 Breitkopf DM, Rosen MP, Young SL, Nagamani M. Efficacy of second versus third generation oral contraceptives in the treatment our academic detailing, book, app or online info & services, see our of hirsutism. Contraception 2003;67:349–353. website at www.RxFiles.ca. 16 Bunka D, Hall J. YAZ / YASMIN: Safety Considerations related to Venous Thromboembolism (VTE). RxFiles Q&A. Saskatoon, SK: RxFiles; 2011. Available from: http://www.rxfiles.ca/rxfiles/uploads/documents/Yaz-Yasmin-Q-A.pdf (accessed 2011 Book Orderform: http://www.rxfiles.ca/rxfiles/uploads/documents/1A‐CHT‐Book‐ORDERFORM.pdf Online store: http://www.rxfiles.ca/rxfiles/modules/products/products.aspx December) RxFiles is funded for academic detailing in SK by Saskatchewan Health. Production and updating of our drug comparison charts book is provided via additional revenue from the sale of books and online subscriptions. We are a not‐for‐profit information program. RxFiles does not receive any funding from the pharmaceutical industry.