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Charmaine Lisa Meade PharmD, CDE Rochester Associate Professor PharmD, CDE, BCPS, BCACP Wingate University Associate Professor School of Pharmacy University of Maryland School of Pharmacy

Disclosure to Participants Blue Pill, Pink Pill? How to Manage

Notice of Requirements For Successful Completion in Women with Please refer to learning goals and objectives Learners must attend the full activity and complete the evaluation in order to claim continuing education credit/hours Conflict of Interest (COI) and Financial Relationship Disclosures: Presenter: Charmaine Rochester, PharmD, CDE – No COI/Financial Relationship to disclose Presenter: Lisa Meade, PharmD, CDE – No COI/Financial Relationship to disclose Non-Endorsement of Products: Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial products displayed in conjunction with this educational activity Off-Label Use: Participants will be notified by speakers to any product used for a purpose other than for which it was approved by the Food and Drug Administration.

Viagra® 100 mg . Retrieved from www.super-potenzmittel.com Addyi® 100 mg. Retrieved from www.hngn.com

Objectives Female Sexual Dysfunction (FSD) is • At the conclusion of this presentation, participants Primarily: should be able to: • Describe the pathophysiology/etiology of female A. Psychological sexual dysfunction (FSD) in diabetes patients B.Physiological • Utilize interviewing techniques to assess FSD C.Multifactorial • Describe the clinical data on Citrate (Viagra®) vs. (Addyi®) for FSD D.Sociocultural • Evaluate a patient vignette to determine indications for pharmacotherapy

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Normal Female Sexual Response Model Normal Female Sexual Response Developed by Masters and Johnson Neuromuscular and vaso-congestive events • Increased clitoral size (diameter and length) • Vaginal lubrication and wall engorgement • Orgasm: the culmination of • Sensory & Autonomic Nervous System’s response to erotic stimuli • The relaxation & increase in blood supply • The regulation of blood supply and clitoral erectile function • Normal levels of hormones for physiologic sexual activity Diabetes Can Disrupt All Of These Systems

Phillips A, Phillips S. Applied Nursing Research. 2015; 28:235-8

DSM-IV - Definition of Female Sexual Disorder (FSD) Four Main Classification of FSD • Disturbances in sexual desire & the • Hypoactive sexual desire disorder psychophysiological changes in the sexual (HSDD); sexual aversion response cycle that causes marked distress and • Female arousal disorder (FAD) interpersonal difficulty • Female orgasmic disorder (FOD) The DSM emphasizes the emotional and • Sexual pain disorder (SPD)(dyspareunia; psychological factors involved in FSD vaginismus)

Mimoun S, Wylie K. Maturitas. 2009; 63:116-8

Etiology/Pathophysiology of FSD in Diabetes Etiology/Pathophysiology of FSD in Diabetes

• Atherosclerosis: Decreased arterial blood supply • Prolonged hyperglycemia: Reduced lubrication, dyspareunia, & the risk of genitourinary/fungal infections • Metabolic Syndrome: Leads to insulin resistance • Polycystic Ovarian Syndrome: Alterations of and • Menopause: Leads to lower estrogen & Androgen (insulin resistance syndromes) levels • Hormonal Imbalances: Thyroid & hypothalamic/pituitary • FSD: Strongly associated with T1DM and T2DM disorders • Vascular and neuropathic complications: • Neuropathy: Alter transduction of sexual stimuli and Decreased nerve stimulation and blood flow consequent sexual response

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Influences of FSD Diseases Associated with Increased Risk of FSD Biological Factors Psychological Factors Contextual (Social) Factors • Diabetes • Psychiatric disorder Medical (neurological, Sexual development Ethnic/religious norms urogenital diseases); pelvic • Cardiovascular • Genitourinary disorder radiation, surgery Disease • Urinary incontinence Psychiatric (depression) Personality Economical/household Hormonal changes and Sexual Experiences Contraception issues • HTN • Pelvic Pain menopausal status (abuse) • Chronic Rheumatic Pharmacological tx Sexual education, body Relationship with partner • Hysterectomy () image disease • Malignant Substance abuse Coping strategies Life stage stressors; family issues; partner’s health • Spinal Cord injury gynecological disease

Palacios S, Castano R, Grazziotin A. Maturitas. 2009;119-123

Some Drugs Associated With FSD Desire Disorder Arousal Disorder Orgasm Disorder Four Female Sexual Disorders (FSD) Antipsychotics + + Barbiturates + + + Benzodiazepines + + + Lithium + + + SSRI’s + + + TCA + + + + + Anti-lipids + Beta Blockers; + Spironolactone; Methyldopa Clonidine + +

Buster JE. Fertility and Sterility. 2013;100 (4):905-15 Buster JE. Fertility and Sterility. 2013;100 (4):905-15

Hypoactive Sexual Desire Disorder (HSDD) • Persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty HYPOACTIVE SEXUAL DESIRE DISORDER (HSDD)

Goldfischer ER, Breaux J, et al. J Sex Med. 2011;8:3160-72

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HSDD Prevalence in Premenopausal FSD and Diabetes Control in Women Women With Diabetes 1 in 10 Premenopausal Women Report Low Sexual Desire With FSD in DM Increased FSD Associated Distress Sexual Desire (36.8%) Risks Orgasm Satisfaction (25.5%) Age Orgasm (24.8%) HbA1c HSDD REMAINS UNDERDIAGNOSED & FSD in 46.7% of DM Complications Women with Low Literacy UNDERTREATED Diabetes – Illiterate > Educated Goldfischer ER, Breaux J, Katz M, et al. J Sex Med. 2011;8:3160-72 Ozcan S, Sahin NH, Bilgiv D, Yilmaz SD. Sex Disabil. 2011; 29:251-61

Why Are We Not Doing Something? Barriers to Recognition and Diagnosis • Women’s reluctance to discuss sexual problems with a physician • Physician’s lack of training and knowledge of sexual issues • Concerns over causing patients’ embarrassment

Goldfischer ER, Breaux J, Katz M, et al. J Sex Med. 2011; 8:3160-72

Treatment of HSDD: Manage the Major Goal of Successful Therapy Underlying Causes • Goal: Restoration of Sexual Desire • Situational, psychiatric and psychosocial dysfunction – Re-assurance, marital counseling, formal psychotherapy HSDD is the principal FSD in that, because they flow • Drugs outward from it, other FSD are frequently resolved – SSRIs – eliminate or reduce dose when the problems leading to HSDD are resolved • Chronic Disease – Treat HTN, DM, hypothyroidism, hypopituitarism, breast cancer

Buster JE. Fertility and Sterility. 2013;100 (4):905-15 Buster JE. Fertility and Sterility. 2013;100 (4):905-15

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Treatment of HSDD (Cont’d) Evaluation Tools for HSDD Tool Description Satisfying Sexual Encounter (SSE) – Diary to enter daily the # of sexual • Depletion of eDiary events experienced and their – Transdermal or intravaginal estrogens satisfaction The Female Sexual Function Index This is a 19-item measure of overall • Depletion of (FSFI) sexual function and includes six – Transdermal domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) The Female Sexual Distress Scale – Assesses the frequency of sexual Revised (FSDS-R) distress or bother during the past 7 days

Buster JE. Fertility and Sterility. 2013;100 (4):905-15

® The Blue Pill vs. The Pink Pill Blue Pill – Sildenafil (Viagra ) Evidence Therapy Population Effects Adverse ® /Dosage effects • Sildenafil Citrate (Viagra ) has been studied Blinded, Sildenafil Premenopausal Increased arousal, Vision for Female (FSAD) prospective, 25 or 50 women enjoyment, problems, HA crossover mg, with female sexual satisfaction, – Not FDA Approved in Women study 1 hr. arousal disorder frequency of before (FSAD) intercourse, and sex sexual fantasies ® Open-label Sildenafil Postmenopausal No significant clinical Clitoral • Flibanserin (Addyi ) has been studied for study - 33 50 mg, women self improvement in discomfort, women 1 hr. referred sexual function hypersens. Hypoactive Sexual Desire Disorder (HSDD) before for Sexual dizziness, sex Dysfunction (SD) HA, – FDA Approved in Women for HSDD dyspepsia

Viagra® 100 mg . Retrieved from www.super-potenzmittel.com Addyi® 100 mg. Retrieved from www.hngn.com http://www.aafp.org/afp/2008/0301/afp20080301p635-s1.pdf#page=2&zoom=90,-7,643

® Blue Pill – Sildenafil (Viagra ) Flibanserin in Premenopausal Women Evidence Therapy/ Population Effects Adverse Dosage effects Aim DB, RCT Sildenafil, Pre- and No improvement HA, hot flashes, • To assess the efficacy and safety of flibanserin x 24 weeks of 10-100 mg, postmenopausal rhinitis, nausea, treatment vs. in premenopausal women with HSDD 1 hr. before women (some vision Methods sexual On hormone problems, activity therapy) with FSAD dyspepsia • Women were treated with open-label, flexible-dose flibanserin (50 mg or 100 mg/day) for 24 weeks. Responders were DB, PC, Sildenafil, Premenopausal Increased sexual desire, HA, nausea, randomized to flibanserin 100 mg/day vs. placebo x 24 wks. crossover 100 mg, women frequency of orgasm, vision Main Outcome Measures study 1 hr. before with T1DM & FSAD enjoyment, satisfaction, problems • Primary Outcome: Change in Satisfying Sexual Encounter sexual and frequency of sexual (SSE) and desire score activity fantasies

http://www.aafp.org/afp/2008/0301/afp20080301p635-s1.pdf#page=2&zoom=90,-7,643http://www.aafp.org/afp/2008/0301/afp20080301p635-s1.pdf#page=2&zoom=90,-7,643 Goldfischer ER. Breaux J, Katz M, et al. J Sex Med. 2011;8:3160-72

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Flibanserin in Premenopausal Women SNOWDROP TRIAL – Flibanserin

Results Objective • Satisfying Sexual Encounter (SSE) Doubled • To assess the efficacy and safety of flibanserin in postmenopausal • Mean Desire Score doubled women with HSDD Methods • FSFI, FSDS-R total, and Item 13 scores improved • Naturally postmenopausal women with HSDD received flibanserin • At the end of the double-blind period, flibanserin was superior 100 mg once daily at bedtime (n = 468) or placebo (n = 481) for 24 to placebo in change from randomization in SSE, desire weeks score, FSFI desire domain and total scores, and FSDS-R total Co-primary endpoints and Item 13 scores (P < 0.05, for all). • Changes from baseline to week 24 in the number of satisfying • Flibanserin was well tolerated and withdrawal reactions were sexual events (SSEs) across 28 days and in the Female Sexual not observed. Function Index (FSFI) desire domain score.

Goldfischer ER. Breaux J, Katz M, et al. J Sex Med. 2011;8:3160-72 Simon JA, Kingsberg SA, Shumel B, et al. The Journal of North American Menopause Society 2014; 21(6):633-40

Efficacy Endpoints: Change from Change in the Number of SSE and FSFI-d from Baseline to Week 24 Baseline to 24 Weeks

Placebo Flibanserin P 100 value Key mg/day SSE = Satisfying Sexual SSE Count 0.6 (0.1) 1.0 0.004 Event FSFI-d = Female Sexual FSFI-d Score 0.4 (0.1) 0.7 (0.1) <0.001 Function Index Desire FSDS-R Item -0.6 (0.1) -0.8 (0.1) 0.008 FSDS-R = Female Sexual 13 Score Distress Scale FSFI = Female Sexual FSDS-R Total -6.3 (0.6) -8.3 (0.6) 0.006 Function Index Score FSFI Total Score 2.7 (0.4) 4.2 (0.4) 0.003

Change in the FSDS and FSFI Total score from ® Baseline to 24 Weeks Flibanserin (Addyi ) • Class: Serotonin 1A receptor agonist and a serotonin 2A receptor antagonist (mechanism unknown) • Indication: Treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Their low sexual desire is not due to: – a medical or mental health problem – problems in the relationship – medicine or other drug use • Not for the treatment of HSDD in menopausal women, men, children or to improve sexual performance

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Flibanserin (Addyi®) Dosage: 100 mg at bedtime to reduce adverse effects Clinical Pearl Adverse Effects: somnolence, insomnia, nausea, HA, dry mouth Availability: Risk Evaluation and Mitigation Strategy (REMS) Sexual Health Is An Important But Program from Certified Providers and Pharmacies Neglected Component Of Health Care In BOXED WARNING AND CONTRAINDICATION: Severe and syncope in patients who drink ETOH, Women With Diabetes use with moderate/severe CYP3A4 inhibitors or have impairment during tx

Question on FDA Approval How many clinicians here present consistently ask patients about FSD? • Which of the following therapies is an FDA approved agent for Hypoactive Sexual Desire Disorder? A. Never or inconsistently PINK Sildenafil (Viagra®) B.1-5 times monthly BLUE Testosterone C.6-10 times monthly GREEN Flibanserin (Addyi®) D.>10 times monthly YELLOW Vagisil® personal lubricating gel

Interview : The Conversation Tips to Facilitate the Dialogue • Use words and body language that put the patient at ease • Maintain an open, non-defensive body posture Generic: ‘‘Many people have concerns or questions about • Sit and maintain eye contact their sexuality. What questions or problems related to sex • Avoid nervous gestures would you like to discuss?’’ • Choose language appropriate to the age, ethnicity, and Health Care Milestone: ‘‘Many women after menopause culture of the patient notice a change in their sexual desire. Have you noticed • Ask open-ended questions with silences that encourage any changes?’’ the patient to speak • ‘‘Tell me about [it]’’ are probably the four most powerful words in medicine

Buster JE. Fertility and Sterility. 2013;100 (4):905-15 Buster JE Fertility and Sterility. 2013;100 (4):905-15

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Sexual Dysfunction in Diabetes Sexual Dysfunction in Diabetes Diabetes Specific Questions Rationale Diabetes Specific Questions Rationale Do you feel uncomfortable or experience Determine if this is causing sexual anxiety What are you taking? Possible influences to be addressed pain during sex? Are you experiencing stress or Review if depression is present or therapy Do you experience recurrent thrush or Is this suboptimal DM control; fungal depressive symptoms? needs to be addressed urine infections? infections are easily treated Have you recently had a baby? Determine if there was a difficult delivery, Do you feel there is a problem with your Explore marital tensions, guilt about birth injuries, sleep, or support relationship with your partner? relationships Do you feel tired all the time? Anxiety, stress, depression, hypoglycemia Do you feel embarrassed by having sex? Discover past negative experiences/abuse causing fatigue Do you feel you have a poor self image? Woman can discuss feelings of Do you experience vaginal dryness? Related to DM control, neuropathy, depression or low self esteem (obesity) medication, hormones, menopause Have you ever experienced sexual or Discover past negative experience physical abuse?

Phillips A, Phillips S. Applied Nursing Research. 2015; 28:235-8 Phillips A, Phillips S. Applied Nursing Research. 2015; 28:235-8

Mini-Case – Patient Sarah Engaging Sarah • HPI: 53-year-old married woman with Type 2 DM We need to engage Sarah in a conversation regarding and HTN x 10 yrs.; postmenopausal x 1 year sexual problems now that she has reached a new life – Vitals: Weight: 220 lb.; Height 5’4”; BMI 37.8 milestone? – Labs: A1C 8.8% Diet: None A. ‘‘Many people have concerns or questions about their – FBG 180-220 mg/dL sexuality. What questions or problems related to sex would you like to discuss?’’ ® • Meds: metformin (Glucophage XR) 1000 mg/d; B. ‘‘Many women after menopause notice a change in their empagliflozin (Jardiance®) 25 mg/d; liraglutide sexual desire. Have you noticed any changes?’’ (Victoza®) 1.8 mg/d; clonidine 0.3mg/d

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Case Discussion: Sarah Case Discussion: Sarah

•Sarah describes tiredness, irritability, has a •She states that 2 years ago the interest was there, but there loss of interest in sex and is unhappy with her were no pleasurable feelings, no physical response; and feelings weight problems of dryness and soreness persisted after sexual activity.

•She states that it was >2 years since she last •She thinks that this loss of feeling may have led to the interest made love. She knows that she does not going but is not sure. She feels it may be part of the menopause but other friends she knows do not feel like this, although a lot of have any interest but does not know why. the women at the diabetes clinic seem to understand

Clegg M, Towner Alison, Wylie K. Maturitas. 2012;72:160-4

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Areas for Consideration

• Diabetes causes sexual dysfunction (46.7%) What are some of the areas for • Vaginal Dryness consideration based on Sarah’s • Medication • Evaluate: blood glucose/lipids/estrogen/testosterone/thyroid conversation? • Review for depression • Examine patient for vulval/vaginal infection and/or atrophy • Refer to psychosexual counselling if required • Follow up patient using multimodal/multidisciplinary approach

Which of the following therapy(ies)/ Conclusion changes will Sarah receive today?

A. Initiate Sildenafil (Viagra®) 100 mg/day • Sexual health matters B. Initiate Flibanserin (Addyi®) 100 mg/day • Clinicians must ask about FSD and HSDD C. Initiate Personal Lubricating Gel • Effective treatments are available D. Initiate Basal insulin • A sex therapist may be consulted in more E. Discontinue Clonidine and switch to an ACE Inhibitor difficult cases

Question for Audience • In evaluating this presentation,

RED I learned at least one important fact today Thanks! BLUE I am still “muddy” about one point GREEN I need one area clarified today Any questions? You can email me at [email protected] YELLOW I slept through, so I have no questions

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