Flibanserin โดย เภสัชกรหญิงคริสติน่า ลี้สุรพลานนท์

Flibanserin for the treatment of premenopausal women with generalized hypoactive sexual disire disorder

Hypoactive Sexual Desire Disorder (HSDD) ภาวะความต้องการทางเพศน้อย เกินไป เป็นภาวะที่พบได้ทั้งในเพศ ชายและเพศหญิง ผู้ป่วยจะมีความ ต้องการทางเพศน้อย แต่เมื่อมี ความต้องการและได้รับการกระตุ้น เพียงพอก็อาจมีกิจกรรมทางเพศ ได้อย่างปกติ

Pathophysiology of HSDD HSDD is imbalance disequilibrium between excitatory and inhibitory influence on sexual function Excitatory role in sexual desire Inhibitory role in sexual desire Dopamine, NE, estrogen, progesterone and testosterone Serotonin, opioids and prolactin

Common causes of HSDD 1.Psychosocial variables 2.Aging 3.Perimenopause/Menopause 4.Comorbidities and medical causes

Common causes of HSDD (cont.) 5. Other causes - Tension/Stress - Relationship difficulty - Intra/interpersonal relationship - Substance abuse

Diagnosis of HSDD 2013 American Phychiatric Association (APA) Guidelines Sexual problem must… 1. Be current and persistent 2. Cause personal distress or interpersonal difficulty 3. Not be caused by diseases/medications

Diagnosis of HSDD (cont.) Validate Questionnaires 1. Decreased Sexual Desire Screener (DSDS) 2. Female Sexual Function Index (FSFI) 3. Sexual Interest and Desire Inventory Female (SIDIF) 4. Brief Hypoactive Sexual Desire Disorder Screener 5. Female Sexual Distress Scale-Revised (FSDS-R)

Diagnosis of HSDD (cont.)

Pharmacotherapy of HSDD 1.Androgen therapy : Oral & transdermal testosterone Involved with sexual arousal, genital sensation, libido and orgasm Off-label: due to safety concerns associated with hormone therapy Non – FDA approved agents

Pharmacotherapy of HSDD 2. Phosphodiesterase-5 (PDE-5) inhbitor (Sildenafil) Improves blood flow to genital tissue Adverse effects: Flushing, Headache, Lightheadedness, Dizziness Non – FDA approved agents

Pharmacotherapy of HSDD 3. Melanocortin receptor agonist (Bremelanotide) Involves activating endogenouse melanocortin hormone pathways involved in sexual arousal response Non – FDA approved agents

Pharmacotherapy of HSDD 4. Psychotropic agents: Bupropion Inhibits dopamine & NE reuptake May increase the frequency of sexual arousal and desire (no efficacy and safety data) Non – FDA approved agents

Pharmacotherapy of HSDD “Flibanserine” (Addyi®) First FDA-approved medication to treat acquired, generalized HSDD in premenopausal women (Aug. 2015) FDA approved as ‘Female Viagra’ with a strong warning on side effects. FDA approved pharmacological options

Mechanism of Actions Multifunctional serotonin agonist antagonist (MSAA) Full agonist at 5-HT1A 5-HT2A antagonist Moderate antagonist at 5-HT2B, 5-HT2C and dopamine D4 receptors  NE and  DA and  5-TH in prefrontal cortex Improve sexual function

Mechanism of Actions

Dose and usage Dose : 100 mg. orally, once daily at bedtime Steady state is achieved after 3 days of dosing Discontinuation of Flibanserin is recommended at 8 weeks in the absence of benefit.

Pharmacokinetics Dose- proportional pharmacokinetics Absolute bioavailability 33% Steady state was achieved after 3 days of dosing Fat-containing meals increased AUC 0-  and C max

Pharmacokinetics 98% bound to human serum proteins, mainly to albumin Metabolism: CYP3A4 (Major) and C CYP2C19 (Minor) Renal excretion: Low (low effects by renal impairment) T 1/2 : 11 hr.

Contraindications Alcohol consumption Moderate CYP3A4 inhibitors: Atazanavir, Ciprofloxacin, diltiazem, verapamil, erythromycin, fluconazole Strong CYP3A4 inhibitors: Ketoconazole, itraconazole,clarithromycin, ritonavir, indinavir Hepatic impairment

Drug interactions

Adverse reactions Risk of severe Hypotension and Syncope (Black box warning) Serious ADRs : CNS depression (somnolence, sedation), Hypotension, Syncope Common ADRs : Dizziness, nausea, fatigue, insomnia, dry mouth, somnolence.

Sildenafil (Viagra®) vs. Flibanserin Sildenafil (Viagra®)Flibanserin (Addyi®) MechanismIncrease blood flow to help men achieve erection Affects the CNS Time to administration Take only when needed and work within 45 min Take every day, effect can be seen 4 weeks after started