Prematür ejakulasyon’un yeni tanımı ve güncel tedavide dapoksetin Doç. Dr. Emin ÖZBEK Okmeydanı Eğitim ve Araştırma Hastanesi Üroloji Kliniği

PE “Psikosomatik rahatsızlık” Schapiro B. Premature ejaculation, a review of 1130 cases. J. Urol 1943; 50:374-9

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 2000 (DSM-IV-TR) “minimal seksüel stimülasyonla kişi istemeden vaginal penetrasyondan hemen önce, penetrasyon sırasında veya çok kısa süre sonra meydana gelen persistan veya reküren ejakülasyon durumu olup kişisel sıkıntıya yol açan bir rahatsızlık”

Yeni tanım:ISSM “Her zaman veya hemen her zaman vaginal penetrasyondan önce veya penetrasyondan sonra 1 dakika içinde meydana gelen ve geciktirilemeyen, negatif kişisel sıkıntı ve problemlere yol açarak kişinin cinsel ilişkiden kaçınmasına neden olan bir durum” An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature ejaculation. McMahon CG, Althof SE, Waldinger MD, Porst H, Dean J, Sharlip ID, Adaikan PG, Becher E, Broderick GA, Buvat J, Dabees K, Giraldi A, Giuliano F, Hellstrom WJ, Incrocci L, Laan E, Meuleman E, Perelman MA, Rosen RC, Rowland DL, Segraves R. J Sex Med. 2008 Jul;5(7):1590-606.

Sekonder PE: ISSM “Akkiz PE’nin kanıta dayalı tanımı için literatürde yeteri kadar basılmış objektif veri yoktur”

Kesin tanı elementleri IELT süresi düşüktür Ejakulasyon kontrol edilememektedir Kişide negatif etkilere yolaçar Distress Kişiyi rahatsız eder Ruhsal sıkıntı Cinsel ilişkiden kaçma

PE’nin tipleri Lifelong veya “primer” Akkiz veya “sekonder” Biyolojik komponenti olduğu tahmin edilmektedir: SSS’de serotonin ve/veya serotonin receptörlerinde bir defekt Akkiz veya “sekonder” Psikolojik komponent olma ihtimali daha yüksektir Sıklıkla ED ile birliktedir

PE’nin hasta ve partneri üzerindeki olumsuz etkileri Seksüel fonksiyonda azalma Cinsel tatminde azalma Genel yaşam kalitesinde azalma Distress derecesinde artma Partnerler arası ilişkide zorlanma İlişkiye zarar verebilir Erkeğin kendine öz saygısını azaltır Rowland DL, et al. J Urol 177: 1065-1070, 2007

CNS Control of Ejaculation Supraspinal Centres Higher Brain Centres Pons: nPGi: Nucleus paragigantocellularis Sensory inputs from genital areas Spinothalamic cells (LSt) L3-L4, coordination of spinal nuclei Excitatory & inhibitory control Sympathetic supply to: Vas Seminal Vesicles Prostate Pelvic Plexus ~L1-L2: Emission afferent Spinal Reflex S1-S3: Expulsion Dorsal Nerve of Penis Pudendal Nerve Motor supply to bulbocavernosus muscle

Seksüel davranışta 5-HT’nin yeri Serotonin’in (5-HT) erkek ratlarda seksüel davranışta rolü olduğu bildirilmiştir 5-HT’in erkek ratlarda seksüel davranışın nöral kontrolünde inhibitör rolü vardır Koe BK, Weismann A J. Pharmacol Exp Ther 1966, 154 : 499-516 Ahlenius S. et al Psychopharmacol. 20 : 383-388 Salis PG, Dewsburry DA Nature 1971, 232 : 400-401 Södersten P. et al Pharmacol. Biochem. Behav.1976, 5 : 319-327 Larsson K. et al Brain Res. 1978,141 : 293-303

Ejakülasyonun serotonerjik kontrolü serotonin 1B 1D 1D 1E 1G 5 4 2B 2A 2C 1A 1F 7 6 Post-Synaptic Neuron Axon Axonal Terminal is locally regulated by the serotonin Serotonin neurotransmission transporter re‑uptake system As serotonin is released, the transporter system is activated, removing serotonin from the synaptic cleft and preventing over-stimulation of postsynaptic serotonin receptors McMahon CG et al, Disorders of orgasm and ejaculation in men. In Sexual Medicine: Sexual dysfunctions in men and women. 2nd International Consultation on Sexual Dysfunctions, Paris, 2004

Prevalans En sık rastlanan erkek cinsel fonksiyon bozukluğudur Doktora başvurma oranı düşüktür Rosen RC (2000) Curr Psychiatr Rep 2: 189-195 Laumann EO et al (1999) JAMA 281: 537-544 Spector JS and Carey MP (1990) Arch Sex Behav 19: 389-408 McMahon CG (1998) J.Urol 159: 1935-1938

Yaş gruplarına göre PE prevelansı Porst et al. European Urology 2006

Ülkelere göre prevelans Porst et al. European Urology 2 006

PE prevelansı ED prevelansından yüksektir *PE defined as ‘climax too early’ (n=1,243) **ED defined as ‘trouble maintaining or achieving an erection’ (n=1,244) Laumann et al. JAMA 1999; 281: 537-544

Tedavi Davranış tedavisi Topical tedaviler (local anesthetics) PDE5 inhibitörleri Antidepressanlar (SSRIs)

AUA’in PE tedavi önerileri ED varsa önce ED’nin tedavisi Tüm tedavi seçenekleri risk ve faydaları hastaya anlatılmalıdır PE tedavisinde hasta ve partner memnuniyeti primer amaç olmalıdır PE, birçok SSRIs veya topical anestetiklerl tedavi edilebilir Optimal tedavi seçeneğini hekim hastanın da tercihini dikkate alarak vermelidir Montague et al (2004) J Urol. 172: 290–294

Tıbbi tedavi seçenekleri (AUA Guidelines) Topical therapy Trade name Recommended dose Lidocaine/ prilocaine cream EMLA Lidocaine 2.5%, prilocaine 2.5%, 20-30 mins pre-intercourse Oral therapies Trade names Nonselective serotonin reuptake inhibitor Clomipramine Anafranil 25-50 mg/day 25 mg, 4-24 h pre-intercourse Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine Prozac, Sarafem 5-20 mg/day Paroxetine Paxil, Seroxat 10-40 mg/day or 20 mg, 3-4 h pre-intercourse Sertraline Zoloft 25-200 mg/day or 50 mg 4-8 h pre-intercourse Montague et al (2004) J Urol. 172: 290–294

PE’de antidepresanların kullanımı PE için spesifik bir antidepresan yoktur Gecikmiş ejakülasyon antidepresanların yan etkilinden biridir Tedavinin etkinliğinde genelde IELT deki düzelme esas alınır Çalışmalarda hasta sayısı genellikle azdır Çoğu çalışmada kronik doz kullanılmıştır Farmakokinetik pofilleri on-demand doz ayarlamasına uygun değildir Preskorn SH Clinical pharmacology of selective serotonin reuptake inhibitors, Professional Comms Inc 1996; Waldinger M et al (2004) Int J Impot Res 16: 369-381; Sharlip I (2005) J Sex Med. Supp 2: 103-109

Kronik SSRI kullanımının sakıncaları Optimal fayda için kronik doz ayarlaması gerekir Etkisi yavaş başlar Yarılanma süresi klirensi yavaştır Vücutta birikme riski vardır Kronik SSRI bazı olumsuz seksüel yan etkilere yol açar ED ve libido azalması gibi Diğer yan etkiler: Ağız kuruluğu Sinirlilik GI yan etkiler Başağrısı Başdönmesi Cognitive boukluklar Preskorn SH Clinical pharmacology of selective serotonin reuptake inhibitors, Professional Comms Inc 1996 Sharlip I (2005) J Sex Med. Supp 2, 103-109

PE teavisinde kullanılan SSRI’ların etkisi yavaş başlar Waldinger MD et al (1998) J Clin Psychopharmacol 18:274-81

Dapoxetine hydrochloride= (S-(+)-N,N-Dimethyl-a-[2-(naphthalenyloxy)ethyl]benzenemethanamine hydrochloride C21H23NO.HCl MW: 341.88

DPX’in etki mekaniması DPX, sinaptik aralıkta aksonal terminallere re-absorbsiyonu inhibe ederek 5-HT seviyesini artırır Deneysel çalışmalarda akut DPX uygulaması ejakülasyonu geciktirir Etki yeri supraspinal seviyededir (ejakülasyonun kontrolünde önemli yapı olan LPGi)

DPX’in etki yeri Higher Brain Centres DPX, beyin sapı veya üzerindeki seviyelerde etkilidir afferent Dorsal Nerve of Penis Data from Giuliano and Clement shows that the action of dapoxetine in delaying ejaculation involves the lateral nucleus paragigantocellularis (LPGi) in the brian stem.. Pudendal Nerve Motor supply to bulbocavernosus muscle 1.Gerstenberg, T. C., Levin, R. J., & Wagner, G. British Journal of Urology. 1990; 65; 395-402 2.Giuliano & Clement. Eur Urol 2005 3.Clément et al. Eur Urol. 2006

SSRIs ‘in etki mekanizması serotonin 1B 1D 1D 1E 1G 5 4 2B 2A 2C 1A 1F 7 6 Post-Synaptic Neuron Axon Axonal Terminal Inhibits reuptake transport mechanism for serotonin  increase in concentration of serotonin in synaptic cleft

DPX’in metabolizması DPX, bir çok izoenzim tarafından metabolize edilir Hızlı ve yoğun şekilde metabolitlerine ayrılır “Dapoxetine-N-oxide” ana metabolittir DPX metabolitleri terapötik dozlarda verildiğinde çok az aktivteye sahiptirler

DPX’in kontrendikasyonları Orta-ciddi derecede kc bozukluğu olanlar Ciddi böbrek yetmezliği olanlar Ciddi kalb problemi olanlar MAO inhibitörleri, thioridazine, antidepresanlar ile birlikte alınmamalıdır CYP3A4 inhibitörleri ile birlikte alınmamalıdır 18 yaş altı ve 64 yaş üstü (18-64 yaş arası) Cinsel ilişkiden 1-3 saat önce alınmalı 24 saatte bir dozdan fazla alınmamalı

DPX hızlı absorbe ve elimine edilir Modi et al. J Clin Pharmacol 2006; 46: 301-309

DPX multipl dozlarda vücutta birikmez Modi et al. J Clin Pharmacol 2006; 46: 301-309

DPX diğer SSRI a göre absorbsiyon ve eliminasyonu hızlıdır Andersson et al. BJU International 2006; 97: 311-315 Antidepressive SSRI data based on Summary Basis of Approval and published reports

ÖZET DPX, hızlı absorbe ve elimine olarak vücutta minimal birikir 30 ve 60 mg dozlarda doza-uygun farmakokinetik gösterir, bu durum multiple dozlarla etkilenmez Pik konsantrasyonlarına yaklaşık 1.3 saatte ulaşır 24 saatte plazma konsantrasyonları pik seviyenin %5 inden düşüktür Tüm bu farmakokinetk özellikler DPX’in PE’nin on-demand tedavisnde iyi bir aday olduğunu göstermektedir

DPX’in IELT skoruna etkisi ilk ve sonraki dozlarda görülür Pivotal US Studies -012 and -013 pooled data Pryor et al. Lancet 2006; 368: 929-937

DPX ejakulasyonda erken kontrol sağlar Pivotal US Studies -012 and -013 pooled data Study endpoint represents final visit values (week 12 or last visit). * p<0.0001 vs placebo; † p=0.0013 vs 30 mg; ‡ p=0.0025 vs 30 mg; ║ = 0.0082 vs 30 mg. ‘Over the past month was your control over ejaculation during sexual intercourse..’ Very poor, poor, fair, good, very good Pivotal US Studies -012 and -013 pooled data Pryor et al. Lancet 2006; 368: 929-937

DPX partner memnuniyetini ciddi şekilde artırır Pivotal US Studies -012 and -013 pooled data Pryor et al. Lancet 2006; 368: 929-937 Studies -012 and -013 pooled data: Data-on-file

DPX, primer ve akkiz her iki PE de de etkilidir Pivotal US Studies -012 and -013 pooled data: Data-on-file

Ejakulasyon kontrolü 12 aya kadar sürer Pivotal US Studies open-label extension Shabsigh et al. Dapoxetine Has Long-term Efficacy in the Treatment of Premature Ejaculation Abstract at AUA 2006 © J & J Pharmaceutical Services LLC, 2007

Hasta memnuniyetinde düzelme 12 aya kadar sürer ‘Over the past month was your satisfaction with sexual intercourse..’ Very poor, poor, fair, good, very good (Prior treatment assignment) All patients on active treatment Pivotal US Studies open label extension *Responses tabulated from enrolled participants at the time of assessment. All subjects started the OLP with dapoxetine 60 mg. Shabsigh et al. Dapoxetine Has Long-term Efficacy in the Treatment of Premature Ejaculation Abstract at AUA 2006 © J & J Pharmaceutical Services LLC, 2007

DPX, IELT skorunu anlamlı şekilde düzeltir * * * * Over the past month was your control over ejaculation during sexual intercourse…. Very poor, poor, fair, good, very good * p<0.001 vs placebo Study conducted in EU, Mexico, Canada, South America, South Africa and Israel © J & J Pharmaceutical Services LLC, 2007 Study 3001: Data-on-File

IELT’deki düzelme uzun süre devam eder Figures are in table 2.1.2 page 12 of Topline results Placebo 382 332 280 238 221 195 182 DPX 30mg 385 356 303 264 240 218 DPX 60mg 387 347 287 249 229 214 198 N Study conducted in EU, Mexico, Canada, South America, South Africa and Israel Study 3001: Data-on-File © J & J Pharmaceutical Services LLC, 2007

Hasta memnuniyeti anlamlı olarak düzelir Patients with at least 1 category improvement in satisfaction Placebo (N=347) Dapoxetine 30mg (N=359) Dapoxetine 60mg (N=353) * * * * % of subjects * p<0.001 vs placebo Study conducted in EU, Mexico, Canada, South America, South Africa and Israel © J & J Pharmaceutical Services LLC, 2007 Study 3001: Data-on-File

Distress anlamlı şekilde düzelir Patients with at least 1 category improvement in distress Placebo (N=347) Dapoxetine 30mg (N=360) Dapoxetine 60mg (N=353) * * * * % of subjects * p<0.001 vs placebo Study conducted in EU, Mexico, Canada, South America, South Africa and Israel Study 3001: Data-on-File © J & J Pharmaceutical Services LLC, 2007

12 haftalık Pan-Asya çalışması 3003 Sites in Asia and Australia 1349 men enrolled Collect Baseline Data Dapoxetine 60mg No study drug Dapoxetine 30mg Placebo Randomisation 1º Efficacy Endpoint Week 14 Post-Study Telephone Contact This is the other, a multicentre study conducted in Asia. Study Design Multicenter, placebo-controlled, double-blind, randomized, parallel-group study Screening phase: subjects must have a minimum of 4 evaluable events with and IELT of <2 minutes in 3 out of 4 or in >75% of intercourse attempts Randomize into treatment groups dapoxetine 60mg, dapoxetine 30mg, or placebo x 12 wks Primary endpoint: average IELT at the end of double-blind treatment phase Key secondary endpoints: “Responder” = Control +2 and Distress –1 Safety will be evaluated by examining incidence, severity, and type of adverse events between treatment groups Subjects recruited from Australia China Korea Taiwan Other Asian Screening Phase ~4 weeks Double-Blind Tx Phase 12 weeks Post-Study Phase -4 4 8 12 14 Visits (weeks) © J & J Pharmaceutical Services LLC, 2007

Dapoksetin’in güvenliği ile ilgili çalışmalar

En sık görülen yan etkiler (12 hafta,US) Dapoxetine use is well tolerated. The most common adverse event is nausea, which appears to show a dose relationship as do the other more common AEs, however they are predominantly mild and transient in nature. Only a few patients with nausea discontinued the study – and these tended to be the patients with a poor response to dapoxetine. Nausea mostly mild and transient and resulted in study discontinuation in only 0.1% (placebo), 1.3% (30mg) and 3.8% (60mg) of subjects. © J & J Pharmaceutical Services LLC, 2007 Studies 012 & 013: Data-on-file

En sık görülen yan etkiler 3001 (24 hafta) Placebo Dapoxetine 30mg Dapoxetine 60mg 30.0 30 25 20 16.5 % Patients reporting AE 15 13.6 13.4 11.3 10 8.3 7.7 7.2 6.4 5 3.9 3.9 2.9 2.6 Dapoxetine use is well tolerated. The most common adverse event is nausea, which appears to show a dose relationship as do the other more common AEs, however they are predominantly mild and transient in nature. Only a few patients with nausea discontinued the study – and these tended to be the patients with a poor response to dapoxetine. 1.6 1.0 Nausea Diarrhea Headache Dizziness Somnolence Study conducted in EU, Mexico, Canada, South America, South Africa and Israel Nausea mostly mild and transient and resulted in study discontinuation in only 0.3% (placebo), 1.0% (30 mg) and (2.6%) 60 mg of subjects © J & J Pharmaceutical Services LLC, 2007 Study 3001: Data-on-file

En sık görülen yan etkiler 3003 (12 hafta) Dapoxetine use is well tolerated. The most common adverse event is nausea, which appears to show a dose relationship as do the other more common AEs, however they are predominantly mild and transient in nature. Only a few patients with nausea discontinued the study – and these tended to be the patients with a poor response to dapoxetine. Study conducted in Australia and Asia Nausea mostly mild and transient and resulted in study discontinuation in only 0.0% (placebo), 0% (30mg) and 2.5% (60mg) of subjects. © J & J Pharmaceutical Services LLC, 2007 Study 3003: Data-on-file

Günlük dozlar iyi tolere edilebilir ,çalışma 3002S (9 hafta) Nausea mostly mild and transient. Discontinuation due to Nausea: 0% PL, 2.2% 60 mg PRN, 3.2% 60 mg QD Study 3002: Data-on-File © J & J Pharmaceutical Services LLC, 2007

Seksüel fonksiyonla ilgili yan etkiler çok azdır (US Pivotal Studies) Placebo Dapoxetine (30mg) Dapoxetine (60mg) 3.8 4 2.9 3 % patients reporting AE 2 1.5 0.8 1 0.7 0.7 0.5 0.2 0.3 0.2 0.2 Erectile Dysfunction Abnormal Ejaculation Libido Decreased Sexual Function Abnormal © J & J Pharmaceutical Services LLC, 2007 Pryor et al. Lancet 2006: 368: 929-937

SSRI larla ilgili suisit düşüncesi ve withdrawal sendrom görülebilir Antidepresan alanlarda suisidal girişimler olabilir SSRI ların ani kesilmesi 5-8 günde withdrawal syndroma yolaçabilir başdönmesi uykusuzluk sinirlilik bulantı ajitasyon Gunnell D, et al. BMJ 2005; 330: 385 Fergusson D, et al. BMJ 2005; 330: 396 Juurlink DN, et al. Am J Psychiatry 2006; 163: 813–21 Rosenbaum et al. Biol Psychiatry. 1998;44:77-87 © J & J Pharmaceutical Services LLC, 2007

DPX suisidal düşüncelere neden olmaz (3001) Beck % MADRS 1 2 3 4 5 6 Placebo 97.7 2.3 99.4 0.3 Dapoxetine 30 mg 0.6 99.5 Dapoxetine 60 mg 100 Beck: 0=I don't have any thoughts of killing myself. 1=I have thoughts of killing myself, but I would not carry them out. 2=I would like to kill myself. 3=I would kill myself if I had the chance. MADRS 0=Enjoys life or takes it as it comes. 2=Weary of life. Only fleeting suicidal thoughts. 4=Probably better off dead. Suicidal thoughts are common and suicide is considered a possible solution, but without specific plans or intention. 6=Explicit plans for suicide when there is an opportunity. Active preparations for suicide. 0=Enjoys life or takes it as it comes. 2=Weary of life. Only fleeting suicidal thoughts. 4=Probably better off dead. Suicidal thoughts are common and suicide is considered a possible solution, but without specific plans or intention. 6=Explicit plans for suicide when there is an opportunity. Active preparations for suicide 0=I don't have any thoughts of killing myself. 1=I have thoughts of killing myself, but I would not carry them out. 2=I would like to kill myself. 3=I would kill myself if I had the chance Study conducted in EU, Mexico, Canada, South America, South Africa and Israel Study 3001: Data-on-File © J & J Pharmaceutical Services LLC, 2007

DPX suisidal düşüncelere neden olmaz (3002) Beck % MADRS SCALE 1 2 3 4 5 6 Placebo 100 Dapoxetine 60 mg PRN 99.7 0.3 99.4 0.6 Dapoxetine 60 mg QD Beck: 0=I don't have any thoughts of killing myself. 1=I have thoughts of killing myself, but I would not carry them out. 2=I would like to kill myself. 3=I would kill myself if I had the chance. MADRS 0=Enjoys life or takes it as it comes. 2=Weary of life. Only fleeting suicidal thoughts. 4=Probably better off dead. Suicidal thoughts are common and suicide is considered a possible solution, but without specific plans or intention. 6=Explicit plans for suicide when there is an opportunity. Active preparations for suicide. 0=I don't have any thoughts of killing myself. 1=I have thoughts of killing myself, but I would not carry them out. 2=I would like to kill myself. 3=I would kill myself if I had the chance 0=Enjoys life or takes it as it comes. 2=Weary of life. Only fleeting suicidal thoughts. 4=Probably better off dead. Suicidal thoughts are common and suicide is considered a possible solution, but without specific plans or intention. 6=Explicit plans for suicide when there is an opportunity. Active preparations for suicide © J & J Pharmaceutical Services LLC, 2007 Study 3002: Data-on-File

Withdrawal Syndrome Defined by Increase of ≥ 4 Points on DESS DPX her gün alınsa dahi WS yönünden plasebo ile fark yoktur (Withdrawal Assessment Period) Withdrawal Syndrome Defined by Increase of ≥ 4 Points on DESS Placebo/ Placebo Dapoxetine 60 mg PRN/Placebo PRN/PRN QD/Placebo QD/QD Withdrawal Syndrome, n (%) 2 (1.3%) 1 (0.7%) 2 (1.4%) 1 (0.6%) Odds of withdrawal syndrome (vs. Placebo) 0.007 0.014 0.006 Observed odds ratio 0.52 2.14 Estimated odds ratio* 0.50 2.02 95% Cl (0.05, 5.64) (0.18, 23.13) *Odds ratio estimated based on a logistic regression model with treatment and pooled center (country) as factors. The incidence of withdrawal syndrome did not differ between the dapoxetine QD/placebo and dapoxetine QD/QD groups, and was no higher in the dapoxetine treated groups than placebo. Because the incidence of discontinuation syndrome was very rare across treatment sequences, there is poor precision for the odds ratio estimates Levine et al. Evaluation of Withdrawal Effects with Dapoxetine In the Treatment of Premature Ejaculation (PE), Poster presented at SMSNA 2006 © J & J Pharmaceutical Services LLC, 2007

Uzun süre güvenliği

9 aylık tedavi sonrası yan etkiler (≥2% Incidence): Study 014 Adverse event Subjects reporting AEs n (%) Discontinuation due to AE Nausea 265 (14.9%) 29 (1.6%) Dizziness 90 (5.1%) 17 (1.0%) Diarrhea 82 (4.6%) 15 (0.8%) Headache 69 (3.9%) 11 (0.6%) Somnolence 58 (3.3%) 7 (0.4%) Insomnia 51 (2.9%) 9 (0.5%) Dyspepsia 46 (2.6%) 7 (0.5%) Asthenia 35 (2.0%) Shabsigh et al. Long-term Safety and Tolerability of Dapoxetine for the Treatment of Men with Premature Ejaculation Poster presented at EAU 2006

ÖZET: İsteğe bağlı DPX, PE tedavisinde iyi tole re edilir Bulantı en sık görülen yan etkidir Hafif derecededir Zamanla azalır 9 aylık tedavi boyunca çok az hasta tedaviyi bırakır 12 ay kullanımda tolerabilitesi olumsuz yönde etkilenmez

Teşekkürler………