Update on the Management of Erectile Dysfunction

1
Update on the Management of Erectile Dysfunction
Premature Ejaculation
Chris G McMahon MBBS FAChSHM Associate Professor,
University of Sydney Australian Centre for Sexual
Health
2
(No Transcript)
3
On-Demand PDE5 Inhibitors

• Oral drug therapy with the PDE5 inhibitors
  Sildenafil, Tadalafil, Vardenafil, Udenafil,
  Mirodenafil and Lodenafil have shown significant
  efficacy and proven safety in the treatment of ED
  with successful completion of coitus rates (SEP 3
  data) of about 70-75

1. Eardley,I, Donatuicci C, Corbin J, El-meliegy A,
   Hatzimouratidis ,McVaryK, Munarriz R, Lee SW
   Pharmacotherapy for Erectile Dsfunction. J Sex
   Med 2010,7524-540
2. Hatzimouratides K, Amar E, Eardley I, Giuliano F,
   Hatzichristou D, Montorsi F, Vardi Y, Wespes E
3. Guidelines on Male Sexual Dysfunction Erectile
   Dysfunction and Premature Ejaculation. Eur Urol
   2010 , 57, 804-814
4. Glina S, Fonseca GN, Bertero EB, Damião R, Rocha
   LC, Jardim CR, Cairoli CE, Teloken C, Torres
   LO,Faria GE, da Silva MB, Pagani E. Efficacy and
   tolerability of lodenafil carbonate for oral
   therapy of erectile dysfunction a phase III
   clinical trial J Sex Med. 2010 May7(5)1928-36.

4
Mechanism of Action of PDE-5i

• Sexual arousal activates the NO-cGMP pathway,
  leading to cavernosal smooth muscle cell
  relaxation, lacunar space engorgement and
  erection
• The enzyme, phosphodiesterase type-5 (PDE5),
  which is predominantly found within the corpora
  cavernosum, hydrolyzes cGMP to 5-GMP, terminating
  the pathway and produces detumescence
• PDE5 inhibitors compete with cGMP for the PDE5
  receptor site, resulting in increased
  intracellular levels of cGMP and erection

Adapted from Lue TF. N Engl J Med 2000 342
1802-1813.
5
On-Demand PDE 5 Inhibitors

• Long-term (1.5-3 years) treatment with PDE5i
  resulted in drop out rates of up to gt50 1,2
• Frequent (28-42) reasons for discontinuation of
  Sildenafil therapy were ...
• Efficacy below expectations, high cost, lost of
  interest in sex, inconvenience in obtaining
  sildenafil 1
• Infrequent (12-15) reasons for discontinuation
  of Sildenafil therapy were
• Recovery of EF, partner resistance, side effects
  1
• 30-35 of patients will fail to respond

1. Jiann,BP, Yu,C.C., Tsai,J.Y. Compliance of
   sildenafil treatment for erectile dysfunction and
   factors affecting it. Int J Impotence Res.
   18,146-149,2006
2. Souverein,PC, Egberts,A.C., Meuleman,E.J. et al 
   Incidence and determinants of sildenafil
   (dys)continuation  The Dutch cohort of
   sildenafil users. Int J Impotence Res
   14,259-265,2004

6
Reasons for On-Demand PDE5i Failure
Initial Delayed
Incorrect Drug Dose Worsening of Endothelial Dysfunction
Poor Treatment Compliance Progression of Penile Atherosclerosis
Severe Vasculogenic ED PDE5i Tachyphylaxis or Tolerance
Uncorrected Co-morbid Risk Factors
Post-Radical Prostatectomy ED
Hypogonadism
Androgen Ablation Treatment
Co-morbid Psychosocial Factors
7
Patient Education

• Treatment failure may result from inadequate
  education and incorrect drug use
• Patients must recognize that sexual arousal,
  ideally with a partner, is required to activate
  the NO-cGMP pathway
• Studies report that as many as 81 of patients
  initially administered sildenafil incorrectly
  1-6
• Patient re-education can salvage up to 55 of
  sildenafil failures 6

1. Hatzichristou,D.,Moysidis,K.,Apostilidis,A.,Bekos,
   A.,Tzortzis V.,Hatzimouratidis,K.,Ioannidis,E.
   Sildenafil failures may be due to inadequate
   patient instructions and follow-up A study on
   100 non-responders.Eur Urol 47,518-522,2005
2. Brock,G.,Carrier,S.,Casey,R.,Tarride,R.C.,Eliott,S
   .,Dugré,H.,Rousseau,C.,DAngelo,P.,Deloy,I.Can
   an Educational Program Optimize PDE 5 Inhibitor
   Therapy? A Study on Canadian Primary Care
   Practices.J Sex Med 4,1404-1412,2007
3. Hatzimouratidis K, Hatzichristou G Treatment
   options for erectile dysfunction in patients
   failing oral drug therapy.EAU Update Series
   2004,2,75-83
4. Vardi Y, Chen Y, Sheinfield O et al A
   multi-center study, evaluating the effect of
   instruction and Redosing of Sildenafil failures.
   Int J Impotence Res 2002,14 Suppl 4 S15 Abstr.
   PS-4-4
5. Atiemo HO, Szostak MJ, Sklar GN Salvage of
   Sildenafil failures referred from primary care
   physicians.J Urol 2003,170,2356-2358
6. Mydlo JH, Volpe MA, Macchia RJ. Initial results
   utilizing combination therapy for patients with a
   suboptimal response to either alprostadil or
   sildenafil monotherapy. Eur Urol 2000 38(1)30-4.

8
Timing of Administration

• It is critical that patients are advised of the
  time of onset of the PDE5 inhibitor prescribed as
  premature attempts at intercourse are likely to
  be unsuccessful
• Sildenafil and vardenafil are rapidly absorbed
  and can be taken 30-60 minutes before intercourse
• Tadalafil does not achieve maximal plasma
  concentrations until 2 hours after dosing due to
  a higher Tmax (time-to-maximum concentration) of
  2.5 hours.
• Although some men may respond to tadalafil as
  early as 16 minutes and approximately half of the
  men may respond by 30 minutes, patients,
  especially older men with vasculogenic ED should
  be advised to take tadalafil at least 2-3 hours
  or longer before sexual activity to achieve Cmax

9
Effect of Alcohol and Food

• The time of onset and extent of response are
  highly dependent upon the effect of alcohol and
  food.
• Moderate to high fat meals or excessive alcohol
  as both may reduce the speed and extent of drug
  absorption of both sildenafil and vardenafil.
• Advising the patient to initially administer
  sildenafil or vardenafil on an empty stomach will
  optimise their initial response following which
  the patient can experiment with the effects of
  alcohol or food on response to determine the best
  timing of administration.
• The absorption of tadalafil is largely unaffected
  by food and alcohol but an occasional patient
  will report a reduced response with
  administration after a fatty meal or excessive
  alcohol.

10
Duration of Response

• Delayed attempts at intercourse which fall
  outside the duration of effective PDE5 inhibitor
  plasma concentrations are likely to be associated
  with either drug failure or a reduced response.
• Sildenafil and vardenafil are rapidly cleared
  from the body and are active for 4 and 8 hours
  respectively.
• Tadalafil, with a T1/2 of 17.5 hours, is active
  for up to 36 hours.
• Anecdotally, some young men with psychogenic ED
  may report a response to PDE5 inhibitors in
  excess of that predicted by the drugs
  pharmacokinetics

11
Adequate Trial of Treatment

• Although most men will respond after 1-2 doses,
  some may require 6-8 uses before an optimal
  response occurs. 1-4

1. Barada JH, Fawzy A, Guay AT, Hatzichristou D.
   Achieving treatment optimization with sildenafil
   citrate (Viagra) in patients with erectile
   dysfunction. Urology 2002 60(2 Suppl 2)28-38
2. Hellstrom WJG,Elhilali,M.,Taylor,T.,Gittleman,M.
   Vardenafil in patients with erectile dysfunction
   achieving treatment optimization. J
   Androl,26,604-609, 2005
3. Porst, H, Rosen R., Padma-Nathan, H. Goldstein,
   I., Guiliano, F., Ulbrich, E. Bandel, T., and the
   Vardenafil Study Group The efficacy and
   tolerability of vardenafil, a new, oral,
   selective phospho-disesterase type 5 inhibitor,
   in patients with erectile dysfunction the first
   at-home clinical trial. Int. J. Impotence Res.
   13, 192 -199, 2001
4. Schulmann CC, Shen,W.Stothard,D.,Schmitt,H.
   Integrated analysis examining first-dose success,
   success by dose, and maintenance of success among
   men taking tadalafil for erectile dysfunctionet
   al. Urology 64 783-788, 2004

12
Dose Optimisation

• PDE5 inhibitor failure may be due to inadequate
  dosage
• Sildenafil should be initiated at 50mg (25mg for
  elderly patients and patients with hepatic
  cirrhosis or renal impairment) and titrated to a
  maximal dose of 100mg to achieve maximal response
  1
• Doses higher than 100mg may be effective, but are
  associated with a significantly higher incidence
  of side effects and a 30 treatment
  discontinuation rate
• Vardenafil should be initiated at 10mg. with dose
  titration to achieve either optimal response or
  maximal dose of 20mg
• Tadalafil should be initiated at 20 mg., the most
  common dose but can be downwards titrated to
  10mg. in responders to identify that lowest
  effective dose

1. Rosen RC, Kostis JB. Overview of
   phosphodiesterase 5 inhibition in erectile
   dysfunction. Am J Cardiol 2003 92(9A)9M-18M.

13
PDE5i Tolerance/Tachyphylaxis

• Loss of efficacy due to tachyphylaxis, i.e.
  decreased tissue responsiveness, is a concern for
  drugs that are administered frequently, and
  tolerance is possible for drugs that are used
  regularly for long periods
• Tachyphylaxis has been suggested as a possible
  cause of a reported 17 sildenafil
  discontinuation rate after 2 years.1

1. El-Galley R, Rutland H, Talic R, Keane T, Clark
   H. Long-term efficacy of sildenafil and
   tachyphylaxis effect. J Urol 2001 166(3)927-31

14
PDE5i Tolerance/Tachyphylaxis

• Several possible biological mechanisms for
  tachyphylaxis and/or tolerance during PDE5
  inhibitor treatment have been evaluated in
  pre-clinical studies
• Although, PDE5 expression or activity can be up-
  or down-regulated in vivo, in animal models
  sildenafil does not affect PDE5 expression in
  corporal smooth muscle.
• Consistent with this, most clinical studies do
  not suggest that clinically relevant tolerance to
  PDE5 inhibition develops during treatment periods
  ranging from approximately 6 months to 4 years.
• A more plausible explanation of the decreased
  efficacy is the progressive worsening of the
  patients underlying cause of ED, for example
  worsening atherosclerosis and/or diabetes.

15
Trial of Another PDE5i

• Although there is no well designed direct
  head-to-head studies comparing the efficacy of
  the three PDE5 inhibitors, it is likely that
  efficacy and tolerability is similar for the 3
  drugs
• However, as individual responses to these drugs
  may vary inexplicably, it is reasonable to offer
  patients a trial of another PDE5 inhibitor before
  proceeding to more invasive treatments.

16
Daily Dosing of PDE 5 Inhibitors

• At present Tadalfil (Cialis 2.5, 5, 10mg) is the
  only PDE 5 inhibitor whose efficacy and safety
  was sufficiently investigated in controlled,
  randomized trials with daily dosing regimen of up
  to 2 years duration 1-3
• Daily dosing with tadalafil results in efficacy
  and side-effect rates comparable with those of
  prn application of the highest doses of either
  tadalafil or other PDE 5 inhibitors and can be
  considered first line therapy

1. Hatzimouratides K, Amar E, Eardley I, Giuliano F,
   Hatzichristou D, Montorsi F, Vardi Y, Wespes E
   Guidelines on Male Sexual Dysfunction Erectile
   Dysfunction and Premature Ejaculation. Eur Urol
   2010 , 57, 804-814
2. Porst H, Rajfer J, Casabé A, Feldman R, Ralph D,
   Vieiralves LF, Esler A, Wolka AM, Klise SR
   Long-term safety and efficacy of tadalafil 5 mg
   dosed once daily in men with erectile
   dysfunction. J Sex Med. 2008 Sep5(9)2160-9.

17
Daily Dosing of PDE-5 inhibitors

• Salvage of on-demand tadalafil failures with
  daily or alternate day administered tadalafil has
  been reported but is limited by the relatively
  high cost of treatment 1
• The mean successful intercourse completion rate
  increased from 21 with on-demand 20mg tadalafil
  to 58 with daily 10mg tadalafil.
• The improved erectile response with daily
  tadalafil is probably related to improved
  endothelial function

1. McMahon CG. Efficacy and safety of daily
   tadalafil in men with erectile dysfunction
   previously unresponsive to on-demand tadalafil. J
   Sex Med. 20041 292-300

18
Intracavernous Injection Therapy (ICI)

• Broad level 2a evidence exists for treatment
  with...
• Alprostadil-(CaverjectTM 5-40µg)
• Mixture of Alprostadil /-Phentolamine /-
  Papaverine /- Atropine (Bimix/Trimix, no
  commercial product available)
• Papaverine/Phentolamine (15-60mg/0.5-2mg

18
19
ICI Alprostadil

• ICI with various vasoactive drugs can be either
  first line therapy in those patients with
  contraindications to oral drug therapy or
  second-line therapy in PDE5i non-responders
• Controlled long-term trials were conducted with
  CaverjectTM of up to 5 years duration in a
  reasonable number of study populations 1-4
• Drop-out-rates in long-term trials ranged between
  28 after 1 year and 78 after 5 years

1. Linet,O.I., Ogrinc,F.G. and Alprostadil Study
   Group Efficacy and safety of intracavernosal
   Alprostadil in men with erectile dysfunction. N E
   J M, 334, 873-877,1996
2. Linet,O.J. Long-term safety of CaverjectTM
   (Alprostadil S.PO, PGE) in erectile dysfunction
   (ED). Int J Impotence Res 10, Suppl.3, S 37, 1998
3. Porst H. The rationale for prostaglandin E1 in
   erectile failure a survey of worldwide
   experience. J Urol 1996 155(3) 802-15.
4. Porst,H., Buvat,J., Meuleman,E. et al
   Intracavernous Alprostadil Alfadex an effective
   and well tolerated treatment for erectile
   dysfunction. Results of a long-term European
   study. Int J Impotence Res 10, 225-231, 1998

20
ICI Side Effects

• Typical drug-independent side effects with
  self-injection therapy are 1-4 ...
• Hematoma, mal-injections (urethra, subcut.,
  intratrabecular)
• Pain (up to 52 ), priapism (PGE 0.4 ,
  papaverine comb ICI 7-8 , fibrosis, curvature
  deformity 1-12 (gtgt papaverine comb ICI)
• Papaverine related hepatotoxicity in up to 5

1. Linet,O.I. et al. N E J M, 334, 873-877,1996
2. Linet,O.J.Int J Impotence Res 10, Suppl.3, S 37,
   1998
3. Porst H. J Urol 1996 155(3) 802-15.
4. Porst,H. et al. Int J Impotence Res 10, 225-231,
   1998

21
Corporal Fibrosis

• Dependent on drug used and ICI technique
• PAP/PHENgtgtPAPgtgtgtgtgtPGE1 1
• 4-5 yr follow-up of US Caverject and European
  EDEX trials showed that 33-47 of nodules and
  plaques healed spontaneously 1,2
• 52 patients with ICI fibrosis showed spontaneous
  improvement despite 91 continuing ICI 3
• 50 develop curvature which may require surgery
• Temporary cessation for 2-3 mo with re-education

1. Porst, H. J Urol 1996 155(3)802-815
2. Porst, H, Buvat, J, Meuleman, E et al. Int J
   Impot Res 1998 10(4)225-231.
3. Linet, OI. Int J Imp Res 1998 10(Suppl 3)S37
4. Chew, KK, Stuckey, BG. Int J Impot Res 2003
   15(2)94-98

22
ICI Drop Out

• Treatment discontinuation rate is high (up to
  50)
• Usually less motivated, less satisfied, found ICI
  difficult, did not like drug-induced erection 1
• Lower drop-out rate with PGE1 ICI compared to
  papaverine ICI (12.5 vs. 28 per annum)
• Poor response (39), pain (11), no partner
  (17), improved erections (170 and dislike of
  ICI (6) 2

1. Lehmann, K, Casella, R, Blochlinger, A et al.
   Urology 1999 53(2)397-400
2. McMahon, CG, Daley, J, Stricker et al. Int J Imp
   Res 1994 6(Suppl 1)D86

23
Therapeutic Algorithm of ED Diagnosis Hx, Exam
/- PharmacoDiagnosis, Penile CDU
More Organic
Cardiovascul. Risk factors/findings
Hormonal
More Psychogenic
Specific endocrine therapy ?ART ?Rx
Hyperprolactinaemia
Sexual-therapy an option, /- combined with PDE5i
PDE5i
Cardiology Referral
Sexual activities permitted
No ED- improvement after 2-3 months
NON-RESPONDERS
Tadalafil daily for 2-3 months
Add PDE5i
PDE5i
Non-Responder
24
Therapeutic Algorithm of ED (Cont.)
Injection-therapy Alprostadil20-40µg
??Pap30mg/Phentol1mg ??TrimixPGE1 20 -40µg /
Papaverine 30 mg / Phentolamine 1 mg)
Injection-therapy Alprostadil 20-40µg
??Pap30mg/Phentol 1mg ??TrimixPGE1 20 -40µg /
Papaverine 30 mg / Phentolamine 1 mg)
ICI Therapy Alprostadil 20-40µg ??Pap30mg/Phentol
1mg ??TrimixPGE1 20 -40µg / Papaverine 30 mg /
Phentolamine 1 mg)
Non-Responder
Non-Responder
Non-Responder
Combination oral or ICI (PGE1 mono (20-40 µg) or
Pap./Phentol.or Trimix)
Vacuum-therapy /- oral, Intraurethral, ICI
therapy
Non-Responder (10)
Penile Implant
24
25
Premature Ejaculation
26
Premature Ejaculation
Common male sexual dysfunction
In the literature, self-reported complaints of PE
as high as 30 are reported
Poor rates of treatment seeking
Epidemiology not firmly established
Neglected area of male sexual health and an
unmet therapeutic need

1. Rosen (2000) Curr Psychiatr Rep 2189-195
   Laumann et al (1999) JAMA 281 537-544
2. Spector Carey (1990) Arch Sex Behav 19
   389-408 Porst et al. (2007) Eur Urology
   51816-824

27
Premature Ejaculation
Rapid ejaculation and associated orgasm with
normal erection
Short plateau phase
Steep excitement phase with normal erection
Normal response
Time
Adapted from Donatucci (2006) J Sex Med 3(suppl
4)303308
28
Neural Control of Ejaculation Key Supraspinal
Centres
Emission and ejection are centrally integrated
and coordinated processes involving several key
brain areas
Cortex
Thalamus
Hypothalamus PVN Paraventricular nucleus MPOA
Medial preoptic area
Midbrain PAG Periaqueductal Grey
Sensory inputs from genital areas
Pons nPGi nucleus paragigantocellularis
Excitatory inhibitory control
Giuliano Clement (2006) Eur Urol 50(3)454466
29
Neurotransmitters Involved in Control of
Ejaculation

• The following neurotransmitters areinvolved in
  the processing of emission and ejaculation
• Serotonin (5-HT)
• Dopamine (DA)
• Gamma-aminobutyric acid (GABA)
• Noradrenaline
• Serotonin is considered tobe the key inhibitory
  neurotransmitter involved in the processing of
  ejaculation
• There are multiple serotonin receptors in the
  hypothalamus, brainstem and the spinal cord

McMahon 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
30
Selective Serotonin Reuptake Inhibitors (SRRIs)
Increase Serotonin Levels In The Synaptic Cleft

• Synaptic cleft 5-HT is regulated by a transporter
  re-uptake system (5-HTT) and several
  autoreceptors
• As serotonin is released, the transporter system
  is activated, removing serotonin from the
  synaptic cleft and preventing over-stimulation
  of postsynaptic serotonin receptors
• SSRIs inhibit the serotonin transporter system,
  increasing levels of serotonin in the synaptic
  cleft

Axon
Axonal Terminal
5-HTT
5-HTT
5-HTT
5-HTT
5-HT
5-HT
5-HT
Synaptic Cleft
Post-Synaptic Neuron

• 5-HT serotonin, 5-HTT serotonin transporter
  system
• Giuliano (2007) Trends Neurosci. 30(2)7984
• Adapted from McMahon et al (2004) Disorders of
  orgasm and ejaculation in men. In Sexual
  Medicine Sexual dysfunctions in men and women.
  2nd International Consultation on Sexual
  Dysfunctions, Paris

31
Epidemiology Poorly Understood
32
Prevalence of PE is Consistent Across Countries
Age Groups

1. PEPA Premature ejaculation perceptions and
   attitudes. Porst et al. (2007) Eur Urol
   51816824

33
Prevalence of PE is higher than ED and consistent
across age groups lt60 60 years
National Health and Social Life Survey analysis
PE defined as climaxing too earlyED defined as
trouble achieving or maintaining erection

1. Laumann et al. (1999) JAMA 281537-544

34
Normative IELT Data
Unselected normal population of 500
heterosexual couple Netherlands, United Kingdom,
Turkey and Spain Stopwatch timing of the
intravaginal ejaculatory latency time (IELT)

• Median stopwatch IELT of 5.4 minutes (range, 0.55
  - 44.1 min.)
• IELT is distributed in a positively skewed
  pattern
• Using an epidemiological approach to assess PE
  risk, men with an IELT lt 1 min. have "definite"
  PE, while men with IELTs 1-1.5 min have
  "probable" PE.

1. Waldinger et al. (2005) J Sex Med 2492497

35
PE Subtypes

• The population of men with PE is not homogenous
  1
• Lifelong (primary)
• IELT is likely to be a genetically influenced
  biological variable suggesting that lifelong PE
  has a genetic basis
• Genetic polymorphism of the 5-TTLPR gene
  determines the regulation of the IELT
• Acquired (secondary)
• Sufferers develop early ejaculation at some point
  in their life having previously had normal
  ejaculation experiences 1
• Heterogenous PE population which is most often
  associated with sexual performance anxiety and
  ED, and rarely with chronic prostatitis,
  hyperthyroidism or may be idiopathic 2-5

1. Schapiro, B., J Urol, 1943. 50 p. 374- 379
2. Screponi, E., Carosa, E., et al., Urology,
   2001. 58(2) p. 198-202.
3. Carani, C., Isidori, A.M., et al., J Clin
   Endocrinol Metab, 2005. 90(12) p. 6472-6479
4. Laumann, E.O., Nicolosi, A., et al., Int J
   Impot Res, 2005. 17(1) p. 39-57
5. Hartmann, U., Schedlowski, M., et al., World J
   Urol, 2005. 10 p. 10.

36
Lifelong PE

• Lifelong male sexual dysfunction characterized by
  1
• ejaculation always/nearly always within about one
  minute of penetration, and
• inability to delay ejaculation,and
• negative personal consequences, such as distress,
  bother, frustration and/or the avoidance of sex

1. McMahon, CG, Althof, SE, Waldinger, MD et al. J
   Sex Med 2008 5(7)1590-1606

37
PE and Co-Morbid ED

• Recent data suggests that as many as half of men
  with ED also experience PE 1,2
• Bi-directional relationship
• Men with ED may require more stimulation to
  achieve erection or may rush sexual intercourse
  to prevent early loss of erection and ejaculate
  rapidly
• Men with PE may limit their arousal to prevent PE
  and lose their erection
• Compounded by high levels of performance anxiety

1. Corona, G., L. Petrone, et al. (2004). Eur Urol
   46(5) 615-22.
2. Laumann, E. O., A. Nicolosi, et al. (2005). Int J
   Impot Res 17(1) 39-57.

38
PE Medical Treatment Strategies

• Psychotherapy/Behavioural Therapy
• Pharmacotherapy
• Daily Dosing
• Off-label anti-depressant SSRI drugs and
  clomipramine
• Off-label alpha-adrenoreceptor antagonists
• On-demand Dosing
• Dapoxetine (ESSTI)
• Off-label anti-depressant SSRI drugs and
  clomipramine
• Off-label Tramadol
• Topical anesthetic sprays or gels
• Off-label PDE-5 inhibitors

39
Psycho-Behavioural Treatment of PE

• Based on assumption that PE is due to a failure
  to pay sufficient attention to pre-orgasmic
  levels of sexual tension
• Stop-start manoeuvre 1, squeeze technique 2
• Treatment success of CBT is relatively good in
  the short term as most men with PE are aware of
  their anxiety and the sources of that anxiety
  tend to be relatively superficial, but
• Convincing long-term treatment outcome data are
  lacking 1-3
• Integrated SSRI pharmacotherapy CBT may achieve
  superior treatment outcomes and reduce relapse in
  many patients

1. Semans JH. Premature ejaculation a new approach.
   South Med J 1956 49(4)353-8.
2. Masters WH, Johnson VE. Human Sexual Inadequacy.
   1970 Boston Little Brown.p 92-115
3. de Carufel F, Trudel G. J Sex Marital Ther 2006
   32(2)97-114
4. De Amicis LA, Goldberg DC et al. Arch Sex Behav
   1985 14(6)467-89.
5. Hawton K, Catalan J et al. Behav Res Ther 1986
   24(6)665-75

40
Pharmacological Treatment

• Over the past 20-30 years, the PE treatment
  paradigm has expanded to include drug treatment
• Level 1A evidence to support the efficacy
  safety of off-label SSRIs 1
• Paroxetine, sertraline, citalopram, fluoxetine
• Serotonergic tricyclic, clomipramine
• Meta-analysis of all drug treatment studies has
  demonstrated that paroxetine exerts the strongest
  ejaculation delay (mean IELT fold increase of
  8.8) 1,2

1. ICSD Paris 2009 2. Waldinger, M. Int J Imp
Res 1-13, 2004
41
Daily SSRI Treatment

• Usually well tolerated
• Adverse effects of SSRIs ...
• Fatigue, yawning, mild nausea, loose stools or
  perspiration
• Start in the first week after intake
• Attenuate within 2-3 weeks
• Occasionally hypoactive sexual desire and mild ED
  
• Occasional agitation - avoid in men with history
  of bipolar depression
• Suspend gradually over 3-4 weeks to avoid
  withdrawal symptoms

42
On-Demand SSRI Treatment

• Several published studies of on-demand off-label
  anti-depressant SSRI treatment using
  clomipramine, paroxetine and sertraline 4-6 hours
  before coitus 1,2,3
• Dapoxetine (Priligy)4

1. McMahon CG, Touma K. J Urol 1999 161(6)1826-30.
   
2. Strassberg DS, de Gouveia Brazao CA, et al. J Sex
   Marital Ther 1999 25(2)89-101.
3. Kim SW, Paick JS. Urology 1999 54(3)544-7
4. Pryor JL, Althof SE, Steidle C et al. Lancet
   2006 368(9539)929-37

43
Dapoxetine

• Dapoxetine is the first compound specifically
  developed for the treatment of PE
• Approved in several EU countries, Mexico, Korea,
  New Zealand with anticipated approval in other
  countries
• Level 1A evidence to support the efficacy and
  safety of on-demand dosing of dapoxetine 1

1. ICSD Paris 2009
44
Dapoxetine Pharmacokinetics

• Dapoxetine undergoes rapid absorption (Tmax of
  1.0 hours), rapidly achieves peak plasma
  concentration (Cmax) and has a mean half-life
  after a single dose is 1.3 hours
• Minimal accumulation with plasma concentration
  rapidly declining to about 5 of Cmax at 24
  hours.
• Dose-dependent pharmacokinetics with plasma
  concentrations and area under the curve (AUC)
  which are unaffected by multiple dosing

45
Dapoxetine First Dose Effect on IELT
Pooled data (baseline Week 12) and 3001 data
(Week 24) plt0.001 vs placebo ANCOVA


Week 12 (012, 013, 3001, 3003) or Week 24 (3001)
or last observation carried forward

• McMahon et al. (2008) Presented at ESSM/ISSM
  Data on file
• Buvat et al. (2009) Eur Urology DOI
  10.1016/j.eururo.2009.01.025

46
Dapoxetine IELT for 1min 0.5min
Pooled IELT values at endpoint for baseline IELT
1min 0.5min
IELTImin
IELT0.5min
McMahon et al. (2008) Presented at ESSM/ISSM
47
Perceived Control Over Ejaculation
Over the past month, was your control over
ejaculation during sexual intercourse very
poor, poor, fair, good, very good
McMahon et al. (2008) Presented at ESSM/ISSM
48
Ejaculation-related Personal Distress
Over the past month, how distressed were you by
how fast you ejaculated during sexual
intercourse? (extremely, quite a bit,
moderately, a little bit, not at all)
McMahon et al. (2008) Presented at ESSM/ISSM
48
49
Safety
AE, n () Placebo (n 1,857) Dapoxetine 30 mg prn (n 1,616) Dapoxetine 60 mg prn (n 2,106)
Nausea 41 (2.2) 178 (11.0) 467 (22.2)
Dizziness 40 (2.2) 94 (5.8) 230 (10.9)
Headache 89 (4.8) 91 (5.6) 185 (8.8)
Diarrhea 32 (1.7) 56 (3.5) 145 (6.9)
Somnolence 10 (0.5) 50 (3.1) 98 (4.7)
Fatigue 23 (1.2) 32 (2.0) 86 (4.1)
Insomnia 28 (1.5) 34 (2.1) 83 (3.9)
Nasopharyngitis 43 (2.3) 51 (3.2) 61 (2.9)
50
Antidepressant SSRIs May Be Associated with
Suicidal Ideation Withdrawal Syndrome

• Evidence of increased risk of suicidal ideation
  and self harm in subjects receiving
  antidepressant SSRIs
• Compared to placebo 1,2
• Compared to other antidepressants (in the
  elderly) 3
• Abrupt interruption of antidepressant SSRI
  therapy for 58 days may be associated with the
  emergence of a withdrawal syndrome 4, including
  
• dizziness, insomnia, nervousness, nausea
  agitation

1. Gunnell et al. (2005) BMJ 330385
2. Fergusson et al. (2005) BMJ 330396l
3. Juurlink et al. (2006) Am J Psychiatry 16381321
4. Rosenbaum et al. (1998) Biol Psychiatry 4477-87

51
Phase III Safety Study to Assess Withdrawal,
Mood Neurocognitive Effects
DPX on demand
Dapoxetine 60 mg on demand
Placebo
DPX daily
Dapoxetine 60 mg daily
Placebo
Placebo
Placebo
1-week baseline
9-week treatment phase
2-week follow-up phase
1-week withdrawal phase
Screen
Randomisation 1
Randomisation 2
Telephone contact
Follow-up visit

• Safety Measures
• Sexual functioning (IIEF)
• Depression (BDI/MADRS)
• Suicidality (BDI/MADRS)
• Anxiety (HAM-A)
• Akathisia (BARS)
• Withdrawal (DESS)

Baseline Assessments
In-clinic Withdrawal Assessments
Post-study follow-up
Study code R096769-PRE-3002 (3002)
Levine et al. (2007) Presented at SMSNA
52
No Withdrawal Syndrome with Dapoxetine

• The incidence of Withdrawal Syndrome did not
  differ between the dapoxetine daily/placebo and
  dapoxetine daily/daily groups
• Dapoxetine was not associated with suicidal
  ideation, anxiety or akathisia and had little
  effect on mood or affect

1. Levine et al. Poster presented at SMSNA 2006.
2. Rosen et al. Poster presented at SMSNA 2006

53
Intracavernous Pharmacotherapy

• Advocated by entrepreneurial clinics
• No evidence-based supportive data
• One case series study of 8 men with poor study
  methodology 1
• Success of treatment was defined by prolongation
  of erection after ejaculation and not by actual
  delay in ejaculation
• No evidence to support the efficacy and safety of
  ICI in the treatment of PE in men with normal
  erectile function 2

1. Fein RL. Urology 1990 35 301-303
2. ICSD Paris 2009

54
Treatment of PE with PDE-5 Inhibitors

• Multiple reports of the use of PDE5i as
  monotherapy or in combination with daily or
  on-demand SSRIs as treatment for PE
• Potential Mechanisms
• Reduced central sympathetic output 1-4
• Peripheral inhibition of contractile response of
  vas deferens, seminal vesicles, prostate and
  urethra 5-8
• Improved erectile function and reduced
  performance anxiety in men with mild ED
• PDE-5 inhibitors may re-set the erectile
  threshold to a lower level of arousal

Pfaus JG. Curr Opin Neurobiol 19999751-758 Pu S et al. Brain Res 1998808310-312 Sato Y et al. Am J Physiol Regul Integr Comp Physiol 2001281R269-278 Kreigsfield LJ. Physiol Behav 199967561-566 Naseem KM et al. Eur J Pharmacol 2000387329-335 Schultz KD et al. Nature 1977265750-751 Hull EM et al. Neuropharmacology 1994331409-1504 Bialy M et al. Physiol Behav 199660139-143
55
Systematic Review of PDE5i in PE

• Systematic review of 14 reported studies (n1102)
  on PDE5i treatment derived from MEDLINE and
  meeting proceedings
• Manuscripts/abstracts were compared and graded
  according to their compliance with the
  contemporary consensus of ideal PE drug clinical
  trial design
• Only 3/14 were RCTs - most were poorly designed,
  open label studies with subjective endpoints
• No evidence for PDE-5i efficacy in lifelong PE
  with normal EF

1. McMahon CG et al, BJU Int 2006 98 259-272
56
PE and Co-Morbid ED

• There is some evidence to suggest that PDE5is
  alone or in combination with SSRIs may have a
  role in the management of acquired PE in men with
  co-morbid ED

57
(No Transcript)
58
Take Home Messages

1. PE is a common sexual disorder and imposes a
   substantial psychological burden upon both
   sufferers and partners
2. Dapoxetine is an effective, safe and well
   tolerated treatment for PE and is likely to
   fulfill the treatment goals of many patients
3. Off-label anti-depressant SSRIs are effective
   treatments for PE
4. Integrated pharmacotherapy and CBT may achieve
   superior treatment outcomes in some patients
5. PDE-5 inhibitors alone or in combination with
   SSRIs or topical anaesthetics should be limited
   to men with acquired PE secondary to co-morbid ED
   
6. Tramadol, a1-adrenoceptor antagonists and penile
   injection therapy are not recommended for the
   treatment of PE

59
Thank You