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      Erectile Function, Erection Hardness and Tolerability in Men Treated With Sildenafil 100 mg vs. 50 mg for Erectile Dysfunction

      M. Kirby; D. L. Creanga; V. J. Stecher
      | Disclosures
      Int J Clin Pract. 2013;67(10):1034-1039. 
       
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      Abstract and Introduction

      Abstract

      Aim To compare efficacy and tolerability between 100-mg and 50-mg sildenafil doses in five double-blind, placebo-controlled (DBPC) fixed-dose studies.
      Methods The doses were compared for change (baseline to end 8v "12 weeks DBPC treatment) in the lead on the erectile function (EF) domain of the International Index of Erectile Function (IIEF, five fixed-dose studies,> 1500 men); approximate share of one patient in case that said erection hardness rating (EHS, two of the five fixed-dose studies,> 500) has been reached, is calculated from the logistic regression odds ratio (OR) achieve EHS3 (hard enough to penetrate, but not completely solid) and EHS4 (completely hard and fully rigid), and the incidence of adverse events by treatment (from the five fixed-dose studies).
      Results For the 100-mg vs. 50-mg dose, IIEF-EF score improvement was consistently greater across the five studies and was statistically significant when data from two studies with similar design were pooled (10.7 ± 0.64 vs. 8.9 ± 0.83, p = 0.0287); and during the first 2 weeks of treatment, the odds of achieving EHS4 erections were almost doubled in one study (OR = 1.77, p = 0.0398). Sildenafil was generally well tolerated at either dose.
      Conclusion Men with erectile dysfunction treated with 100-mg compared with 50-mg sildenafil may be more likely to achieve a greater improvement in erectile function and, within the first 2 weeks, completely hard and fully rigid erections, with little or no greater risk to tolerability.

      Introduction

      The effectiveness and safety of sildenafil citrate for treating erectile dysfunction (ED) have been well established in 136 manufacturer-sponsored clinical studies and in other independent studies. In most of the clinical trials, sildenafil was administered on demand as a flexible-dose regimen (starting dose of 50 mg and subsequent adjustment to 25 or 100 mg, depending on tolerability and efficacy).
      For most men with ED, 50 mg (the recommended starting dose of sildenafil) is effective and provides a clinically meaningful benefit.[1] However, the 100-mg dose may provide a superior clinical benefit. Evidence of a dose–response between sildenafil 50 and 100 mg was seen in early controlled clinical studies supporting regulatory approval.[1] More recently, a comparison of two double-blind, placebo-controlled (DBPC) studies of similar design, except for a flexible-dose vs. fixed-dose regimen, suggested that an initial dose of 100-mg sildenafil may be a better choice because it would reduce the need for titration and could prevent discouragement and treatment abandonment if 50 mg should be insufficient for optimal efficacy.[2]
      The tolerability and safety of sildenafil 50 and 100 mg in men with ED have been established using collated data from 67 DBPC studies (> 14,000 men) conducted by the manufacturer and from the manufacturer's postmarketing safety database (39,277 cases).[3] Sildenafil was well tolerated, overall, in those aged ≥ 65 years and in those aged ≥ 75 years, with no apparent causal link to cardiovascular events and no new safety risks relating to cardiovascular events, priapism, non-arteritic anterior ischaemic optic neuropathy, hearing loss or drug interactions.
      The objective of the current analyses was to compare efficacy and tolerability between treatment with 100-mg and 50-mg doses of sildenafil in a subset of five fixed-dose studies (> 1500 men).Continue Reading
       
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      Latest in Internal Medicine
      Int J Clin Pract. 2013;67(10):1034-1039. © 2013  Blackwell Publishing
      Table 1.  Change from baseline in erectile function
        IIEF-EF score LS mean ± SE change from baseline (baseline value)
      Study Placebo 50 mg 100 mg 100 mg vs. 50 mg, p-value
      Individual study data
         148–102 n = 189 1.9 ± 0.65 (11.8) n = 100 10.1 ± 0.80* (10.5) n = 96 11.3 ± 0.84* (11.2) 0.2400
         148–106 n = 109
      1.7 ± 0.76 (10.8)
      n = 116
      9.0 ± 0.75* (10.9)
      n = 112
      10.9 ± 0.77* (10.7)
      0.0648
         148–361 n = 57
      −0.1 ± 1.07 (10.3)
      n = 60
      8.6 ± 1.07* (12.8)
      n = 65
      10.2 ± 1.03* (10.5)
      0.2745
         148–364 n = 115
      0.1 ± 0.70 (11.8)
      n = 124
      8.0 ± 0.67* (12.9)
      n = 119
      9.2 ± 0.67* (12.4)
      0.1802
         A1481239 n = 90
      2.1 ± 0.66 (15.9)
      n = 93
      7.7 ± 0.65* (14.9)
      n = 98
      9.1 ± 0.64* (16.3)
      0.0822
      Pooled study data
         148–106 and 148–361 n = 166
      1.2 ± 0.64 (10.6)
      n = 176
      8.9 ± 0.63* (11.6)
      n = 177
      10.7 ± 0.64* (10.6)
      0.0287
      IIEF-EF, erectile function domain of the International Index of Erectile Function (score range, 6–30: 6–10 = severe ED, 11–16 = moderate ED, 17–21 = mild-to-moderate ED, 22–25 = mild ED and 26–30 = no ED); LS, least squares.
      *p < 0.0001 vs. placebo. †Change in score at week 12, except at week 8 for trial A1481239.
      Table 2.  Estimated per-patient percentage of occasions of sexual activity at which erections were hard enough for penetration
      Treatment week study (n: 100, 50 mg) Sildenafil 100 mg vs. sildenafil 50 mg, odds ratio†
      EHS3 EHS4 EHS3 or EHS4
      Week 2
         148–102 (71, 68) 1.69 0.74 1.09
         A1481239 (92, 85) 0.58* 1.77* 0.83
         148–102 + A1481239 (163, 153) 0.84 1.19 0.9
      Week 8
         148–102 (72, 74) 1.22 1.02 1.13
         A1481239 (95, 90) 0.81 1.56 1.27
         148–102 + A1481239 (167, 164) 0.93 1.29 1.17
      EHS, Erection Hardness Score (EHS3 = hard enough for penetration, but not completely hard; EHS4 = 4 (completely hard and fully rigid). *p < 0.05. †Estimated percentage of occasions computed from logistic regression, adjusting for model covariates: treatment group, baseline percentage, duration of ED, aetiology of ED and patient age.
      Table 3.  Overview of adverse events and discontinuations, and common adverse events by dose
      Adverse eventsa Placebo (n = 619) Sildenafil
      50 mg (n = 522) 100 mg (n = 523)
      AE, all-causality, n 426 670 882
      AE, n (%) of patients 273 (44.1) 310 (59.4) 354 (67.7)
         Severe 24 (3.9) 25 (4.8) 37 (7.1)
         Serious 14 (2.3) 12 (2.3) 10 (1.9)
         DC 13 (2.1) 6 (1.1) 13 (2.5)
         Dose reduction or temporary DC 9 (1.5) 13 (2.5) 12 (2.3)
      Common treatment-related AEs, n (%) of patients b
         Headache 21 (3.4) 75 (14.4) 109 (20.8)
         Flushing 8 (1.3) 85 (16.3) 75 (14.3)
         Dyspepsia 3 (0.5) 22 (4.2) 56 (10.7)
         Nasal congestion 0 11 (2.1) 18 (3.4)
         Dizziness 6 (1.0) 12 (2.3) 9 (1.7)
      Eye events, n (%) of patients
         Chromatopsia 0 2 (0.4) 10 (1.9)
         Cyanopsia 0 0 5 (1.0)
         Vision blurred 0 3 (0.6) 9 (1.7)
         Visual disturbance 1 (0.2) 1 (0.2) 29 (5.5)
      AE, adverse event; DC, discontinuation.
      *An event was categorised according to investigator judgment as severe if it interrupted daily activity and required systemic drug therapy or other medical treatment. A serious AE was defined as any untoward medical occurrence that resulted in death, was life threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, or resulted in a persistent or significant disability/incapacity or a congenital anomaly/birth defect. Listed are DCs, dose reductions and temporary DCs that were caused by an AE.
      †Events that occurred in ≥ 2% of men in ≥ 1 treatment group.

      References

      1. Goldstein I, Lue TF, Padma-Nathan H et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998; 338: 1397–404.
      2. Stroberg P, Kaminetsky JC, Park NC et al. Hardness, function, emotional well-being, satisfaction and the overall sexual experience in men using 100-mg fixed-dose or flexible-dose sildenafil citrate. Int J Impot Res 2010; 22: 284–9.
      3. Giuliano F, Jackson G, Montorsi F et al. Safety of sildenafil citrate: review of 67 double-blind placebo- controlled trials and the postmarketing safety database. Int J Clin Pract 2010; 64: 240–55.
      4. VIAGRA_. Summary of Product Characteristics, Sildenafil Citrate. Sandwich, Kent, UK: Pfizer Limited, 2013.
      5. Cappelleri JC, Rosen RC, Smith MD et al. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 1999; 54: 346–51.
      6. Mulhall JP, Goldstein I, Bushmakin AG et al. Validation of the Erection Hardness Score (EHS). J Sex Med 2007; 4: 1626–34.
      7. Claes H, Opsomer R-J, Andrianne RS et al. Characteristics and expectations of patients with erectile dysfunction: results of the SCORED study. Int J Impot Res 2008; 20: 418–24.
      8. Mulhall JP, Althof SE, Brock GB et al. Erectile dysfunction: monitoring response to treatment in clinical practice – recommendations of an international consensus panel. J Sex Med 2007; 4: 448–64.
      9. Cappelleri JC, Bushmakin AG, Symonds T, Schnetzler G. Scoring correspondence in outcomes related to erectile dysfunction treatment on a 4-point scale (SCORE-4). J Sex Med 2009; 6: 809–19.
      10. 10 Loran OB, Stroberg P, Lee SW et al. Sildenafil citrate 100 mg starting dose in men with erectile dysfunction in an international, double-blind, placebo- controlled study: effect on the sexual experience and reducing feelings of anxiety about the next intercourse attempt. J Sex Med 2009; 6: 2826– 35.
      11. 11 Buvat J, Hatzichristou D, Maggi M et al. Efficacy, tolerability, and satisfaction with sildenafil citrate 100-mg titration compared with continued 50-mg dose treatment in men with erectile dysfunction. BJU Int 2008; 102: 1645–50.
      12. 12 Mulhall JP, Creanga DL, Stecher VJ. Improvement in erection hardness and intercourse success with first dose of sildenafil citrate 100 mg. Int J Gen Med 2013; in Press.
      13. 13 Carson C, Siegel R, Orazem J. Sildenafil citrate treatment for erectile dysfunction: rate of adverse events decreases over time. J Urol 2002; 167 (Suppl.): 179.
      14. 14 Gresser U, Gleiter CH. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil – review of the literature. Eur J Med Res 2002; 7: 435–46.
      15. 15 Campbell HE. Clinical monograph for drug formulary review: erectile dysfunction agents. J Manag Care Pharm 2005; 11: 151–71.
      16. 16 Brock GB, McMahon CG, Chen KK et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol 2002; 168: 1332–6.
      17. 17 Hellstrom WJ, Gittelman M, Karlin G et al. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl 2002; 23: 763–71.
      18. 18 Hellstrom WJ, Gittelman M, Karlin G et al. Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo- controlled pivotal trial. Urology 2003; 61 (4 Suppl. 1): 8–14.

      Authors and Disclosures

      M. Kirby,1 D. L. Creanga,2 V. J. Stecher2

      1The Centre for Research in Primary and Community Care (CRIPACC), University of Hertfordshire, Hatfield, Herts UK,
      2Pfizer Inc, New York, NY, USA

      Disclosures
      M. Kirby has received funding from the pharmaceutical industry for research, conference attendance, lecturing and providing advice. No fees have been received in relation to this work. D. L. Creanga is a contractor to Pfizer Inc. V. J. Stecher is an employee and shareholder of Pfizer Inc.

      Correspondence to
      Dr Michael Kirby, The Prostate Centre, 32 Wimpole St, London, W1G 8GT, UK Tel.: + (0)20 7935 9720 Fax: + 01462896771 Email: kirbym@co.uk

      Sidebar

      What's Known

      • For most men with erectile dysfunction, 50-mg sildenafil (the recommended starting dose of sildenafil) is effective and provides a clinically meaningful benefit. However, 100-mg sildenafil may provide a superior clinical benefit.

      What's New

      • With little or no greater risk of drug tolerance, the initial 100 mg (as compared to the 50-mg) dose of sildenafil may be beneficial, except the people for whom it is inappropriate. The greater the likelihood of achieving completely hard and fully rigid erection during the first 2 weeks of treatment will reduce the need for titration, and can prevent pessimism and abandonment of treatment. Superior improvement in erectile function would increase the likelihood of achieving optimal efficiency.
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