Hardness, function, emotional well-being, satisfaction and the overall sexual experience in men using 100-mg fixed-dose or flexible-dose sildenafil citrate

ABSTRACT The prescribing information for sildenafil citrate (VIAGRA, Pfizer, New York, NY, USA) recommends flexible dosing (50 mg initially, adjusted to 100 or 25 mg based on effectiveness

and tolerability) in most men with erectile dysfunction (ED). In many men, however, 100 mg may be the most appropriate initial dose because it would reduce the need for titration and could

prevent discouragement and treatment abandonment should 50 mg be insufficient. Results of two previously published double-blind, placebo-controlled sildenafil trials of similar design except

for a fixed-dose vs flexible-dose regimen were analyzed. Relative to the flexible-dose, approximately one-third more men were satisfied with an initial and fixed dose of 100 mg. In

addition, tolerability was similar, and improvements from baseline in outcomes on validated, ED-specific, patient-reported questionnaires were either similar (erectile function and the

percentage of completely hard and fully rigid erections) or greater (emotional well-being and the overall sexual experience). The similarity in outcomes is not surprising given that almost

90% of the men in the flexible-dose trial titrated to 100 mg after 2 weeks. These data suggest prescription of an initial dose of 100 mg for men with ED, except in those for whom it is

inappropriate. SIMILAR CONTENT BEING VIEWED BY OTHERS EFFECTIVENESS AND PATIENT SATISFACTION WITH THE NEW SILDENAFIL ORAL SUSPENSION FORMULATION COMPARED TO SILDENAFIL ORO-DISPERSIBLE FILM:

A REAL-LIFE STUDY Article 29 January 2025 BEDTIME SILDENAFIL ORAL SUSPENSION IMPROVES SEXUAL SPONTANEITY AND TIME-CONCERNS COMPARED TO ON-DEMAND TREATMENT IN MEN WITH ERECTILE DYSFUNCTION:

RESULTS FROM A REAL-LIFE, CROSS-SECTIONAL STUDY Article 24 February 2025 MIRABEGRON IMPROVES ERECTILE FUNCTION IN MEN WITH OVERACTIVE BLADDER AND ERECTILE DYSFUNCTION: A 12-WEEK PILOT STUDY

Article 02 July 2021 INTRODUCTION For most men with erectile dysfunction (ED), the prescribing information for sildenafil citrate (VIAGRA, Pfizer) recommends an initial dose of 50 mg,

increased to 100 mg or decreased to 25 mg based on effectiveness and tolerability (flexible dose).1 However, 100 mg sildenafil produced optimal erection hardness (fully hard and rigid) in a

substantial proportion of men with ED.2 In addition, in dose-optimization studies3, 4 and at the end of double-blind, placebo-controlled (DBPC) treatment in recent reports of flexible-dose

trials,5, 6 100 mg was the dose that was used by most men. Thus, the 100-mg dose may provide some additional benefit beyond that achieved with the 50-mg dose and may be the most appropriate

choice for initiation of therapy in many men. This report assesses erection hardness, erectile function, emotional well-being, satisfaction (disease related and treatment related) and the

overall sexual experience in men treated with 100 mg fixed-dose sildenafil and in men treated with flexible-dose sildenafil (50 and 100 mg), using data from two DBPC trials that were

similarly designed except for a fixed-dose vs flexible-dose regimen.7, 8 The objective was to assess the efficacy and tolerability of an initial dose of sildenafil 100 mg relative to the

flexible-dosage regimen recommended in the prescribing information. MATERIALS AND METHODS One trial was a multinational (Republic of Korea, Russian Federation, Spain and Sweden),

parallel-group, randomized (1:1:1) DBPC trial of fixed-dose sildenafil (50 or 100 mg) or placebo administered on demand over an 8-week treatment period.7 The other trial was a multicenter

(United States), parallel-group, randomized (1:1) DBPC trial of flexible-dose sildenafil (50 or 100 mg) administered on demand over a 10-week treatment period.8 In both trials, ⩽1 dose of

study medication was to be taken per day. Details of the patients and methods of the two trials have been published previously.7, 8 As described previously,7, 8 several efficacy assessments

were conducted, including the Erection Hardness Score (EHS9), the International Index of Erectile Function (IIEF),10 the Self-Esteem And Relationship (SEAR) questionnaire,11, 12, 13 the

Sexual Experience Questionnaire (SEX-Q),14 the Quality of Erection Questionnaire,15 the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS)16 and three global efficacy

assessment questions. Except for the global efficacy assessment questions, all assessment tools are validated, and a higher score indicates better outcome. Safety data included all adverse

events (AE) reports from the original trials. In this study, analyses were conducted on data from the intent-to-treat population for each study, which was defined as men who took at least

one dose of study medication and who provided sufficient efficacy data for at least one efficacy analysis. Treatment effects were estimated using least square means from an analysis of

covariance model for change scores from baseline to DBPC end of treatment on the IIEF, SEAR and SEX-Q, and the end-of-treatment EDITS Index score. The model used terms of baseline value,

treatment group, investigator site and prognostic factors (age, ED duration, ED etiology) with _P_ values calculated at the 5% significance level for the test of treatment group differences.

Logistic regression (terms of treatment group, age, ED duration and ED etiology) was used to analyze the proportion of men who were satisfied with treatment (dichotomized EDITS score). The

percentages of EHS 3, EHS 4 and EHS 3 or 4 erections based on all of the event log data since the previous visit were analyzed as clustered binomial data using a logistic regression (terms

for baseline percentage, treatment group, age, ED duration and ED etiology), with a scale adjustment for overdispersion (estimated by Williams method) and model; treatment effects were

estimated using predicted percentages from the model. Pearson correlations were computed between the SEX-Q change from baseline scores and all other outcomes (change from baseline or end of

treatment); 95% confidence intervals for the correlation coefficient were constructed using Fisher's _Z_-transformation. RESULTS POPULATION AND EXPOSURE In both trials, each treatment

group comprised ∼100 men, most of whom had ED that was of organic or mixed etiology and that was mild to moderate in severity (Table 1). At week 2, 88% (92/104) of patients randomized to

flexible-dose sildenafil and 92% (97/105) randomized to flexible-dose placebo increased their dose from 50 mg to 100 mg; at the end of the DBPC treatment, 87% (90/104) and 92% (97/105),

respectively, remained on the higher dose. During the DBPC phase of each trial, patients in each treatment group received an average of seven or eight doses per month. Across both trials,

only one man discontinued sildenafil (flexible dose) because of lack of efficacy and only two men discontinued sildenafil because of treatment-related AEs: moderate dyspepsia (100-mg fixed

dose) and moderate headache (100-mg flexible dose). EFFICACY Sildenafil, whether initiated at a fixed dose of 50 or 100 mg, or initiated at a dose of 50 mg and titrated as needed up to 100 

mg, was significantly more effective than placebo (Table 2). The 100-mg fixed dose was significantly more effective than the 50-mg fixed dose in improving the IIEF Overall Satisfaction

domain score; the SEAR Sexual Relationship Satisfaction domain, Overall Relationship Satisfaction subscale and Total scores; all SEX-Q domain scores; and the SEX-Q total score (Table 2). In

addition, the EDITS Index was significantly higher in the fixed-dose sildenafil 100-mg group vs the fixed-dose sildenafil 50-mg group, although the difference between the dosage groups in

the estimated percentage of men who were satisfied with sildenafil treatment (dichotomized EDITS scores: 93 vs 88%) was not statistically significant (Table 2). For the fixed-dose sildenafil

100-mg group relative to the flexible-dose sildenafil group (Table 2), there was a similar improvement from baseline in the percentage of EHS 4 erections (33 and 35%, respectively), EHS 3

or 4 erections (36 and 35%, respectively) and IIEF scores (⩽1 point difference between the groups across IIEF domains). However, for the fixed-dose sildenafil 100-mg group relative to the

flexible-dose sildenafil group there was a greater improvement from baseline in SEAR scores (8–16 point difference between the groups across SEAR components) and in SEX-Q scores (3–7 point

difference between the groups across SEX-Q domains), a greater least square mean±s.e. EDITS Index (78.4±2.0 and 66.5±3.3, respectively), and a larger estimated percentage of men who were

satisfied with sildenafil treatment (dichotomized EDITS scores: 93 vs 69%). The SEX-Q total score, which assesses the sexual experience overall in the domains of erection, individual

satisfaction and couples satisfaction, correlated positively with all other outcomes in both trials (Table 3). SAFETY In both trials, most AEs were mild or moderate in severity. The most

frequently reported AEs were flushing, dyspepsia, headache and nasal congestion in the fixed-dose trial, which occurred at similar frequencies in the sildenafil 50-mg and 100-mg groups, and

flushing, headache, nasal congestion and dizziness in the flexible-dose trial (Table 4). No treatment-related serious or severe AEs were reported in the sildenafil arms. DISCUSSION As

reported previously, sildenafil, whether initiated at a fixed dose of 50 or 100 mg,7 or at a dose of 50 mg and titrated as needed up to 100 mg,8 was significantly more effective than placebo

in the treatment of ED, and there were additional benefits to the use of 100 mg fixed-dose sildenafil compared with 50 mg fixed-dose sildenafil.8 Although definitive statements about the

comparative efficacy of 100-mg fixed-dose sildenafil and the flexible-dose sildenafil regimen are limited by the fact that the regimens were not compared within a controlled trial and the

protocols of the two trials collated herein were not identical, the results of the current collated report suggest that an initial dose of sildenafil 100 mg is at least as effective and well

tolerated as an initial dose of 50 mg with the option to titrate as needed. Definitive statements about the comparative tolerability of 100-mg fixed-dose sildenafil and the flexible-dose

sildenafil regimen are also limited by the collated nature of the data presented in this report, although the low rate of discontinuation because of treatment-related AEs suggests that both

regimens are generally well tolerated. The results of the current report are generalizable to the population of men with ED. For the 100-mg fixed-dose regimen relative to the flexible-dose

regimen, there was a similar increase from baseline in the percentage of EHS 4 erections and EHS 3 or 4 erections, a similar improvement from baseline in IIEF scores, a greater improvement

from baseline in SEAR scores and SEX-Q scores, and a higher EDITS Index; approximately one-third more men in the 100-mg fixed-dose vs the flexible-dose regimen were satisfied with their

sildenafil treatment. The similarity in outcomes between the two regimens is not surprising given that almost 90% of the men who initiated treatment with flexible-dose sildenafil titrated to

a dose of 100 mg after 2 weeks. The apparent difference in outcomes on the SEAR, SEX-Q and EDITS between the two regimens may represent cultural differences between the European and Asian

population treated with 100 mg fixed-dose sildenafil and the US (mainly white) population treated with flexible-dose sildenafil. The SEAR, SEX-Q and EDITS assess health-related

quality-of-life concepts, which are likely to be more susceptible to cultural differences than are more functional concepts, such as those assessed by the EHS and IIEF. Cultural differences

on SEAR responses were published previously.13, 17 Given that almost 90% of the men who initiated treatment with flexible-dose sildenafil titrated to a dose of 100 mg after 2 weeks,

initiating treatment with 100-mg sildenafil should greatly decrease the need for dose titration and, in those men for whom a dose of 50 mg might prove ineffective, may decrease the risk of

discouragement and treatment abandonment because of inadequate dosing. The high proportion of men titrating to a dose of 100 mg supports earlier results, which showed that 100-mg sildenafil

produced optimal erection hardness (fully hard and rigid) in a substantial proportion of men with ED2 and that 100 mg was the dose used by most men in dose-optimization studies.3, 4, 6

Several studies reported that titration to the highest well-tolerated approved dose and/or early dose optimization contributed to treatment success.6 Treatment optimization, which includes

selecting the most appropriate dose, ‘…may promote treatment adherence and thus facilitate optimal patient outcomes.’6 Some patients who are prescribed sildenafil for ED in the clinical

practice setting neither refill their initial prescription nor seek alternative therapies.18, 19 For example, an analysis of sildenafil use during the first 24 weeks of availability at a

large health maintenance organization revealed that only 61% of patients filled a second sildenafil prescription within 3 months of their first prescription.20 In addition, in a large

dose-optimization study in which sildenafil was initiated at a dose of 50 mg for 4 weeks according to the package instructions, 14% (153/1109) failed to return for the second visit for

scheduled dosage optimization.6 In several studies, incorrect administration, including suboptimal dosing, was the most frequent cause of nonresponse to sildenafil.6 An initial dose of

sildenafil 100 mg may not be appropriate in some men. For example, higher plasma concentrations of sildenafil than those seen in healthy young volunteers occurred in men aged >65 years,

in those who have hepatic impairment (for example, cirrhosis) or severe renal impairment (for example, creatinine clearance <30 ml min−1), and in those using concomitant potent cytochrome

P450 3A4 inhibitors (for example, ketoconazole, itraconazole, erythromycin, saquinavir).1, 21, 22, 23 Because ritonavir greatly increased the systemic level of sildenafil in a study of

healthy volunteers not infected with the human immunodeficiency virus, it is recommended not to exceed a maximum single dose of 25 mg of sildenafil in a 48-h period.1, 23 In addition, men

with left ventricular outflow obstruction (for example, aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can

be particularly sensitive to the actions of vasodilators, including sildenafil.1 When sildenafil is coadministered with an α-blocker, patients should be stable on α-blocker therapy before

initiating sildenafil treatment, and sildenafil should be initiated at the lowest dose.1, 24 In conclusion, sildenafil in doses of 50 and 100 mg is effective for the treatment of ED, and

both doses are generally well tolerated. An initial dose of sildenafil 100 mg appears to be at least as efficacious and well tolerated as an initial dose of 50 mg with the option to titrate

to the optimal dose. Furthermore, an initial dose of 100 mg may reduce the need for dose titration and may prevent discouragement and treatment abandonment in men for whom a dose of 50 mg is

insufficient. This suggests prescription of an initial dose of 100 mg, except in those for whom it is inappropriate. REFERENCES * VIAGRA. _Full Prescribing Information, Sildenafil Citrate_.

Pfizer, Inc.: New York, NY, 2008. * King R, Juenemann KP, Levinson IP, Stecher VJ, Creanga DL . Correlations between increased erection hardness and improvements in emotional well-being and

satisfaction outcomes in men treated with sildenafil citrate for erectile dysfunction. _Int J Impot Res_ 2007; 19: 398–406. Article  CAS  Google Scholar  * Steidle C, McCullough A,

Kaminetsky J, Crowley A, Siegel R, Deriesthal H _et al_. Early sildenafil dose optimization and personalized instruction improves the frequency, flexibility, and success of sexual

intercourse in men with erectile dysfunction. _Int J Impot Res_ 2007; 19: 154–160. Article  CAS  Google Scholar  * Jiann BP, Yu CC, Su CC, Huang JK . Rechallenge prior sildenafil

nonresponders. _Int J Impot Res_ 2004; 16: 64–68. Article  CAS  Google Scholar  * Lowy M, Collins S, Bloch MT, Gillman M, Lording DW, Sutherland P _et al_. Quality of erection questionnaire

correlates: change in erection quality with erectile function, hardness, and psychosocial measures in men treated with sildenafil for erectile dysfunction. _J Sex Med_ 2007; 4: 83–92.

Article  CAS  Google Scholar  * McCullough AR, Carson C, Hatzichristou D . A prospective study of the beneficial effects of dose optimization and customized instructions on patient

satisfaction with sildenafil citrate (VIAGRA) for erectile dysfunction. _Urology_ 2006; 68: 38–46. Article  Google Scholar  * Loran OB, Stroberg P, Lee SW, Park NC, Kim SW, Tseng LJ _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: 2826–2835. Article  CAS  Google Scholar  * Jones LA, Klimberg IW, McMurray JG, Padula R, Tseng L-J, Stecher VJ _et al_.

Effect of sildenafil citrate on the male sexual experience assessed with the Sexual Experience Questionnaire; a multicenter, double-blind, placebo-controlled trial with open-label extension.

_J Sex Med_ 2008; 5: 1955–1964. Article  CAS  Google Scholar  * Mulhall JP, Goldstein I, Bushmakin AG, Cappelleri JC, Hvidsten K . Validation of the Erection Hardness Score (EHS). _J Sex

Med_ 2007; 4: 1626–1634. Article  Google Scholar  * Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A . The International Index of Erectile Function (IIEF): a

multidimensional scale for assessment of erectile dysfunction. _Urology_ 1997; 49: 822–830. Article  CAS  Google Scholar  * Cappelleri JC, Althof SE, Siegel RL, Shpilsky A, Bell SS,

Duttagupta S . Development and validation of the Self-Esteem And Relationship (SEAR) questionnaire in erectile dysfunction. _Int J Impot Res_ 2004; 16: 30–38. Article  CAS  Google Scholar  *

Cappelleri JC, Bell SS, Althof SE, Siegel RS, Stecher VJ . Comparison between sildenafil-treated subjects with erectile dysfunction and control subjects on the Self-Esteem And Relationship

Questionnaire. _J Sex Med_ 2006; 3: 274–282. Article  CAS  Google Scholar  * Althof SE, O'Leary MP, Cappelleri JC, Hvidsten K, Stecher VJ, Glina S _et al_. Sildenafil citrate improves

self-esteem, confidence, and relationships in men with erectile dysfunction: results from an international, multi-center, double-blind, placebo-controlled trial. _J Sex Med_ 2006; 3:

521–529. Article  CAS  Google Scholar  * Mulhall JP, King R, Kirby M, Hvidsten K, Symonds T, Bushmakin AG _et al_. Evaluating the sexual experience in men: validation of the Sexual

Experience Questionnaire. _J Sex Med_ 2008; 5: 365–376. Article  Google Scholar  * Porst H, Gilbert C, Collins S, Huang X, Symonds T, Stecher V _et al_. Development and validation of the

Quality of Erection Questionnaire. _J Sex Med_ 2007; 4: 372–381. Article  Google Scholar  * Althof SE, Corty EW, Levine SB, Levine F, Burnett AL, McVary K _et al_. EDITS: development of

questionnaires for evaluating satisfaction with treatments for erectile dysfunction. _Urology_ 1999; 53: 793–799. Article  CAS  Google Scholar  * O'Leary MP, Althof SE, Cappelleri JC,

Crowley A, Sherman N, Duttagupta S . Self-esteem, confidence and relationship satisfaction of men with erectile dysfunction treated with sildenafil citrate: a multicenter, randomized,

parallel group, double-blind, placebo controlled study in the United States. _J Urol_ 2006; 175: 1058–1062. Article  Google Scholar  * Jiann BP, Yu CC, Tsai JY, Wu TT, Lee YH, Huang JK .

What to learn about sildenafil in the treatment of erectile dysfunction from 3-year clinical experience. _Int J Impot Res_ 2003; 15: 412–417. Article  Google Scholar  * McCullough AR, Barada

JH, Fawzy A, Guay AT, Hatzichristou D . Achieving treatment optimization with sildenafil citrate (Viagra) in patients with erectile dysfunction. _Urology_ 2002; 60: 28–38. Article  Google

Scholar  * Harrold LR, Gurwitz JH, Field TS, Andrade SE, Fish LS, Jarry PD _et al_. The diffusion of a novel therapy into clinical practice: the case of sildenafil. _Arch Intern Med_ 2000;

160: 3401–3405. Article  CAS  Google Scholar  * Muirhead GJ, Wilner K, Colburn W, Haug-Pihale G, Rouvieux B . The effects of age and renal and hepatic impairment on the pharmacokinetics of

sildenafil citrate. _Br J Clin Pharmacol_ 2002; 53: 21S–30S. Article  CAS  Google Scholar  * Muirhead GJ, Faulkner S, Harness JA, Taubel J . The effects of steady-state erythromycin and

azithromycin on the pharmacokinetics of sildenafil in healthy volunteers. _Br J Clin Pharmacol_ 2002; 53: 37S–43S. Article  CAS  Google Scholar  * Muirhead GJ, Wulff MB, Fielding A,

Kleinermans D, Buss N . Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. _Br J Clin Pharmacol_ 2000; 50: 99–107. Article  CAS  Google Scholar  * Kloner RA .

Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions. _Am J Cardiol_ 2005; 96: 42M–46M. Article  CAS  Google Scholar  Download

references ACKNOWLEDGEMENTS These studies were funded by Pfizer Inc. Editorial support was provided by Deborah M Campoli-Richards, BSPHA, RPh, at Complete Healthcare Communications, Inc and

was funded by Pfizer. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Urohålsan/ED-kliniken, Skövde Sweden P Ströberg * University Urology Associates, New York, NY, USA J C Kaminetsky *

Department of Urology, Pusan National University School of Medicine, Pusan, Korea N C Park * Hudson Valley Urology, PC, Poughkeepsie, NY, USA E R Goldfischer * Contractor to Pfizer Inc, New

York, NY, USA D L Creanga * Pfizer Inc, New York, NY, USA V J Stecher Authors * P Ströberg View author publications You can also search for this author inPubMed Google Scholar * J C

Kaminetsky View author publications You can also search for this author inPubMed Google Scholar * N C Park View author publications You can also search for this author inPubMed Google

Scholar * E R Goldfischer View author publications You can also search for this author inPubMed Google Scholar * D L Creanga View author publications You can also search for this author

inPubMed Google Scholar * V J Stecher View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to P Ströberg. ETHICS

DECLARATIONS COMPETING INTERESTS Peter Ströberg is a scientific study/trial investigator for Pfizer. Jed C. Kaminetsky is a consultant/advisor for Pfizer and Slate Pharmaceuticals; a meeting

participant/lecturer for Astellas, Auxilium, Boehringer Ingelheim, GlaxoSmithKline, Lilly, Pfizer, and Solvay; and a scientific study/trial investigator for Aeterna Zentaris, Astellas,

Auxilium, Indevas, Lilly, Pfizer, Plethora Solutions, and Spectrum. Nam Cheol Park has nothing to declare. Evan R. Goldfischer is a consultant/advisor for Astellas; a clinical trial

investigator for Amgen, Astellas, Bayer, GlaxoSmithKline, Indevus, Lilly, Johnson & Johnson, Merck, Novartis, Pfizer, Ortho McNeil, Sanofi, Schering-Plough, Schwartz, and Unimed; and a

lecturer for Astellas, Auxilium, Bayer, GlaxoSmithKline, Indevus, Lilly, and Pfizer. Dana L. Creanga was a paid consultant to Pfizer in connection with the statistical analyses performed in

this study. Vera J. Stecher is an employee of Pfizer. RIGHTS AND PERMISSIONS This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported

License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Ströberg, P., Kaminetsky, J.,

Park, N. _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_ 22, 284–289 (2010). https://doi.org/10.1038/ijir.2010.17 Download citation * Received: 22 January 2010 * Revised: 06 May 2010 * Accepted: 23 May 2010 * Published: 01 July 2010 * Issue

Date: July 2010 * DOI: https://doi.org/10.1038/ijir.2010.17 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a

shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * erectile dysfunction * quality of

life * sildenafil