Oral Sildenafil in the Treatment of Erectile Dysfunction

In a 24-week dose–response study, 532 men were treated with oral sildenafil (25, 50, or 100 mg) or placebo. In the dose–response study, increasing doses of sildenafil were associated with improved erectile function (P values for increases in scores for questions about achieving and maintaining erections were <0.001). Oral sildenafil is an effective, well-tolerated treatment for men with erectile dysfunction. Erectile dysfunction, the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance, is estimated to affect up to 30 million men in the United States.1 The disorder is age-associated,1–3 with estimated prevalence rates of 39 percent among men 40 years old and 67 percent among those 70 years old.2 The available treatments include vacuum-constriction devices; intracavernosal injections of vasoactive agents, including alprostadil (prostaglandin E1)4; transurethral delivery of alprostadil5; implantation of penile prostheses; and venous or arterial surgery. No effective oral therapy for erectile dysfunction is currently available.6 Normal penile erection depends on the relaxation of smooth muscles in the corpora cavernosa. In response to sexual stimuli, cavernous nerves and endothelial cells release nitric oxide, which stimulates the formation of cyclic guanosine monophosphate (GMP) by guanylate cyclase.7–9 The mechanism by which cyclic GMP stimulates relaxation of the smooth muscles remains to be elucidated. Sildenafil is a selective inhibitor of cyclic-GMP–specific phosphodiesterase type 5, the predominant isozyme metabolizing cyclic GMP in the corpus cavernosum.10 By selectively inhibiting cyclic-GMP catabolism in cavernosal smooth-muscle cells,11 sildenafil would be expected to restore the natural erectile response to sexual stimulation but not cause erections in the absence of such stimulation.

Renal Dose Adjustments

How should I store sildenafil?

Sildenafil is rapidly absorbed, with maximal plasma concentrations occurring within one hour after oral administration and a mean terminal half-life of three to five hours.10 In a placebo-controlled pilot study of 12 men, sildenafil significantly improved the erectile response during visual sexual stimulation.10,12 We therefore undertook two studies to evaluate in a home setting the efficacy and safety of sildenafil in men with erectile dysfunction. In two sequential studies, we studied a total of 861 men 18 years of age or older with a clinical diagnosis of erectile dysfunction (as defined previously1) of six months' duration or longer at 37 centers in the United States.

Each man had to be in a stable relationship with a female partner that had begun at least six months earlier.

Sildenafil Citrate 20 mg/mL, Oral Paste, 60mL Syringe

The cause of erectile dysfunction was determined from the medical history, physical examination, and other diagnostic procedures, including a test involving the intracavernosal injection of a vasoactive drug (done in 31 percent of the men), a RigiScan test of nocturnal penile tumescence (26 percent), penile duplex ultrasonography (21 percent), and endocrine testing (21 percent). On the basis of these evaluations, the men were classified as having organic, psychogenic, or mixed erectile dysfunction. Of the 861 men studied, 605 (70 percent) were judged to have organic erectile dysfunction, 99 (11 percent) to have psychogenic erectile dysfunction, and 157 (18 percent) to have mixed erectile dysfunction. Men were excluded if they had penile anatomical defects, a primary diagnosis of another sexual disorder (e.g., premature ejaculation), spinal cord injury, any major psychiatric disorder not well controlled with treatment, poorly controlled diabetes mellitus, active peptic ulcer disease, a history of alcohol or substance abuse, major hematologic, renal, or hepatic abnormalities, or a recent (within the previous six months) stroke or myocardial infarction or if they were receiving nitrate therapy. Other erectile-dysfunction therapies were discontinued at the time of screening (four weeks before the subjects received the study medication). Sildenafil (Viagra) and an identical-looking placebo were supplied by Pfizer. The men were instructed to take a dose approximately one hour before planned sexual activity but not more than once daily. The protocols were approved by the institutional review board at each center, and all the men gave written informed consent.

Dosing & Uses

Each man completed the International Index of Erectile Function at 0, 12, and 24 weeks and was asked about global efficacy at 12 and 24 weeks. The event logs were reviewed at 0, 2, 4, 8, 12, 16, 20, and 24 weeks. In the flexible dose-escalation study, 329 different men were randomly assigned to take placebo or 50 mg of sildenafil approximately one hour before sexual activity for 12 weeks. At each follow-up visit, the dose could be doubled or reduced by 50 percent on the basis of the therapeutic response and adverse effects. Each man completed the International Index of Erectile Function at 0 and 12 weeks and was asked about global efficacy at week 12.

Serious Side Effects (Rare)

The event logs were reviewed at 0, 2, 4, 8, and 12 weeks. The men who completed the study and who did not have any serious adverse effects were eligible to receive open-label sildenafil for an additional 32 weeks. The mean frequency of responses to questions 3 and 4 of the International Index of Erectile Function for each treatment group was calculated. An analysis-of-covariance model was fitted for each question, which included main-effect terms for investigational center and treatment effect (as ordered categorical variables), with base-line score, patient age, smoking, and duration and cause of erectile dysfunction as covariates. Mean domain scores from the International Index were calculated, and the treatment effect was analyzed by using the analysis-of-covariance model described above. We assessed efficacy by using the responses to question 3 (frequency of penetration) and question 4 (maintenance of erections after penetration) of the 15-question International Index of Erectile Function, a validated, multidimensional, self-administered questionnaire used for the clinical assessment of erectile dysfunction and treatment outcomes in clinical studies.11 The responses to these two questions pertaining to the ability to achieve and maintain an erection sufficient for sexual intercourse, as described in the definition of erectile dysfunction,1 were rated on a scale of 1 (almost never or never) to 5 (almost always or always). A score of 0 indicated no attempt at sexual intercourse. The mean score for each of the two questions was 4.3 for 109 normal men, 31 to 86 years old, with an age distribution similar to that of the men with erectile dysfunction (unpublished data).

Related/similar drugs

From the event log, the mean numbers of grade 3 and grade 4 erections (in the dose–response study) or the percentage of attempts at sexual intercourse that were successful (in the dose-escalation study) was calculated. Analysis of covariance (dose–response study), with adjustment for the covariates listed above, or a chi-square test (dose-escalation study) was used to determine the association between the treatment groups. The answers of each treatment group to the global-efficacy question (yes or no) were analyzed with the use of logistic-regression analysis, accounting for the same covariates as those listed for the analysis-of-covariance models. Intention-to-treat analyses were performed on all variables and included all the men who were randomly assigned to treatment (and received treatment) and who had any assessments after base line, regardless of protocol deviations or whether the men completed the study. The base-line characteristics of the men with erectile dysfunction enrolled in each study were similar, but there were differences between the studies (Table 1).

Serious Side Effects

The men in the dose–response study had had erectile dysfunction for longer periods, and fewer of them had organic erectile dysfunction. Among the 532 men in the dose–response study, 465 (87 percent) completed the 24-week study (285 of 316 in the sildenafil group and 180 of 216 in the placebo group). Among the 329 men in the dose-escalation study, 307 (93 percent) completed the 12-week study (154 of 163 in the sildenafil group and 153 of 166 in the placebo group). Efficacy was also assessed on the basis of the scores for the five separate response domains of male sexual function of the International Index13: erectile function (questions 1 through 5 and 15; possible total score, 1 to 30); orgasmic function (questions 9 and 10; possible total score, 0 to 10); sexual desire (questions 11 and 12; possible total score, 2 to 10); intercourse satisfaction (questions 6, 7, and 8; possible total score, 0 to 15); and overall satisfaction (questions 13 and 14; possible total score, 2 to 10). The domain scores were computed by adding the scores for the individual questions in each domain.

Other means of assessing efficacy were an event log, in which we asked the men to record the date and dose of medication taken, the presence of sexual stimulation, the hardness of erections (graded on a four-point scale), and whether sexual intercourse was successful, and a global-efficacy question (“Did the treatment improve sildenafil citrate 100 mg your erections?”), with a response of yes or no. The end points of the International Index quantified the magnitude of the response, and the global-efficacy question and the event log provided qualitative assessments of efficacy. Physical examinations and standard blood-chemistry and hematologic laboratory tests were performed throughout the studies. Adverse effects were recorded by the investigators. In this double-blind, placebo-controlled, fixed-dose study, 532 men were randomly assigned to take placebo or 25, 50, or 100 mg of sildenafil (approximately one hour before planned sexual activity but not more than once daily) for 24 weeks. Each dose consisted of three tablets from the same row of a blister pack (placebo–placebo–placebo; placebo–placebo–25 mg; placebo–placebo–50 mg; or placebo–50 mg–50 mg). The men were instructed not to consume more than two alcoholic drinks within one hour of sexual activity. Each man completed the International Index of Erectile Function at 0, 12, and 24 weeks and was asked about global efficacy at 12 and 24 weeks. The event logs were reviewed at 0, 2, 4, 8, 12, 16, 20, and 24 weeks. In the flexible dose-escalation study, 329 different men were randomly assigned to take placebo or 50 mg of sildenafil approximately one hour before sexual activity for 12 weeks.

• The medication may cause a sudden decrease in blood pressure in some users.
• Use sildenafil cautiously if you are also taking blood pressure medications.
• Do not share your medication with others to prevent misuse.

At each follow-up visit, the dose could be doubled or reduced by 50 percent on the basis of the therapeutic response and adverse effects. Each man completed the International Index of Erectile Function at 0 and 12 weeks and was asked about global efficacy at week 12. The event logs were reviewed at 0, 2, 4, 8, and 12 weeks. The men who completed the study and who did not have any serious adverse effects were eligible to receive open-label sildenafil for an additional 32 weeks.

• Sildenafil is not a cure for erectile dysfunction but helps improve function.
• Use sildenafil only as prescribed to ensure safety and efficacy.
• It is not intended for recreational use and can be harmful.

The mean frequency of responses to questions 3 and 4 of the International Index of Erectile Function for each treatment group was calculated.

An analysis-of-covariance model was fitted for each question, which included main-effect terms for investigational center and treatment effect (as ordered categorical variables), with base-line score, patient age, smoking, and duration and cause of erectile dysfunction as covariates. Mean domain scores from the International Index were calculated, and the treatment effect was analyzed by using the analysis-of-covariance model described above.

Liver Dose Adjustments

In a 24-week dose–response study, 532 men were treated with oral sildenafil (25, 50, or 100 mg) or placebo. In the dose–response study, increasing doses of sildenafil were associated with improved erectile function (P values for increases in scores for questions about achieving and maintaining erections were <0.001). Oral sildenafil is an effective, well-tolerated treatment for men with erectile dysfunction. Erectile dysfunction, the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance, is estimated to affect up to 30 million men in the United States.1 The disorder is age-associated,1–3 with estimated prevalence rates of 39 percent among men 40 years old and 67 percent among those 70 years old.2 The available treatments include vacuum-constriction devices; intracavernosal injections of vasoactive agents, including alprostadil (prostaglandin E1)4; transurethral delivery of alprostadil5; implantation of penile prostheses; and venous or arterial surgery. No effective oral therapy for erectile dysfunction is currently available.6 Normal penile erection depends on the relaxation of smooth muscles in the corpora cavernosa.

New England Journal of Medicine

In response to sexual stimuli, cavernous nerves and endothelial cells release nitric oxide, which stimulates the formation of cyclic guanosine monophosphate (GMP) by guanylate cyclase.7–9 The mechanism by which cyclic GMP stimulates relaxation of the smooth muscles remains to be elucidated. Sildenafil is a selective inhibitor of cyclic-GMP–specific phosphodiesterase type 5, the predominant isozyme metabolizing cyclic GMP in the corpus cavernosum.10 By selectively inhibiting cyclic-GMP catabolism in cavernosal smooth-muscle cells,11 sildenafil would be expected to restore the natural erectile response to sexual stimulation but not cause erections in the absence of such stimulation. Sildenafil is rapidly absorbed, with maximal plasma concentrations occurring within one hour after oral administration and a mean terminal half-life of three to five hours.10 In a placebo-controlled pilot study of 12 men, sildenafil significantly improved the erectile response during visual sexual stimulation.10,12 We therefore undertook two studies to evaluate in a home setting the efficacy and safety of sildenafil in men with erectile dysfunction. In two sequential studies, we studied a total of 861 men 18 years of age or older with a clinical diagnosis of erectile dysfunction (as defined previously1) of six months' duration or longer at 37 centers in the United States. Each man had to be in a stable relationship with a female partner that had begun at least six months earlier. From the event log, the mean numbers of grade 3 and grade 4 erections (in the dose–response study) or the percentage of attempts at sexual intercourse that were successful (in the dose-escalation study) was calculated. Analysis of covariance (dose–response study), with adjustment for the covariates listed above, or a chi-square test (dose-escalation study) was used to determine the association between the treatment groups. The answers of each treatment group to the global-efficacy question (yes or no) were analyzed with the use of logistic-regression analysis, accounting for the same covariates as those listed for the analysis-of-covariance models.

Intention-to-treat analyses were performed on all variables and included all the men who were randomly assigned to treatment (and received treatment) and who had any assessments after base line, regardless of protocol deviations or whether the men completed the study.

What to avoid

The cause of erectile dysfunction was determined from the medical history, physical examination, and other diagnostic procedures, including a test involving the intracavernosal injection of a vasoactive drug (done in 31 percent of the men), a RigiScan test of nocturnal penile tumescence (26 percent), penile duplex ultrasonography (21 percent), and endocrine testing (21 percent). On the basis of these evaluations, the men were classified as having organic, psychogenic, or mixed erectile dysfunction. Of the 861 men studied, 605 (70 percent) were judged to have organic erectile dysfunction, 99 (11 percent) to have psychogenic erectile dysfunction, and 157 (18 percent) to have mixed erectile dysfunction. Men were excluded if they had penile anatomical defects, a primary diagnosis of another sexual disorder (e.g., premature ejaculation), spinal cord injury, any major psychiatric disorder not well controlled with treatment, poorly controlled diabetes mellitus, active peptic ulcer disease, a history of alcohol or substance abuse, major hematologic, renal, or hepatic abnormalities, or a recent (within the previous six months) stroke or myocardial infarction or if they were receiving nitrate therapy. Other erectile-dysfunction therapies were discontinued at the time of screening (four weeks before the subjects received the study medication).

Other Interactions

Sildenafil (Viagra) and an identical-looking placebo were supplied by Pfizer. The men were instructed to take a dose approximately one hour before planned sexual activity but not more than once daily. The protocols were approved by the institutional review board at each center, and all the men gave written informed consent. We assessed efficacy by using the responses to question 3 (frequency of penetration) and question 4 (maintenance of erections after penetration) of the 15-question International Index of Erectile Function, a validated, multidimensional, self-administered questionnaire used for the clinical assessment of erectile dysfunction and treatment outcomes in clinical studies.11 The responses to these two questions pertaining to the ability to achieve and maintain an erection sufficient for sexual intercourse, as described in the definition of erectile dysfunction,1 were rated on a scale of 1 (almost never or never) to 5 (almost always or always). A score of 0 indicated no attempt at sexual intercourse. The base-line characteristics of the men with erectile dysfunction enrolled in each study were similar, but there were differences between the studies (Table 1). The men in the dose–response study had had erectile dysfunction for longer periods, and fewer of them had organic erectile dysfunction. Among the 532 men in the dose–response study, 465 (87 percent) completed the 24-week study (285 of 316 in the sildenafil group and 180 of 216 in the placebo group).

Warnings & Precautions

The mean score for each of the two questions was 4.3 for 109 normal men, 31 to 86 years old, with an age distribution similar to that of the men with erectile dysfunction (unpublished data). Efficacy was also assessed on the basis of the scores for the five separate response domains of male sexual function of the International Index13: erectile function (questions 1 through 5 and 15; possible total score, 1 to 30); orgasmic function (questions 9 and 10; possible total score, 0 to 10); sexual desire (questions 11 and 12; possible total score, 2 to 10); intercourse satisfaction (questions 6, 7, and 8; possible total score, 0 to 15); and overall satisfaction (questions 13 and 14; possible total score, 2 to 10). The domain scores were computed by adding the scores for the individual questions in each domain. Other means of assessing efficacy were an event log, in which we asked the men to record the date and dose of medication taken, the presence of sexual stimulation, the hardness of erections (graded on a four-point scale), and whether sexual intercourse was successful, and a global-efficacy question (“Did the treatment improve sildenafil citrate 100 mg your erections?”), with a response of yes or no. The end points of the International Index quantified the magnitude of the response, and the global-efficacy question and the event log provided qualitative assessments of efficacy.

Erectile dysfunction

Physical examinations and standard blood-chemistry and hematologic laboratory tests were performed throughout the studies. Adverse effects were recorded by the investigators. In this double-blind, placebo-controlled, fixed-dose study, 532 men were randomly assigned to take placebo or 25, 50, or 100 mg of sildenafil (approximately one hour before planned sexual activity but not more than once daily) for 24 weeks. Each dose consisted of three tablets from the same row of a blister pack (placebo–placebo–placebo; placebo–placebo–25 mg; placebo–placebo–50 mg; or placebo–50 mg–50 mg). The men were instructed not to consume more than two alcoholic drinks within one hour of sexual activity. Among the 329 men in the dose-escalation study, 307 (93 percent) completed the 12-week study (154 of 163 in the sildenafil group and 153 of 166 in the placebo group).

Unser Haus