Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmö, Sweden on 23-24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.

Effects of erythromycin at steady-state concentrations on the pharmacokinetics of ulipristal acetate.

WHAT IS KNOWN AND OBJECTIVE: Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for the treatment of benign gynaecological conditions such as uterine myoma. In vitro, it is mainly metabolized by the cytochrome P450 isoenzyme CYP3A4 and to a small extent by CYP1A2 and CYP2D6. Erythromycin, a macrolide antibiotic, has been shown to be a moderate CYP3A4 inhibitor. Thus, the aim of this study was to determine the effects of erythromycin at steady-state concentrations on the pharmacokinetics of UPA. Effects on the pharmacokinetics of the mono-demethylated metabolite of UPA (PGL4002) were also evaluated. METHODS: This was a non-randomized, single-sequence, two-period, open, single-dose study in 18 healthy female subjects. Subjects received oral UPA (20 mg) once daily on days 1 and 13 and twice-daily erythromycin propionate administrations (500 mg) from days 9 through 17. RESULTS: Geometric mean Cmax and AUCs of UPA were increased by 24% [geometric mean ratio point estimate (90% CI): 1·24 (1·01-1·52)] and +224% and +227% [geometric mean ratio point estimates (90% CI): AUC0-t 3·24 (2·75-3·83) and AUC0-∞ (3·27 (2·79-3·83)], respectively, with no effect on median tmax or t1/2. Geometric mean Cmax of PGL4002 was decreased by 47% [geometric mean ratio point estimate (90% CI): 0·523 (0·44-0·62)], but AUCs were increased by +62% and +66% [geometric mean ratio point estimates (90% CI): AUC0-t 1·62 (1·43-1·85) and AUC0-∞ by 1·66 (1·47-1·88)], respectively, with no effect on median tmax. However, geometric mean t1/2.doubled from 24 h to 48 h. No subject was discontinued from the study due to adverse events. WHAT IS NEW AND CONCLUSION: Concomitant use of ulipristal acetate with erythromycin at therapeutic concentrations led to a limited increase in Cmax and a 3-fold increase in AUCs for UPA and to a decrease in Cmax and an increase in AUCs and prolonged elimination for PGL4002. This indicates that inhibition of CYP3A4 impacted rate and extent of absorption of UPA and also its metabolism by slowing the elimination of its metabolite PGL4002.

Ulipristal acetate - safety and pharmacokinetics following multiple doses of 10-50 mg per day.

WHAT IS KNOWN AND OBJECTIVE: Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for benign gynaecological conditions such as uterine myoma. The safety and pharmacokinetics of multiple-dose UPA and its N-mono-demethylated metabolite, PGL4002, were investigated in women. METHODS: The double-blind, placebo-controlled study randomized 32 healthy women of reproductive age to receive 10 consecutive daily doses of placebo, 10, 20 or 50 mg UPA. Safety assessments included vital signs, physical examination, ECG, clinical laboratory tests and reporting of adverse events. Blood samples for pharmacokinetic analysis were collected on Days 1 and 10 at intervals until 168 h after multiple dosing. RESULTS: UPA was well tolerated at all doses. Mild or moderate adverse events occurred with similar frequency in UPA and placebo groups. UPA median tmax was 0·75 and 0·89 h, and mean plasma half-life was between 38 and 49 h. Cmax values (Day 1) were 42·2, 130·9 and 354·8 ng/mL for the UPA 10, 20 and 50 mg treatment groups, respectively. Corresponding Cmax values for Day 10 were 63·7, 169·8 and 454·9 ng/mL. AUCSS values on Day 10 were 216·6, 602·8 and 1655·7 ng h/mL after 10, 20 and 50 mg UPA, respectively. For the principal metabolite PGL4002, tmax and plasma elimination half-life values were similar to those of UPA. PGL4002 AUCSS Day 10 values were 84·7, 203·6 and 452·1 ng h/mL for 10, 20 and 50 mg groups, respectively. WHAT IS NEW AND CONCLUSION: Daily administration of UPA at therapeutic and supratherapeutic doses was well tolerated by women of reproductive age. UPA exposure increases with dose. Exposure to PGL4002 is approximately one-third that of UPA.

Past, present, and future: a 7-year update of Viagra (sildenafil citrate).

More than 30 million men are estimated to have erectile dysfunction (ED) in the United States. Worldwide, ED is estimated to affect more than 150 million men, and that number is expected to exceed 300 million men by the year 2025. The prevalence of ED ranges from 7% in men aged 18-29 years to 85% in men aged 76-85 years. In addition, a recent report showed that 68% of patients with ED aged 18 years and older have at least one comorbid diagnosis of hypertension, hyperlipidaemia, diabetes or depression, and research suggests that ED may be an early indicator of systemic vascular disease. Viagra (sildenafil citrate), the first-in-class phosphodiesterase type 5 (PDE5) inhibitor, was introduced in 1998 for the treatment of ED. In the 7 years since its market launch, more than 750,000 physicians have prescribed sildenafil to more than 23 million men, helping establish an excellent safety and efficacy record. Clinical studies have demonstrated that sildenafil successfully treats ED of varied organic, psychogenic or mixed aetiology, and is effective in men with ED and comorbidities such as hypertension, hyperlipidaemia, diabetes or depression. Sildenafil was a breakthrough medication that addressed a previously unfulfilled medical need. The impact of sildenafil has stimulated academic, clinical and industrial research to better understand the nature of sexual function and develop better treatment and management for sexual dysfunctions such as ED. With the advent of other erectogenic therapies for the treatment of ED, this 7-year update will focus on the unique history and development of sildenafil, its current use and applications and its future directions and indications. Special emphasis is placed on the impact of sildenafil on our understanding of sexual health and on the extensive safety and efficacy data that have been amassed from numerous clinical trials.

Relationship between patient self-assessment of erectile dysfunction and the sexual health inventory for men.

BACKGROUND: The Sexual Health Inventory for Men (SHIM) has been shown to possess favorable statistical properties in diagnosing the presence and severity of erectile dysfunction (ED). However, the SHIM has not been compared with patient self-assessment of ED. OBJECTIVE: This article describes an independent-validation study examining the correlation and agreement between the SHIM and patient self-assessment of ED with respect to the severity of ED at baseline and after treatment, and in terms of change from baseline. METHODS: The study population consisted of 247 male outpatients with ED participating in a multicenter, double-blind, placebo-controlled, flexible-dose (25-100 mg/d) Phase IIIb clinical trial in which they were randomized equally to sildenafil citrate or placebo. Patients assessed their degree of ED as severe, moderate, minimal/mild, or no problem at baseline and after 12 weeks of treatment. They also responded to the 5 questions on the SHIM, after which their degree of ED was calculated based on the SHIM total score. RESULTS: In general, the SHIM and the single-item self-assessment question produced similar descriptive profiles of the severity of ED. Kendall tau-b correlations were 0.66 (95% CI, 0.58-0.74) at baseline, 0.86 (95% CI, 0.82-0.90) after treatment, and 0.72 (95% CI, 0.67-0.77) for change from baseline. Agreement between instruments, measured by the weighted kappa statistic, mirrored the correlations at baseline and after treatment. As expected, both measures correlated moderately with improvement in erections and treatment satisfaction of both patient and partner. CONCLUSION: The moderate-to-high correlation and agreement between the SHIM and patient self-assessment of ED validate the SHIM for use in the diagnostic classification of ED severity.

A dose-escalation study to assess the efficacy and safety of sildenafil citrate in men with erectile dysfunction.

OBJECTIVE: To assess the efficacy and safety of sildenafil citrate (Viagra, Pfizer Inc., USA) in a double-blind, placebo-controlled, dose-escalation study over a period of 26 weeks in men with erectile dysfunction of a broad spectrum of aetiology. PATIENTS AND METHODS: In all, 315 patients from five countries were randomized to receive treatment with placebo (156 men) or sildenafil (159 men). Significant concomitant medical conditions were hypertension (20%), a history of pelvic surgery (19%), diabetes mellitus (15%), and ischaemic heart disease (10%). Patients randomized to treatment received a starting dose of 25 mg of sildenafil or matching placebo, which could be increased to 50 mg and then to 100 mg of sildenafil, based on efficacy and tolerability. Assessments of efficacy comprised the 15-item International Index of Erectile Function (IIEF), including question three (ability to achieve an erection) and question four (ability to maintain an erection), a partner questionnaire, an overall efficacy question, and event-log data. RESULTS: After 12 weeks of treatment, 26%, 32% and 42% of patients were taking 25, 50 and 100 mg of sildenafil, respectively. A similar distribution of doses was reported after 26 weeks of treatment. Treatment with sildenafil significantly improved the patients' abilities to achieve and maintain an erection compared with treatment with placebo (P < 0.001). Scores for four of the five sexual function domains of the IIEF (erectile function, orgasmic function, intercourse satisfaction and overall satisfaction) also improved significantly (P < 0.001). There was a significant improvement in the mean score for the erectile function domain, regardless of the aetiology of erectile dysfunction (P < 0.001). After 12 weeks and 26 weeks of treatment, 82% and 79% of patients receiving sildenafil reported improved erections, compared with 24% and 23% of patients receiving placebo, respectively (P < 0.001). Treatment-related adverse events were mild to moderate and occurred in 27% of patients receiving sildenafil, compared with 8% of patients receiving placebo. CONCLUSION: Sildenafil is an effective and well-tolerated treatment for men with erectile dysfunction of a broad spectrum of aetiology.

Long-term efficacy and safety of oral Viagra (sildenafil citrate) in men with erectile dysfunction and the effect of randomised treatment withdrawal.

The long-term efficacy and safety of oral Viagra (sildenafil citrate), a selective phosphodiesterase 5 inhibitor, and the effect of withdrawing treatment were evaluated in men with erectile dysfunction (ED). In 233 men with ED of psychogenic or mixed organic/psychogenic aetiology, 16 weeks of open-label, flexible-dose sildenafil treatment (10-100 mg) was followed by eight weeks of double-blind, fixed-dose, randomised withdrawal to placebo or continued treatment with sildenafil. Sildenafil was taken as needed (not more than once daily) approximately 1 h prior to sexual activity. The main outcome measures were a global efficacy question, a sexual function questionnaire, an event log of erections, and adverse event recording. In the open-label phase, 200 of 216 patients (93%) reported improved erections with sildenafil; 28 patients (12%) discontinued treatment. In the double-blind phase, the significant improvements in the frequency and duration of erections were maintained in the sildenafil group but returned to pre-treatment values in patients on placebo (P values < 0.0001 versus placebo). The most frequent adverse events in the sildenafil group during the double-blind phase were flushing (7%), headache (6%), and dyspepsia (5%). Of the 192 patients enrolled in the 1-y extension, 90% completed the study; only two patients (1%) were withdrawn due to lack of efficacy. In men with ED of psychogenic or mixed aetiology, oral sildenafil is effective and well-tolerated both at the initiation of therapy and during long-term treatment. For most patients, sildenafil treatment must be continued for improvements in erectile function to be maintained.

Relationship between patient self-assessment of erectile function and the erectile function domain of the international index of erectile function.

OBJECTIVES: To assess the validity of severity classes on the erectile function (EF) domain of the International Index of Erectile Function by determining their relationship with the self-assessment of EF, before and after treatment, in an independent cohort of patients. METHODS: Two hundred forty-seven men with clinically diagnosed erectile dysfunction (ED) and in a stable heterosexual relationship were enrolled in a randomized, double-blind, multicenter, placebo-controlled, parallel-group, 12-week, flexible-dose study. Patients assessed their degree of ED as severe, moderate, minimal/mild, or no problem at baseline and after treatment. They also responded to the six questions of the EF domain, with the total score indicating the following degrees of ED: severe, EF score 1 to 10; moderate, EF score 11 to 16; mild to moderate, EF score 17 to 21; mild, EF score 22 to 25; and no ED, EF score 26 to 30. Descriptive profiles of the two diagnostic instruments were compared. The correlations between the instruments were evaluated with Kendall's tau-b at baseline, after treatment at 12 weeks, and at change from baseline. RESULTS: The two measures gave generally similar descriptive profiles of ED severity. The correlations were 0. 65 (95% confidence interval 0.57 to 0.73) at baseline, 0.86 (95% confidence interval 0.83 to 0.89) after 12 weeks of treatment, and 0. 73 (95% confidence interval 0.67 to 0.79) at change from baseline. CONCLUSIONS: The moderate-to-high correlation between the patients' self-assessment of EF and the EF domain of the International Index of Erectile Function provides a validation of this domain for the reliable diagnostic classification of ED severity.

Sildenafil citrate (Viagra) is effective and well tolerated for treating erectile dysfunction of psychogenic or mixed aetiology.

Sildenafil citrate (Viagra) has been shown to be an effective treatment for erectile dysfunction (ED) of organic aetiology. This study assessed the efficacy and tolerability of sildenafil for treating ED of psychogenic and mixed psychogenic/organic aetiology. Men with ED of psychogenic and mixed aetiology were randomised in a double-blind, fixed-dose study to placebo (n = 95) or sildenafil 10 mg (n = 90), 25 mg (n = 85), or 50 mg (n = 81) once daily for 28 days. Efficacy was evaluated with two global efficacy questions, a patient log of erectile activity, a sexual function questionnaire and a partner questionnaire. Patients receiving sildenafil had significantly more grade 3 (hard enough for penetration) or grade 4 (fully hard) erections per week than patients receiving placebo, and a greater proportion of patients receiving sildenafil reported that treatment had improved their erections (p < 0.001). Results of the sexual function questionnaire demonstrated significant improvement for patients with ED receiving sildenafil compared with patients receiving placebo for frequency, hardness and duration of erections (p < 0.01), and for enjoyment of sexual intercourse and satisfaction with sex life (p < 0.05). The results of the partner questionnaire were consistent with the results reported by patients and showed that treatment with sildenafil was associated with significant improvement in the partners' own sex lives (p < 0.001). Adverse events were mostly mild to moderate in nature. The commonest adverse events were headache, dyspepsia, flushing, myalgia, arthralgia and flu syndrome. Discontinuations due to treatment-related adverse events were few, ranging from 1.1% to 6.2% for patients receiving different doses of sildenafil and 4.2% for patients receiving placebo. Sildenafil is an effective and well-tolerated treatment for ED of psychogenic or mixed aetiology with once-daily dosing.

Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function.

OBJECTIVES: To evaluate the erectile function (EF) domain of the International Index of Erectile Function (IIEF) as a diagnostic tool to discriminate between men with and without erectile dysfunction (ED) and to develop a clinically meaningful gradient of severity for ED. METHODS: One thousand one hundred fifty-one men (1035 with and 116 without ED) who reported attempting sexual activity were evaluated using data from four clinical trials of sildenafil citrate (Viagra) and two control samples. The statistical program Classification and Regression Trees was used to determine optimal cutoff scores on the EF domain (range 6 to 30) to distinguish between men with and without ED and to determine levels of ED severity on the EF domain using the IIEF item on sexual intercourse satisfaction. RESULTS: For a 0.5 prevalence rate of ED, the optimal cutoff score was 25, with men scoring less than or equal to 25 classified as having ED and those scoring above 25 as not having ED (sensitivity 0.97, specificity 0.88). Sensitivity analyses revealed a robust statistical solution that was well supported with different assumed prevalence rates and several cross-validations. The severity of ED was classified into five categories: no ED (EF score 26 to 30), mild (EF score 22 to 25), mild to moderate (EF score 17 to 21), moderate (EF score 11 to 16), and severe (EF score 6 to 10). Substantial agreement was shown between these predicted and "true" classes (weighted kappa 0.80). CONCLUSIONS: The EF domain possesses favorable statistical properties as a diagnostic tool, not only in distinguishing between men with and without ED, but also in classifying levels of ED severity. Clinical validation with self-rated assessments of ED severity is warranted.

Randomized trial of sildenafil for the treatment of erectile dysfunction in spinal cord injury. Sildenafil Study Group.

Erectile dysfunction is a common complication of spinal cord injury. This double-blind, placebo-controlled, two-way crossover study assessed the efficacy and safety of oral sildenafil in men with erectile dysfunction caused by traumatic spinal cord injury. A total of 178 men (mean age, 38 years) received placebo or sildenafil 1 hour before sexual activity for 6 weeks; after a 2-week washout period, the men received the alternate treatment for 6 weeks. The 50-mg starting dose could be adjusted to 100 or 25 mg based on efficacy and tolerability. Efficacy was assessed by using global efficacy questions, the International Index of Erectile Function (IIEF), and a patient log of erectile activity. Of 143 men with residual erectile function at baseline, 111 (78%) reported improved erections and preferred sildenafil to placebo. For all men (including those who reported no residual erectile function at baseline), 127 of 168 (76%) reported improved erections and preferred sildenafil to placebo. For all men, 132 of 166 (80%) reported that sildenafil improved sexual intercourse compared with 17 of 166 men (10%) reporting improvement with placebo. IIEF questions assessing the ability to achieve and maintain erections and satisfaction with sexual intercourse demonstrated significant improvement with sildenafil. Sildenafil was well tolerated, with a low rate of discontinuation because of treatment-related adverse events (2% vs 1% for placebo). Oral sildenafil is an effective and well-tolerated treatment for erectile dysfunction caused by spinal cord injury.

Efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfunction of various etiologies.

OBJECTIVES: To determine the efficacy and safety of fixed-dose oral sildenafil in patients with erectile dysfunction (ED) of various etiologies. METHODS: In a 12-week, double-blind, randomized, placebo-controlled, fixed-dose study, 514 men (mean age 56 years) with ED were randomized to receive 25, 50, or 100 mg of sildenafil or placebo. The primary etiology of ED was determined to be organic in 32% of men, psychogenic in 25%, or mixed in 43%. Sildenafil or placebo was taken in the home setting approximately 1 hour before sexual activity, not more than once daily. Efficacy was determined by responses to question 3 (ability to achieve an erection) and question 4 (ability to maintain an erection) of the 15-item International Index of Erectile Function (IIEF). Other measures of efficacy included the five sexual function domains of the IIEF, a global efficacy question, event log data, and a partner questionnaire. RESULTS: Sildenafil significantly increased patients' ability to achieve and maintain erections (P <0.0001), with efficacy increasing with increasing dose. Significant improvements were also observed in the IIEF domains for erectile function, orgasmic function, intercourse satisfaction, and overall sexual satisfaction (P <0.0001). The proportion of subjects who felt that treatment with sildenafil improved their erections was significantly greater (67% to 86%) than that with placebo treatment (24%, P <0.0001). The proportion of successful attempts at sexual intercourse also increased significantly with sildenafil treatment (P <0.001). Partner responses corroborated patient reports. Sildenafil was well tolerated at the three doses studied. CONCLUSIONS: Oral sildenafil is an effective, well-tolerated treatment for ED of various etiologies.

Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects.

OBJECTIVES: To evaluate the efficacy, safety, and tolerability of sildenafil in men with broad-spectrum erectile dysfunction (ED), with reference to age-matched healthy control subjects. METHODS: One hundred eleven patients were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, 12-week, flexible-dose study. Efficacy assessments included the International Index of Erectile Function (IIEF), a global assessment question, and patient event log data. In a separate, nontreatment study, 109 control subjects also completed the IIEF. RESULTS: Mean IIEF scores at baseline were significantly lower for patients with ED than for control subjects without a history of ED. After treatment, mean IIEF scores for patients receiving sildenafil approached values observed in control subjects and were significantly higher than mean scores for patients receiving placebo (P<0.01). Responses to the global assessment question and patient log data corroborated the IIEF results. Sildenafil was well tolerated, with no discontinuations because of adverse events. CONCLUSIONS: The results indicate that sildenafil, an effective oral therapy for the treatment of broad-spectrum ED, is associated with a near normalization of patient erectile function.

A two-part pilot study of sildenafil (VIAGRA) in men with erectile dysfunction caused by spinal cord injury.

STUDY DESIGN: This was a two-part pilot study in men with erectile dysfunction (ED) due to spinal cord injury (SCI: cord level range T6-L5). Part I was a randomised, double-blind, two-way cross-over study comparing a single dose of sildenafil 50 mg or placebo. Part II was a randomised, double-blind, parallel-group evaluation of sildenafil 50 mg or placebo, taken as required (not more than once daily) approximately 1 h prior to sexual activity, over a period of 28 days. OBJECTIVES: To assay the efficacy and safety of sildenafil 50 mg and placebo. SETTING: Clinic- and home-based assessments in the United Kingdom. METHODS: A total of 27 subjects who were able to achieve at least a grade 2 erection (hard, but not hard enough for penetration) in response to penile vibratory stimulation (PVS) were recruited. In Part I, the reflexogenic response of the penis to PVS was evaluated in the clinic while in Part II, the response to treatment was assessed in the home (global efficacy. questionniare, diary). RESULTS: In Part I, 17/26 (65%) subjects had erections of >60% rigidity at the penile base (median duration 3.5 min) after sildenafil compared with 2/26 (8%) (median duration 0 min) alter placebo (P=0.0003). In Part II, 9/12 (75%) subjects on sildenafil and 1/14 (7%) subjects on placebo reported that the treatment had improved their erections (P<0.005), and 8/12 (67%) and 2/13 (15%) men, respectively, indicated that they wished to continue treatment (P<0.02). An analysis of diary data showed no difference between the groups with respect to the mean number of erections hard enough for penetration (P = 0.08). The mean proportion of attempts at sexual intercourse that were successful was 30 and 15%, respectively (P=0.21). Similarly, responses to the end-of-treatment questionnaire indicated that there were no significant differences between the groups with respect to the frequency of erections hard enough for sexual intercourse (P=0.47) or that lasted as long as the subject would have liked (P=0.11). No subject discontinued sildenafil due to adverse events. CONCLUSION: Sildenafil is an effective, well-tolerated oral treatment for ED in SCI subjects.

Overall cardiovascular profile of sildenafil citrate.

Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is the first in a new class of orally effective treatments for erectile dysfunction. During sexual stimulation, the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smooth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus blocking the breakdown of cGMP. Sildenafil alone can cause mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose related, whereas the heart rate is unchanged. Sildenafil and nitrates both increase cGMP levels in the systemic circulation but at different points along the NO-cGMP pathway. The combination is contraindicated because they synergistically potentiate vasodilation and may cause excessive reductions in blood pressure. Erectile dysfunction is a significant medical condition that shares numerous risk factors with ischemic heart disease, and hence a substantial overlap exists between these patient groups. From extensive clinical trials, the most commonly reported cardiovascular adverse events in patients treated with sildenafil were headache (16%), flushing (10%), and dizziness (2%). The incidences of hypotension, orthostatic hypotension, and syncope and the rate of discontinuation of treatment due to adverse events were <2% and were the same in patients taking sildenafil and those taking placebo. Retrospective analysis of the concomitant use of antihypertensive medications (beta blockers, alpha blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists) in patients taking sildenafil did not indicate an increase in the reports of adverse events or significant episodes of hypotension compared with patients treated with sildenafil alone. In clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treated with sildenafil or placebo. Concurrent disease states, such as renal or hepatic impairment, or concomitant use of inhibitors of the cytochrome P450 isozyme CYP3A4 could increase systemic exposure to sildenafil. Since the US market launch in April 1998, monitoring of spontaneous adverse event reports in association with sildenafil has demonstrated a pattern that is generally consistent with the experience observed during clinical development, with the exception of infrequent reports of priapism. In conclusion, extensive clinical testing has shown that overall treatment with sildenafil for up to 1 year is well tolerated and is associated with a low incidence of adverse events that result in discontinuation of treatment in <3% of patients.