Viagra - Sildenafil
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Sildenafil is used orally as vasoactive therapy to facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence) and to reduce symptoms (e.g., improved exercise capacity) in patients with pulmonary arterial hypertension (PAH). • Erectile Dysfunction
Sildenafil is used orally as vasoactive therapy to facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence). Erectile dysfunction is the persistent or repeated inability to attain and/or maintain an erection sufficient for satisfactory sexual performance in the presence of adequate sexual stimulation; some experts state that the complaint of such dysfunction generally should be present over a period of at least 3 months, although individual circumstances (e.g., surgical or traumatic causes, temporary dysfunction associated with stress of producing sperm specimens) may prompt an earlier diagnosis and/or therapy.
Patient Assessment
A thorough medical history and physical examination should be undertaken to diagnose erectile dysfunction, determine potential underlying causes, exclude potentially reversible or treatable causes (e.g., hypogonadism with inadequate testosterone replacement, hyperprolactinemia, drug-induced dysfunction, dyslipidemias, alcoholism, other substance abuse, hypertension, thyroid disease, cardiovascular or cerebrovascular disease, neurologic disease, adrenal dysfunction, psychologic dysfunction, marital discord, smoking), and identify appropriate treatment in conjunction with or prior to initiating vasoactive therapy. Since erectile dysfunction may be one of the first manifestations of certain underlying chronic or progressive diseases (e.g., atherosclerosis, diabetes mellitus, pituitary tumors, neurologic disorders), a thorough medical examination may lead to early detection of such conditions. If erectile dysfunction is treated without adequately examining possible underlying causes, potentially reversible and treatable underlying conditions could remain undetected. Patient assessment may also uncover related dysfunctions such as premature ejaculation, increased latency time associated with age, and psychosexual relationship problems. A review of the patient’s current drug regimens should be conducted to detect possible drug-induced erectile dysfunction (e.g., certain antihypertensive, antidepressant, antipsychotic, or antiarrhythmic agents); it may be possible to substitute alternative drug(s) that lessen the risk of such dysfunction. In instances where substitution therapy is not feasible, concomitant sildenafil may promote patient compliance by counteracting erectile dysfunction as an adverse effect.
Because diagnosis of erectile dysfunction depends on self-reporting, men who do not have such dysfunction but wish to try sildenafil in an attempt to enhance normal performance† may exaggerate manifestations in an effort to increase their likelihood of being prescribed the drug. (See Uses: Misuse and Abuse.) The erectile benefit of sildenafil in men without erectile dysfunction is uncertain, and the health benefit (e.g., improved quality of life) and long-term safety from such use remain to be established by adequate studies; therefore, such use currently is not generally recommended. However, because of the reliance on self-diagnosis, such use may be difficult to avoid.
Assessment of clinical need for therapy, including sildenafil, should take into account the psychologic effect on the man and his partner and an assessment of their needs and expectations of therapy. Some men and their partners tolerate severe erectile dysfunction well, while others are severely distressed by even mild dysfunction. Therefore, while the decision to initiate sildenafil often is based on predisposing conditions and the estimated severity of erectile dysfunction (e.g., the percent of occasions on which erection is inadequate for penetration or completion of intercourse), the psychologic effect of the dysfunction also may be an important determinant of need. Assessment of the patient also should consider the effect on the partner of resumption of penetrative intercourse (e.g., the possible need for contraception in premenopausal women, the possibility of cystitis, the possibility of dyspareunia in postmenopausal women, the need for lubricants and/or hormone replacement therapy). In human immunodeficiency virus (HIV)- infected individuals, restoration of erectile function requires careful counseling about safe sexual practices.
Attention should be given to clearly defining the problem, clearly distinguishing erectile dysfunction from complaints about ejaculation and/or orgasm, and establishing the severity and chronology of manifestations.
Therapeutic Options
Sildenafil is effective in patients with organic (neurogenic, vasculogenic) or psychogenic erectile dysfunction and in those whose erectile dysfunction is of mixed etiology. Sildenafil also has been effective in counteracting drug-induced erectile dysfunction. The goal of such therapy is to provide an erection of adequate rigidity and duration to be sexually functional and that is satisfying to the patient and his partner, and the main health benefit is improved quality of life. Most clinicians consider a stepped-care approach in the treatment of erectile dysfunction to be appropriate, including vasoactive therapy (oral, intra-urethral and intracavernosal therapies), psychotherapy/behavioral (psychosexual) therapy, devices (e.g., vacuum constriction, implanted prosthesis), and surgery. In general, treatment options should be applied in a stepwise manner with increasing invasiveness and risk being balanced against the likelihood of efficacy. Some clinicians consider psychotherapy/behavioral therapy to be the initial intervention in patients in whom psychogenic erectile dysfunction (comprising up to 30% of all cases of erectile dysfunction) is suspected, and psychotherapy/behavioral therapy combined with vasoactive therapy or vacuum constriction devices to be appropriate in patients with such erectile dysfunction who have not responded to psychotherapy/behavioral therapy alone. Other clinicians consider psychotherapy/behavioral therapy alone or in conjunction with vasoactive therapy or vacuum constriction devices to be appropriate in patients with psychogenic erectile dysfunction or coexisting organic and psychogenic erectile dysfunction.
With the availability of orally active and convenient vasoactive (erectogenic) therapies (e.g., selective PDE type 5 inhibitors such as sildenafil, vardenafil, tadalafil), most experts now consider these drugs, vacuum constriction devices, and/or psychosexual therapy to be suitable first-line therapies for a broad range of patients with erectile dysfunction. Second-line therapy may be considered for patients who fail to respond to, or are not candidates for, first-line therapy (e.g., patients who require nitrate therapy). Intracavernosal or intraurethral vasoactive therapy generally is considered a second-line option. Vasoactive therapy or vacuum constriction devices generally are considered or attempted before resorting to more invasive (e.g., surgical) therapies.
Ultimately, the choice of therapy for erectile dysfunction should be individualized, taking into account differences in response, tolerability and safety, administration considerations, cost and patient reimbursement factors, experience and judgment of the clinician, and individual patient and partner preference, expectations, and satisfaction.
Most experts currently recommend that oral selective PDE type 5 inhibitors be offered as first-line therapy for erectile dysfunction unless contraindicated. Although differences in the pharmacokinetics (certain adverse effects (e.g., potential visual effects, back pain, QT prolongation) may exist, there currently is insufficient evidence to support the superiority of one selective PDE type 5 inhibitor over another. Because selective PDE type 5 inhibitors are effective in restoring normal sexual function in most men with erectile dysfunction and are given orally, they are likely to be more acceptable than injections or mechanical devices and may be less expensive. In addition, because of the risk of exposure to infected blood by intracavernosal therapy, selective PDE type 5 inhibitor therapy may be particularly useful when such risk is of concern, such as in HIV-infected individuals. Oral selective PDE type 5 inhibitor therapy generally is well tolerated, associated with absent or minimal risk of many of the troublesome penile complications of intracavernosal or intraurethral therapies (e.g., priapism, morphologic effects such as fibrosis), easy to administer, and associated with increased sexual satisfaction and decreased dropout rates compared with other currently employed forms of vasoactive therapy for erectile dysfunction; however, because selective PDE type 5 inhibitors are administered systemically rather than locally, adverse systemic effects are more likely. In addition, unlike intracavernosal or intraurethral therapy or vacuum constriction devices, selective PDE type 5 inhibitors are only effective in the presence of adequate sexual stimulation.
Prior to proceeding to alternative therapies in patients reporting failure of selective PDE type 5 inhibitor therapy, an evaluation to determine whether there was an adequate trial should be undertaken. The possibility that another selective PDE type 5 inhibitor therapy may be effective should be considered in patients who fail an adequate trial with one inhibitor, and patients should be informed of the benefits and risks of other drug and nondrug therapies.
Clinical Experience
Efficacy.
Efficacy of sildenafil is variable in patients with erectile dysfunction, in part depending on the underlying etiology, severity, and dose employed, but the drug generally appears to be effective in restoring sexual function to an acceptable level in the majority of treated men. The erectile response generally increases with increasing sildenafil dose and plasma drug concentration, with response becoming greater at 50- and 100-mg doses than at 25 mg. Analyses of subgroups of patients with erectile dysfunction indicate that efficacy of sildenafil is not affected by race or age, duration of erectile dysfunction, or duration of select underlying disease states (e.g., diabetes mellitus), and the drug has been effective in a broad range of patients with erectile dysfunction, including those with a history of coronary artery disease (e.g., coronary artery bypass graft [CABG]), hypertension, other cardiac disease (including ischemic heart disease), peripheral vascular disease, type 1 or 2 diabetes mellitus, mental depression, radical prostatectomy, prostate brachytherapy, transurethral resection of the prostate (TURP), spina bifida, and spinal cord injury. Pooled data from numerous fixed-dose and flexible-dose studies in men with erectile dysfunction secondary to a broad spectrum of organic and psychogenic causes showed increases in mean rates of successful intercourse (total successes divided by total attempts) to about 66–69% in those receiving sildenafil compared with about 20–22% for placebo. Erectile response to sildenafil is better in patients whose erectile function is less impaired at treatment initiation (e.g., those with some spontaneous successful intercourse, with partial erections, with erections during sleep, or with psychogenic causes). In one flexible-dose study (dosage titration and maintenance up to 100 mg), mean scores for number of successful penetrations returned to normal in a subgroup of patients with psychogenic causes of erectile dysfunction; however, mean scores for maintenance of erections during intercourse in these men were lower than in untreated healthy men. In a study in men with erectile dysfunction secondary to radical prostatectomy receiving fixed-dose sildenafil (100 mg), response to therapy was greatest in those who had undergone bilateral-nerve-sparing surgery than in those who had undergone unilateral or non-nerve-sparing procedures. Pooled data from various clinical trials indicate that sildenafil improved the erections of 43% of patients with erectile dysfunction secondary to radical prostatectomy compared with 15% of those receiving placebo. A pooled analysis of 10 placebo-controlled studies of men with severe erectile dysfunction (organic etiology in 60%, psychogenic in 15%, and mixed in 25% of patients) treated with sildenafil (50–100 mg in fixed- or flexible-dose studies) indicated that 48% of the patients usually had erections sufficient for intercourse (score of 4, with 0 being unsuccessful and 5 being almost always successful) after treatment with sildenafil, compared with 8% of those receiving placebo. In several randomized, double-blind, placebo-controlled studies in patients receiving sildenafil (flexible doses up to 100 mg or fixed doses ranging from 10–100 mg for 12 weeks) for the treatment of erectile dysfunction attributed to complications of diabetes mellitus, complications of spinal cord injury, or psychogenic causes, 48, 59, or 70% of all attempts at intercourse were successful, respectively, compared with 12, 13, or 29% of all attempts in those receiving placebo.
In these studies, sildenafil improved several aspects of sexual function including frequency, firmness, and maintenance of erection; frequency of orgasm; satisfaction and enjoyment of intercourse; and overall relationship satisfaction. Pooled data from fixed- and flexible-dose studies indicate that sildenafil (50 or 100 mg) has no effect on sexual desire (i.e., rates of attempted intercourse, which averaged about 2 per week), but the rate of success increased to an average of 1.3 events per patient per week from 0.4 events per week with placebo. In part, the absence of an effect on sexual desire may be attributed to the fact that men enrolling in erectile dysfunction studies generally have a near-normal level of sexual desire upon study entry. Improvement in erectile function sufficient for successful intercourse can be achieved with sildenafil in a substantial percentage of patients with erectile dysfunction, and the strength and duration of erection achieved with the drug in such patients approached those achieved in untreated healthy men. However, the dependence on adequate sexual stimulation for the erectile activity of sildenafil may not alleviate patient and partner performance pressures and therefore may limit efficacy in some patients.
Sildenafil also has been effective in a limited number of men with temporary erectile dysfunction associated with the stress of providing a sperm sample (e.g., for intrauterine insemination or in vitro fertilization during assisted reproduction). In men with a history of such temporary dysfunction, planned use of sildenafil for subsequent attempts at obtaining a sperm specimen may improve attainment of an erection adequate for self-stimulated ejaculation.
Treatment Failures.
While most males with erectile dysfunction respond to oral sildenafil therapy, treatment failures do occur; pooled data from various placebo-controlled, dose-response, or open-label studies (25–100 mg for 6–12 months) indicate that up to 5% of patients discontinued therapy because of lack of effectiveness. Sildenafil is less likely to be effective in patients with erectile dysfunction secondary to severe arterial insufficiency, loss of trabecular smooth muscle, non-nerve-sparing radical prostatectomy, or incompressible cavernosal veins. Vardenafil has been effective as alternate therapy in treating severe erectile dysfunction that failed to respond to sildenafil.
Long-term Use.
Information on the long-term effects of sildenafil is limited, and thus the optimum duration of therapy is not known. In clinical studies, sildenafil was used in patients ranging in age from 19–87 years of age with a duration of erectile dysfunction averaging 5 years. In several long-term and open-label studies, sildenafil remained effective for at least 0.5–3 years, with no evidence of tachyphylaxis during long-term use, and current evidence indicates that continued therapy is necessary as long as the condition persists (i.e., sildenafil is not a cure for erectile dysfunction). However, following marketing approval, decreased efficacy (tachyphylaxis) of sildenafil over a 2-year period of use was self-reported in a limited number of men with erectile dysfunction. Although overall experience to date suggests that the drug can be used throughout life in sexually active men if clinically indicated, the likelihood of contraindications to sildenafil therapy (e.g., presence of an underlying cardiovascular disease requiring nitrate therapy) increases with age; in addition, the possibility that prolonged use of vasoactive therapy could mask the progression of a serious underlying disease must be considered.
Use in Patients with Cardiovascular Disease
Erectile dysfunction in men is common following a diagnosis of coronary artery disease or myocardial infarction, principally because of a fear that the exertion of sexual activity will precipitate a new myocardial infarction. In addition, epidemiologic evidence indicates that there is potential for a high incidence of overt and covert coronary artery disease in patients with erectile dysfunction. Clinicians treating erectile dysfunction should consider the potential implications of coronary artery disease in sedentary patients who plan to resume sexual activity and should review the patient’s ability to tolerate cardiovascular stresses associated with intercourse, particularly in those with known coronary artery disease or at increased risk for the disease. (See Precautions and Contraindications: Cardiovascular Precautions and Contraindications, in Cautions.) In reported clinical studies with sildenafil in patients with erectile dysfunction, cardiac patients represented only a small proportion of studied patients, and patients with heart failure, myocardial infarction or stroke within 6 months, or uncontrolled hypertension (blood pressure exceeding 170/110 mmHg) or hypotension (blood pressure less than 90/50 mmHg) were excluded from these studies. No controlled clinical trial data are available on the safety and efficacy of sildenafil in patients with pulmonary arterial hypertension and recent myocardial infarction, life-threatening arrhythmia, or stroke (within last 6 months), coronary artery disease causing unstable angina, or hypertension (blood pressure exceeding 170/110 mmHg). In addition, only 21–23% of patients in clinical trials for erectile dysfunction were 65 years of age and older. Patients with cardiovascular disease principally at risk for adverse vasodilatory effects are those receiving organic nitrates or nitrites, and use of selective PDE type 5 inhibitors is contraindicated in such patients. (See Drug Interactions: Organic Nitrates and Nitrites.) Other patients with cardiovascular disease who may be at potential risk during PDE type 5 inhibitor therapy include those with active cardiac ischemia (e.g., myocardial infarction or cardiovascular accident within the previous 2 weeks, unstable or refractory angina); those with uncontrolled hypertension; those with congestive heart failure and borderline low blood volume or fluid depletion and low blood pressure (blood pressure less than 90/50 mmHg) status; those with left-ventricular outflow obstructions; and those with high-risk arrhythmias or moderate-to-severe valvular disease; patients with hypertrophic obstruction or other cardiomyopathies also may be at risk. Clinicians should carefully consider use of sildenafil in patients with underlying conditions that could be adversely affected by the vasodilatory effects of sildenafil (e.g., resting hypotension [blood pressure less than 90/50 mmHg], fluid depletion, severe left ventricular outflow obstruction, autonomic dysfunction). Pulmonary vasodilators may adversely affect the cardiovascular status of patients with pulmonary veno-occlusive disease. No clinical data are available on the use of sildenafil in patients with pulmonary veno-occlusive disease†; use of sildenafil in such patients is not recommended.Should signs of pulmonary edema occur during the use of sildenafil, the possibility of associated pulmonary veno-occlusive disease should be considered.
Although patients with complicated antihypertensive regimens also may be at risk during selective PDE type 5 inhibitor therapy, some experts (e.g., the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC 7]) state that selective PDE inhibitors such as sildenafil generally can be used without substantial likelihood of adverse effects in patients receiving antihypertensive therapy provided nitrates and nitrites are avoided. (See Drug Interactions: Antihypertensive and Hypotensive Agents.) Lifestyle modifications (e.g., physical activity, weight control, smoking cessation) should be encouraged to forestall the development of erectile dysfunction in hypertensive men. If erectile dysfunction develops after the initiation of antihypertensive drug therapy, the offending agent should be discontinued if possible and an alternative antihypertensive initiated. It should be recognized that reduction of blood pressure itself may cause a decrease of perfusion in genital organs.
Because of the high incidence of erectile dysfunction in cardiovascular patients and the general efficacy of selective PDE type 5 inhibitors, many such patients could benefit from therapy with the drug. While caution is necessary, undue alarm should be avoided. For patients with cardiac disease, the patient and clinician should carefully weigh the risks and benefits of sildenafil therapy. (See Precautions and Contraindications: Cardiovascular Precautions and Contraindications, in Cautions.)
Combination Therapy
The safety and efficacy of sildenafil in combination with other treatments for erectile dysfunction have not been established. Such combined therapy currently is not recommended by the manufacturer of sildenafil. However, some clinicians have reported the use of combination therapy in selected patients.
•Sexual Dysfunction in Women
The role, if any, of sildenafil in the management of sexual dysfunction in women† remains to be established. It is postulated that a portion of female sexual dysfunction may result from of a lack of blood flow to sexual organs and that sildenafil may improve such flow. (See Genitourinary Effects: Clitoral Effects, in Pharmacology.) In an open-label study in a limited number of postmenopausal women with a history of sexual dysfunction, sildenafil 50 mg administered approximately 1 hour before planned sexual activity did not improve overall sexual function, as reflected in scores from an index measuring quality of intercourse (e.g., degree of lubrication), desire, overall satisfaction, orgasm, and clitoral sensation. In this study, degree of lubrication, orgasm, and clitoral sensation improved by only 23.2, 7.4, and 31.3%, respectively, at 12 weeks, and only 21% of women reported improved sexual function to a global efficacy question. In a controlled study in a limited number of postmenopausal women or women who had undergone a hysterectomy, sildenafil 100 mg administered prior to visual stimulation and masturbation appreciably increased vaginal pH; a trend toward an increase in genital blood flow, mainly clitoral, also was noted. Sildenafil has been effective in a limited number of women for the management of sexual dysfunction induced by selective or nonselective serotonin-reuptake inhibitors (SSRIs or SRIs).
Additional study in women with sexual dysfunction is needed.
Sildenafil also has been misused and abused by women in an attempt to heighten their sexual desire and experience. (See Uses: Misuse and Abuse.)
•Pulmonary Arterial Hypertension
Sildenafil is used for the symptomatic treatment (e.g., to improve exercise capacity) of pulmonary arterial hypertension (PAH; World Health Organization [WHO] group I pulmonary hypertension). While therapy with sildenafil can improve exercise capacity, NYHA/WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension, the precise role of the drug, alone and combined with other therapies, remains to be more fully elucidated. Also remaining to be established is whether long-term sildenafil therapy has a beneficial effect on mortality, although some preliminary data suggest a survival benefit.
Efficacy of sildenafil has been established in a randomized, double-blind, placebo-controlled clinical trial in patients with pulmonary arterial hypertension (e.g., pulmonary artery pressure of 25 mm Hg or more and a pulmonary capillary wedge pressure of 15 mm Hg or less at rest); most patients had pulmonary arterial hypertension of New York Heart Association (NYHA/WHO) functional class II (39%) or class III (58%). Patients in this study were principally white females with WHO group I pulmonary arterial hypertension subgroups that included primary pulmonary hypertension (idiopathic and familial PAH; 63% of patients) or PAH associated with connective tissue disease (30% of patients) or with surgically repaired congenital systemic-to-pulmonary shunts (7% of patients). Addition of sildenafil (20, 40, or 80 mg orally 3 times daily for 12 weeks) to standard therapy (e.g., anticoagulants, digoxin, diuretics, oxygen, or calcium-channel blocking agents, but not prostacyclin analogs, endothelin receptor antagonists, or arginine) substantially increased exercise capacity. The mean increase in the placebo-corrected 6-minute walking distance (the primary end point) was 45–50 meters with all 3 dosages of sildenafil at 12 weeks; no difference in efficacy was observed among the dosage groups. Improvement in walking distance was apparent after 4 weeks of therapy with sildenafil and improvement was maintained for the duration of the trial. Sildenafil therapy also resulted in beneficial hemodynamic changes (e.g., reductions in pulmonary artery pressure and pulmonary vascular resistance, increases in cardiac output) and improvement in NYHA/WHO function class. Following completion of the 12-week study, patients entered into an uncontrolled extension study. Results of the extension study indicate that the effect of sildenafil on exercise capacity is maintained after 1 year of treatment.
•Misuse and Abuse
Because of the potential effects on sexual performance, sildenafil has been misused and abused for enhancing erections† by men who do not have documented erectile dysfunction. Such use may be difficult to avoid since clinicians rely on self-reporting as the principal mechanism for diagnosing erectile dysfunction. In addition, whether sildenafil combined with adequate sexual stimulation can produce more prolonged and possibly stronger erections in such men remains to be determined and has been questioned. However, anecdotal reports and expectations about the effects of sildenafil have prompted the interest of men without dysfunction in using the drug for potentially enhanced sexual performance. Because the safety, particularly with frequent and/or long-term use, and efficacy of such use have not been established, sildenafil currently is not recommended for simply enhancing erections in men who are not impotent. In addition to misuse by patients without erectile dysfunction, some patients for whom sildenafil is indicated (i.e., those with established impotence) may take the drug more frequently and/or at higher doses than recommended.
Sildenafil is readily available with little or no physician/pharmacist intervention (e.g., via the Internet), potentially increasing the risk of misuse and abuse as well as the risk of adverse effects. Sildenafil also may be readily available illicitly (i.e., without a prescription) for recreational use by men and women in an attempt to enhance sexual desire and performance. Men and women using the drug recreationally have reported positive effects on the sexual experience, such as enhanced desire and ‘‘love making’’ and a feeling of warmth, but some experts question whether any benefit is likely with such use.
The potential exists for serious consequences (e.g., hypotensive crises) if such misuse and abuse of sildenafil were combined with certain other drugs and illicit substances that are misused and abused recreationally for sexual pleasure enhancement (e.g., ‘‘poppers’’ such as amyl or other volatile [e.g., butyl] nitrites). (See Drug Interactions: Organic Nitrates and Nitrites.) There is some evidence that individuals who misuse and abuse sildenafil recreationally are highly likely to engage in such potentially serious combined misuse of drugs and illicit substances.
from: www.medscape.com