Uses
Sildenafil is used orally as vasoactive therapy to facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence). Sildenafil also is used orally or IV to improve exercise capacity and delay clinical worsening in patients with pulmonary arterial hypertension (PAH). The FDA and manufacturer state that use of sildenafil, particularly chronic use, is not recommended in children with PAH because of an increased risk of mortality.
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Erectile Dysfunction
Sildenafil is used orally as vasoactive therapy to facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence). ED 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.
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Patient Assessment
A thorough medical history and physical examination should be undertaken to diagnose ED, 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 ED 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 ED 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 ED (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 ED as an adverse effect.
Because diagnosis of ED 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 ED 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 ED 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 ED (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 ED from complaints about ejaculation and/or orgasm, and establishing the severity and chronology of manifestations.
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Therapeutic Options
Sildenafil is effective in patients with organic (neurogenic, vasculogenic) or psychogenic ED and in those whose ED is of mixed etiology. Sildenafil also has been effective in counteracting drug-induced ED. 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 ED 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 ED (comprising up to 30% of all cases of ED) is suspected, and psychotherapy/behavioral therapy combined with vasoactive therapy or vacuum constriction devices to be appropriate in patients with such ED 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 ED or coexisting organic and psychogenic ED.
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 ED. Because sildenafil is administered orally, it is likely to be more acceptable to men with ED than other vasoactive therapies (e.g., intracavernosal injections, intraurethral suppositories) or mechanical or prosthetic devices since it can be administered discreetly and less invasively. 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 ED 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 ED 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 ED 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 ED; 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.
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Clinical Experience
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Efficacy
Efficacy of sildenafil is variable in patients with ED, 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 ED indicate that efficacy of sildenafil is not affected by race or age, duration of ED, or duration of select underlying disease states (e.g., diabetes mellitus), and the drug has been effective in a broad range of patients with ED, 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 ED 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 ED; 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 ED 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 ED secondary to radical prostatectomy compared with 15% of those receiving placebo. A pooled analysis of 10 placebo-controlled studies of men with severe ED (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 ED 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 ED 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 ED, 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 ED 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.
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Treatment Failures
While most males with ED 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 ED 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 ED that failed to respond to sildenafil.
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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 ED 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 ED). 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 ED. 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.
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Use in Patients with Cardiovascular Disease
ED 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 ED. Clinicians treating ED 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 Cardiovascular Precautions and Contraindications under Cautions: Precautions and Contraindications.) In reported clinical studies with sildenafil in patients with ED, 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 mm Hg) or hypotension (blood pressure less than 90/50 mm Hg) were excluded from these studies. In addition, only 21-23% of patients in clinical trials for ED 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 mm Hg) 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 mm Hg], fluid depletion, severe left ventricular outflow obstruction, autonomic dysfunction).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 ED in hypertensive men. If ED 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 ED 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 Cardiovascular Precautions and Contraindications under Cautions: Precautions and Contraindications.)
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Combination Therapy
The safety and efficacy of sildenafil in combination with other treatments for ED 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.
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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 a lack of blood flow to sexual organs and that sildenafil may improve such flow.
(See Clitoral Effects under Pharmacology: Genitourinary Effects.) Although physiologic changes such as improved blood flow in the vaginal or clitoral area have been demonstrated with sildenafil use, such changes have not been associated with an overall benefit for the treatment of sexual dysfunction in a mixed population of women with sexual dysfunction of various etiologies. Insufficient genital vasocongestion is thought to be part of the pathogenesis of female sexual arousal disorder of physiologic origin. Limited data indicate that women with sexual arousal disorder, including those with type 1 diabetes, without concomitant hypoactive sexual desire disorder may benefit from sildenafil. Sildenafil has not been effective in women with hypoactive sexual desire disorder and other dysfunctions not related to vasocongestion and lubrication.Sildenafil has been effective in a limited number of women for the management of sexual dysfunction induced by selective or nonselective serotonin-reuptake inhibitor antidepressants. In a small, randomized, double-blind trial in premenopausal women with major depressive disorder who were taking selective or nonselective serotonin reuptake inhibitors and who had satisfactory sexual function prior to the onset of depression and antidepressant use, use of sildenafil prior to sexual activity was associated with an improvement in global sexual functioning as measured by a Clinical Global Impression Scale (i.e., a composite of functional domains of desire, arousal-sensation, arousal-lubrication, orgasm, enjoyment, pain, partner) and a secondary efficacy measure of orgasm delay compared with that observed with placebo.
Data are limited concerning the use of sildenafil in women with neurogenic sexual dysfunction, such as those with spinal cord injury or multiple sclerosis. In a limited number of women with spinal cord injury, an increase in subjective levels of sexual arousal (scale from 0 [no arousal) to 10 [fully aroused]) during visual and manual sexual stimulation was observed with sildenafil compared with placebo. In a limited number of women with multiple sclerosis, results of sexual function questionnaires indicated an increase in lubrication with sildenafil compared with placebo; other components of sexual function such as desire, enjoyment, sensation, or orgasm were not affected.
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.)
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Pulmonary Arterial Hypertension
Sildenafil is used in adults for the symptomatic management of pulmonary arterial hypertension (PAH; World Health Organization [WHO] group 1 pulmonary hypertension) to improve exercise capacity and delay clinical worsening. Clinical studies establishing the efficacy of sildenafil for the treatment of PAH were short term (12-16 weeks) and conducted principally in adults with New York Heart Association (NYHA)/WHO functional class II-III symptoms and a diagnosis of idiopathic pulmonary hypertension or PAH associated with connective tissue diseases. While therapy with sildenafil can improve exercise capacity, NYHA/WHO functional class, and hemodynamics in patients with symptomatic PAH, the precise role of the drug alone or combined with other therapies (e.g., epoprostenol) remains to be more fully elucidated.
Because sildenafil at higher (more effective) dosages has been associated with increased mortality in children with PAH, FDA currently recommends against use of the drug in patients younger than 18 years of age with PAH. However, FDA states that there may be situations in which the risk-benefit profile of sildenafil may be acceptable in individual children.
(See Cautions: Pediatric Precautions.) Whether long-term sildenafil therapy has a beneficial effect on mortality in adults with PAH remains to be established.In addition to general treatment measures and supportive therapy (e.g., warfarin anticoagulation, diuretics, supplemental oxygen, digoxin), experts recommend PDE type 5 inhibitors (e.g., sildenafil, tadalafil) as one of several treatment options for the initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy has failed; alternative therapies include endothelin-receptor antagonists (e.g., ambrisentan, bosentan, macitentan), soluble guanylate cyclase stimulators (e.g., riociguat), or prostanoids (e.g., IV epoprostenol; inhaled iloprost; inhaled, IV, or subcutaneous treprostinil). Current guidelines for the management of PAH state that an oral agent such as a PDE type 5 inhibitor generally is preferred for initial therapy in patients with NYHA/WHO functional class II symptoms, while those with more advanced NYHA/WHO functional class III disease may be treated with any currently approved PAH therapy; IV epoprostenol generally is recommended as the treatment of choice for patients with NYHA/WHO class IV PAH because of its demonstrated survival benefit. In general, choice of therapy should be individualized, taking into account factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.
Efficacy of sildenafil for the management of PAH has been established in 2 randomized, double-blind, placebo-controlled clinical studies in patients with PAH (e.g., pulmonary artery pressure of 25 mm Hg or more and a pulmonary capillary wedge pressure less than 15 mm Hg at rest). Patients in these studies were principally white females who had WHO group I PAH, including those with primary pulmonary hypertension (idiopathic and familial) and PAH associated with connective tissue disease or congenital systemic-to-pulmonary shunts; most had NYHA functional class II or III symptoms at baseline.
In the first study, 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 functional 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.
The second study evaluated the efficacy and safety of oral sildenafil as an adjunct to long-term IV epoprostenol therapy in patients with PAH. Patients who were stabilized on IV epoprostenol received oral sildenafil (initial dosage of 20 mg 3 times daily, increased to 40 mg 3 times daily, then 80 mg 3 times daily as tolerated) or placebo for 16 weeks. Compared with epoprostenol monotherapy, the addition of sildenafil resulted in substantial improvements in exercise capacity, as measured by the change in 6-minute walking distance, from baseline to 16 weeks. Patients receiving sildenafil experienced a mean increase in placebo-corrected 6-minute walking distance of 28.8 meters; greater improvements were observed in those with a baseline 6-minute walking distance of 325 meters or more. When used as an adjunct to epoprostenol, sildenafil also resulted in substantial reductions in mean pulmonary artery pressures and slowed the rate of clinical worsening (defined as the time from randomization to the first occurrence of death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy) compared with placebo.
In another randomized, double-blind, dose-ranging study, patients with PAH receiving sildenafil 5 or 20 mg 3 times daily achieved similar changes (i.e., increases) from baseline in 6-minute walk distance at 12 weeks (primary end point); results at both of these dosages were substantially better than those observed with sildenafil 1 mg 3 times daily. The study was terminated prematurely after enrollment of 129 of a planned 219 patients. Patients in the study had predominantly WHO functional class II (57%) or III (41%) PAH and were predominantly female (67%) and Asian (67%).
Although results of a randomized, double-blind study revealed a lack of effect (no difference in 6-minute walking distance) of sildenafil (20 mg 3 times daily) added to bosentan (62.5-125 mg twice daily) therapy in patients with PAH, current expert consensus guidelines recommend combination therapy in patients who have an inadequate response to initial monotherapy with a PAH-specific agent. Combination therapy with drugs that target the different pathophysiologic pathways in PAH may provide additive and/or synergistic benefits. These experts state that combined use of a PDE type 5 inhibitor with a prostanoid or an endothelin-receptor antagonist (added sequentially) may be considered; however, concomitant use of PDE type 5 inhibitors and riociguat is contraindicated because of the risk of hypotension.
(See Drug Interactions: Riociguat.)
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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 ED. Such use may be difficult to avoid since clinicians rely on self-reporting as the principal mechanism for diagnosing ED. 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 ED, 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.
