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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.(See Cautions: Pediatric Precautions.)

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.

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.

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.

Clinical Experience

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.

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.

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.

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.)

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.

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.)

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.)

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.

Dosage and Administration

Reconstitution and Administration

Sildenafil is administered orally for the treatment of erectile dysfunction (ED). Administration of the drug with a high-fat meal decreases the rate but not extent of absorption, potentially delaying the onset of action of sildenafil.

When used for the treatment of pulmonary arterial hypertension (PAH), sildenafil usually is administered orally (as tablets or oral suspension); however, an IV preparation of the drug is available for continued treatment of PAH in patients who are temporarily unable to take oral medication.

Sildenafil powder for oral suspension should be prepared by adding a total of 90 mL of water (regardless of the dose of sildenafil prescribed) to provide 112 mL of suspension containing 10 mg of sildenafil (as the citrate) per mL. To reconstitute the powder, the bottle should be tapped to release the powder. The water should then be added in 2 portions (60 mL for the first addition and 30 mL for the second addition); after each addition, the bottle should be capped and shaken vigorously for at least 30 seconds. Following reconstitution, the bottle cap should be removed and the supplied bottle adapter pressed into the neck of the bottle; this adapter is provided so the 2-mL oral syringe (also provided, with 0.5- and 2-mL dose markings) can be filled with the suspension from the bottle. The expiration date of the reconstituted oral suspension (60 days from the date of reconstitution) should be written on the bottle label.

In patients with PAH, sildenafil is administered orally at the same times every day without regard to meals.(See Pharmacokinetics: Absorption.) If a dose of sildenafil is missed, the missed dose should be taken as soon as it is remembered, followed by resumption of the regular dosing schedule. Patients should be advised not to double the next dose if a dose is missed.

Dosage

Dosage of sildenafil citrate is expressed in terms of sildenafil.

For the treatment of ED, dosage of sildenafil, including both the dose and frequency of use, must be individualized carefully according to the patient's tolerance and erectile response.

Erectile Dysfunction

Initial Dosage

For most men with ED, the recommended initial dose of sildenafil is 50 mg taken orally if needed approximately 1 hour before anticipated sexual activity. It currently is recommended that the drug be taken no more frequently than once daily; in early studies, more frequent administration (e.g., 3 times daily) was associated with an increased incidence of certain adverse effects (e.g., myalgias). Although the sildenafil dose may be taken anywhere from 4 hours to 30 minutes before sexual activity, peak plasma concentrations usually are achieved within 1 hour (range: 30-120 minutes) when taken on an empty stomach; the erectile response is substantially diminished at 4 hours compared with 2 hours after administration.

Depending on effectiveness and tolerance, the dose subsequently may be increased to a maximum recommended dose of 100 mg once daily or decreased to 25 mg once daily. Evidence from dose-ranging studies indicates that erectile response is greater at 50- or 100-mg doses than at 25 mg.

Because geriatric patients may have age-related decreases in renal function and both the pharmacologic and adverse effects of sildenafil may be increased in such patients, consideration should be given to initiating therapy with the drug at a reduced dose of 25 mg in geriatric men 65 years of age and older with ED. The initial dose should be 25 mg in patients with ED and hepatic or severe renal impairment (see Dosage and Administration: Dosage in Renal and Hepatic Impairment).

A reduced initial sildenafil dose also is recommended for patients receiving drugs concomitantly that are potent cytochrome P-450 (CYP) isoenzyme 3A4 inhibitors including certain macrolide anti-infectives (e.g., erythromycin), azole antifungals (e.g., itraconazole, ketoconazole), or certain antiretrovirals (human immunodeficiency virus [HIV] protease inhibitors, delavirdine). For ketoconazole, itraconazole, and erythromycin, the manufacturer recommends that the dose be initiated at 25 mg for the treatment of ED and if well tolerated, the dose can be titrated upward cautiously as necessary. Some experts recommend that sildenafil be used with caution and at a reduced dosage of no more than 25 mg once every 48 hours in patients receiving any HIV protease inhibitor or the nonnucleoside reverse transcriptase inhibitor (NNRTI) delavirdine. Some experts and the manufacturer of etravirine, another NNRTI, state that sildenafil can be administered concomitantly with etravirine without dosage adjustment, but an increase in the dosage of sildenafil may be needed based on clinical effect.(See Antiretroviral Agents under Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Maintenance Dosage

Oral sildenafil self-medication therapy for ED usually is maintained at the dose that was determined as optimal during initial dosage titration. The optimal maintenance dose should result in an erection that is sufficient for intercourse and maintained after penetration. Adjustments to the initial titrated dose may be required if the underlying cause of ED progresses or if ED improves.

Follow-up monitoring of patients should be performed periodically (e.g., initially at 1-3 months and then annually) to determine patient tolerance, continuing need, and the possible need for dosage adjustment. Data from a large, open-label study in patients with ED of no known organic cause indicate that the dose at the end of a maintenance period (16 weeks) was 25 mg in 11.3% of patients, 50 mg in 29.1% of patients, and 100 mg in 58.1% of patients. In another clinical trial in patients with impotence as a result of complications of diabetes mellitus completing the recommended dose titration, no patients opted to decrease the dose to 25 mg from 50 or 100 mg; at the end of the 12-week study, 93% of patients were receiving the 100-mg dose and 7% were receiving the 50-mg dose. At the end of several large, 12-week, flexible-dose escalation studies with sildenafil (initial dose of 25-50 mg, then increasing or decreasing to 100 or 25 mg as tolerated or needed) in men with a broad spectrum of ED, 79-98% of the patients were taking 50 or 100 mg. Dosages exceeding 100 mg once daily are not recommended because of the increased risk of adverse effects and lack of evidence that such doses provide increased efficacy compared with a 100-mg dose.(See Uses: Erectile Dysfunction.)

Sildenafil has been shown to remain effective for at least 0.5-3 years in controlled and uncontrolled studies. Although such experience 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 the drug could mask the progression of a serious underlying disease must be considered. There currently are no specific limitations to continued sildenafil therapy based on patient age and/or duration of therapy alone.

Pulmonary Arterial Hypertension

For the symptomatic management of PAH (World Health Association [WHO] group 1 pulmonary hypertension), the recommended adult oral dosage of sildenafil is 5 or 20 mg 3 times daily, with doses given 4-6 hours apart. Although higher dosages (e.g., up to 80 mg 3 times daily) have been studied, they have not been more effective than 20 mg 3 times daily and therefore currently are not recommended by the manufacturer. Higher dosages of sildenafil have been associated with increased mortality in pediatric patients with PAH, and the manufacturer states that sildenafil is not recommended for use in patients younger than 18 years of age with PAH.(See Cautions: Pediatric Precautions.)

The recommended IV dosage of sildenafil in adults with PAH who are temporarily unable to take the drug orally is 2.5 or 10 mg 3 times daily by direct IV injection; the 10-mg IV dose is predicted to be equivalent to the 20-mg oral dose in terms of pharmacologic effects of sildenafil and its N-desmethyl metabolite.

Concomitant use of sildenafil with potent CYP isoenzyme 3A4 inhibitors including certain azole antifungals (e.g., itraconazole, ketoconazole), or certain antiretrovirals (e.g., ritonavir) is not recommended in patients with PAH, since increased serum sildenafil concentrations may occur. The manufacturer states that no dosage adjustments are needed with concomitant therapy with less potent CYP3A4 inhibitors such as erythromycin or saquinavir in patients with PAH.(See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Dosage selection should be cautious in geriatric patients with PAH, reflecting the greater frequency of decreased hepatic, renal, and/or cardiac function, and of concomitant disease or drug therapy.

Dosage in Renal and Hepatic Impairment

Because sildenafil is not extensively eliminated in the urine, pharmacokinetics of the drug are not altered substantially in patients with mild to moderate renal impairment. Therefore, dosage adjustment is not necessary in patients with ED with a limited degree of renal impairment. However, clinically important reductions in drug clearance can occur in patients with more severe impairment, and dosage modification is recommended for patients with ED. In patients with severe renal impairment (creatinine clearance less than 30 mL/minute), the initial sildenafil dose for the treatment of ED should be decreased to 25 mg, since the drug's effects may be prolonged and enhanced in such patients. Particular care should be taken in such patients who also are receiving concomitant therapy with a drug that may decrease blood pressure. However, in patients with PAH and renal impairment, including these with severe renal impairment (creatinine clearance less than 30 mL/minute), no dose adjustment is necessary.

Sildenafil is extensively metabolized in the liver, and substantially reduced drug clearance can occur in patients with impaired liver function. Therefore, sildenafil should be initiated at a reduced dose of 25 mg in patients with ED and hepatic impairment since the drug's effects may be prolonged and enhanced. In patients with PAH and mild to moderate hepatic impairment (Child Pugh class A and B), no dose adjustment of sildenafil is necessary. Sildenafil has not been studied in patients with PAH and severe hepatic impairment (Child-Pugh class C).(See Pharmacokinetics: Elimination.)

Cautions

Sildenafil generally is well tolerated, with common adverse effects being well characterized, mild to moderate in intensity, and generally transient. In flexible-dose clinical studies in patients with erectile dysfunction (ED), 62% of all reported adverse effects were classified as mild, with only about 7% being classified as severe. The most common adverse effects of sildenafil result from the pharmacologic activity of the drug as a phosphodiesterase (PDE) inhibitor, including those secondary to vascular smooth muscle relaxation and vasodilation from PDE type 5 inhibition, those secondary to relaxation of the lower esophageal sphincter from PDE type 5 inhibition, those secondary to mucosal hyperemia from PDE type 5 inhibition, and those secondary to ocular PDE type 6 inhibition. Such adverse effects include cardiovascular (e.g., flushing) and nervous system (e.g., headache) effects secondary to the vasodilatory activity of the drug, and adverse GI effects (e.g., reflux-induced dyspepsia and heartburn) secondary to sildenafil-induced reduction in lower esophageal sphincter tone.

In placebo-controlled clinical studies in patients with ED, the drug discontinuance rate secondary to adverse effects (e.g., headache, flushing, nausea) was similar for recommended sildenafil doses (25-100 mg) compared with placebo (2.5 versus 2.3%). In fixed-dose studies for the treatment of ED, the incidence of some of the adverse effects (e.g., headache, dizziness, vasodilation, dyspepsia, nausea, visual disturbances) increased with dose; in particular, dyspepsia and visual abnormalities are more common with doses of 100 mg or more than with lower doses. In general, the adverse effect profile of sildenafil doses exceeding the recommended range is similar to that of usual doses, but the frequencies are increased. For adverse effects reported in patients receiving sildenafil for ED, a causal relationship to the drug has not always been established, particularly for those occurring in less than 2% of patients.

In patients with pulmonary arterial hypertension (PAH), the drug discontinuance rate secondary to adverse effects was the same (3%) for sildenafil at the recommended dosage (20 mg 3 times daily) and placebo. The incidence of certain adverse effects (e.g., flushing, diarrhea, myalgia, visual disturbances) in these patients also increased with dosage.

Rarely, serious, potentially fatal effects (e.g., severe cardiovascular events) have been reported temporally in association with sildenafil use, but the contribution of the drug to a fatal outcome is unclear.(See Other Precautions and Contraindications under Cautions: Precautions and Contraindications and also see Drug Interactions.)

Cardiovascular and Cerebrovascular Effects

The most common adverse effects of sildenafil are vascular in origin, and resultant cardiovascular effects usually are transient and mild to moderate in severity, with 79% being classified as mild in clinical studies for the treatment of ED and only 6% being classified as severe. Rarely, cardiovascular effects may be severe enough to result in discontinuance of the drug, but the rate of discontinuance secondary to intolerable cardiovascular effects has been similar for sildenafil (0.9%) and placebo (0.9%) in controlled clinical trials for the treatment of ED.

Headache(see Cautions: Nervous System Effects) and flushing were the most common adverse vascular effects reported in controlled clinical trials with sildenafil, with the latter effect occurring in 10% of patients with ED and rarely (0.4% in flexible-dose ED studies) resulting in discontinuance of the drug. Although the incidence of common adverse effects with sildenafil reportedly has decreased as the duration of therapy increased, it remains to be established whether tolerance to common adverse vascular effects occurs with continued use.

While sildenafil-induced vasodilation generally results in only transient modest reductions in systolic and diastolic blood pressure that usually are clinically unimportant when the drug is taken alone (see Pharmacology: Cardiovascular and Cerebrovascular Effects), dizziness(see Cautions: Nervous System Effects), which rarely may be severe; hypotension, including postural (orthostatic) hypotension; and syncope have been reported in about 2% or less of patients receiving the drug for the treatment of ED, with the latter effects occurring at a rate comparable to that reported with placebo. Potentially severe and fatal hypotensive effects can occur in certain patients (e.g., those receiving an organic nitrate or nitrite concomitantly) (see Cardiovascular Precautions and Contraindications under Cautions: Precautions and Contraindications and also see Drug Interactions: Organic Nitrates and Nitrites). Blood pressure should be monitored in patients receiving concomitant antihypertensive drug therapy, particularly those receiving multidrug regimens.(See Drug Interactions: Antihypertensive and Hypotensive Agents.) However, no increase in blood pressure-related adverse effects or increase in blood pressure-lowering effects of thiazide, loop, or potassium-sparing diuretics; angiotensin-converting enzyme (ACE) inhibitors; calcium-channel blockers; or β-adrenergic receptor blocking agents has been observed in patients receiving these antihypertensives and sildenafil concomitantly in controlled clinical trials for the treatment of ED.

The risk of hypotension is of particular concern in patients with congestive heart failure who have borderline low blood volume and low blood pressure status, and additional study and experience are needed to determine the potential cardiovascular consequences of sildenafil use in high-risk cardiac patients (e.g., those with severe heart failure).(See Cardiovascular Precautions and Contraindications under Cautions: Precautions and Contraindications.) Of particular concern is the general absence of study and experience to assess the specific risks of sildenafil use in high-risk groups of patients with clinically important cardiac disease (e.g., heart failure, myocardial infarction, life-threatening arrhythmias, or stroke within the previous 6 months, uncontrolled hypertension) or blood pressures (systolic/diastolic) less than 90/50 or exceeding 170/100 mm Hg.

Angina pectoris, AV block, tachycardia, palpitation, myocardial ischemia and infarction, sudden cardiac death, chest pain, cerebral thrombosis, cerebrovascular hemorrhage (e.g., subarachnoid, intracerebral hemorrhage), transient ischemic attack, stroke (e.g., hemorrhagic or brainstem), cardiac or cardiopulmonary arrest, coronary artery disease, heart failure, electrocardiographic (ECG) abnormalities including ventricular arrhythmia (e.g., tachycardia, premature complexes) or Q-wave abnormalities (without myocardial infarction), hypertension, edema (including facial and peripheral), shock, and cardiomyopathy also have occurred in less than 2% of patients with ED receiving sildenafil in controlled clinical trials and in postmarketing surveillance, but have not been directly attributed to the drug. The incidence of myocardial infarction or stroke was similar in patients receiving sildenafil for the treatment of ED or placebo, and most cases occurred within a few hours to days after a sildenafil dose or placebo. Most patients experiencing serious adverse cardiovascular effects had preexisting cardiovascular risk factors, and many of these effects were reported to occur shortly after taking sildenafil, either with or without sexual activity.(See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.) In at least one patient with hypertrophic cardiomyopathy, decreased blood pressure, marked reductions in ventricular dimensions, increased ejection fraction and subaortic gradient at rest, ventricular premature complexes, and unsustained ventricular tachycardia occurred following sildenafil administration for the treatment of ED.

A precipitous reduction in blood pressure may occur with nitrate or nitrite use over the initial 24 hours following a dose of sildenafil; therefore, such concomitant therapy is contraindicated.(See Cardiovascular Precautions and Contraindications under Cautions: Precautions and Contraindications and also see Drug Interactions: Organic Nitrates and Nitrites.) Symptoms of hypotension in patients taking concomitant nitrates or nitrites may range from dizziness, lightheadedness, orthostatic hypotension, or syncope to an appreciable lowering of coronary perfusion and conversion of an area of myocardial ischemia to infarction and sudden death. It should be noted, however, that concomitant therapy with inhaled nitric oxide, and sildenafil may have beneficial augmented cardiovascular effects in patients with PAH.

Thrombosis occurred at the anastomosis site in a hypertensive patient with ED, chronic renal failure, and a forearm arteriovenous anastomosis. A varicose vein developed in at least one diabetic patient with ED receiving sildenafil. However, a causal relationship between these effects and sildenafil has not been established.

Headache, flushing, and erythema occurred in 46, 10, and 6%, respectively, of patients with PAH receiving sildenafil in a controlled clinical trial. Postural hypotension also has occurred in at least one patient with PAH after an initial 40-mg dose. Left ventricular dysfunction has occurred in at least one patient receiving the recommended sildenafil dosage for PAH. Vaso-occlusive crises requiring hospitalization were reported more frequently in patients with pulmonary hypertension secondary to sickle cell disease who received sildenafil than in those who received placebo in a small study; the study was terminated prematurely because of these findings. The manufacturer states that efficacy and safety of sildenafil in patients with sickle cell anemia have not been established.

Nervous System Effects

Headache was the most common adverse effect reported in controlled clinical trials with sildenafil, occurring in 16% of patients with ED and 46% of patients with PAH, and may be severe enough to result in discontinuance of the drug; migraine occurred in less than 2% of patients. Headache probably results from the vasodilatory effects of sildenafil, but it remains to be established whether tolerance to this effect develops with continued use. In clinical studies, headache was the most common reason for drug discontinuance, with 0.6-1.1% of sildenafil-treated patients with ED discontinuing the drug.

Dizziness, which also may be related to the drug's vasodilatory effects, occurred in 2% of patients with ED receiving sildenafil in controlled clinical trials. In fixed-dose studies, the incidence of dizziness was comparable across recommended doses (25-100 mg), but increased with higher doses (200 mg). At relatively high doses in clinical studies, dizziness rarely was severe. Ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, mental depression, insomnia, somnolence, abnormal dreams, decreased reflexes, asthenia, and hypoesthesia were reported in less than 2% of treated patients with ED, but a causal relationship to the drug has not been established. Seizures and seizure recurrence also have been associated with sildenafil use.

Insomnia or paresthesia was reported in 7 or 3%, respectively, of patients with PAH receiving sildenafil in a controlled clinical trial.

GI Effects

Dyspepsia/heartburn or diarrhea occurred in 7 or 3% of patients, respectively, receiving sildenafil in controlled clinical trials for the treatment of ED. Dyspepsia occurred in 13% of patients with PAH receiving sildenafil in a controlled clinical trial. Dyspepsia usually was mild to moderate in severity and described as an occasional burning sensation in the epigastrium, suggesting esophageal reflux as the cause. Dyspepsia occurred more often (17%) in patients receiving 100-mg doses of sildenafil for the treatment of ED compared with lower doses. Rarely, dyspepsia or nausea has been severe enough to result in discontinuance of the drug. PDE type 5 appears to be responsible for maintaining constriction of the lower esophageal sphincter and thus the integrity of the gastroesophageal junction, and inhibition of this enzyme by sildenafil can relax the sphincter resulting in gastroesophageal reflux and accompanying symptoms (e.g., dyspepsia, heartburn, esophagitis).

Vomiting, abdominal pain, glossitis, colitis, dysphagia, gastritis, gastroenteritis, stomatitis, dry mouth, rectal hemorrhage, thirst, or gingivitis occurred in less than 2% of patients receiving sildenafil for the treatment of ED in controlled clinical trials, but a causal relationship to the drug has not been established.

Diarrhea or gastritis occurred in 9 or 3%, respectively, of patients with PAH receiving sildenafil in a controlled clinical trial.

Ocular and Otic Effects

Ocular Effects

Dose-related visual abnormalities (e.g., blue/green color tinge or haze, increased brightness, light sensitivity, blurred vision) have been reported by men with ED receiving sildenafil, occurring only occasionally (e.g., 3%) at doses of 25-50 mg but more frequently (11%) in those receiving 100 mg and in 40% or greater of those receiving 200 mg. Similar dose-related visual changes have been reported at higher than recommended dosage (i.e., exceeding 20 mg 3 times daily) of sildenafil for the treatment of PAH. Visual changes principally have involved a blue/green color tinge to vision and have been mild and transient, persisting for a few minutes to hours after dosing, and only rarely have resulted in discontinuance of the drug. Such visual abnormalities probably result from sildenafil's pharmacologic activity at retinal photoreceptors secondary to inhibition of PDE type 6.(See Pharmacology: Ocular Effects.) While sildenafil is less selective than other PDE type 5 inhibitors (e.g., tadalafil, vardenafil), data from controlled clinical trials indicate that ocular effects do occur with other PDE type 5 inhibitors. The incidence and nature of adverse ocular effects associated with sildenafil were similar in open-label studies in diabetic versus nondiabetic patients.

While experience to date suggests that sildenafil-induced visual changes are acute and transient, there are theoretical concerns about the potential for more persistent and/or serious retinal changes with long-term use and in older patients and those with preexisting retinal abnormalities.(See Ocular Precautions and Contraindications under Cautions: Precautions and Contraindications.) However, current data and experience from animals and humans receiving sildenafil have failed to reveal clear evidence of a risk of toxic retinal effects at usual dosages, and the frequency of visual abnormalities has not been reported to increase with the duration of sildenafil therapy to date nor have long-term visual sequelae been reported. Even reported changes in electroretinographic parameters (see Pharmacology: Ocular Effects) in healthy individuals receiving the drug have not been alarming; there was no evidence of decreased sensitivity in visual field data, and the magnitude of decreases in a- and b-amplitude correlated with only a very weak loss in light sensitivity, comparable to the light-absorbing effect of a car windshield, and were reversible. In addition, daily exposure of dogs to 65 times the maximum recommended human dose for 12 months suggests that repeated therapeutic doses in humans are unlikely to impair retinal function or alter retinal morphology.

In studies measuring visual function, single oral sildenafil doses of 100-200 mg in healthy individuals resulted in transient dose-related impairment of color discrimination (blue/green), with effects peaking near the time of peak plasma drug concentrations and persisting for 1-3 hours after dosing; similar effects were noted in patients with diabetic retinopathy receiving 200 mg of sildenafil. In pilots receiving sildenafil before flying, blue/green color discrimination impairment may lead to pilot error in detecting taxiway, tower, and runway lights or in detecting color differences in video terminal displays.(See Ocular Precautions and Contraindications under Cautions: Precautions and Contraindications.)

Nonarteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely during postmarketing experience in temporal association with use of all PDE type 5 inhibitors for the treatment of ED. Most, but not all, of these patients had underlying anatomic or vascular risk factors for the development of NAION, including but not limited to low cup-to-disc ratio (''crowded disc''), age (older than 50), diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. Causality assessment is difficult because of the small number of events, the large number of patients receiving PDE type 5 inhibitors, the occurrence of optic neuropathy in a similar population of individuals who have not been exposed to PDE type 5 inhibitors, and plausible alternative causes (e.g., vascular risk factors, anatomic defects).(See Ocular Precautions and Contraindications under Cautions: Precautions and Contraindications.) Available data suggest that the annual incidence of NAION in the general population of men 50 years of age or older is 2.5-11.8 cases per 100,000. Results of an observational study involving patients with recent, episodic PDE type 5 inhibitor use (typical of ED treatment) suggest an approximately twofold increase in the risk of NAION within 5 half-lives of such use. Clinicians should discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE type 5 inhibitors.

Mydriasis, conjunctivitis, photophobia, ocular pain, ocular hemorrhage, cataract, or dry eyes occurred in less than 2% of patients with ED receiving sildenafil in controlled clinical trials, but a causal relationship to the drug has not been established. Diplopia, temporary vision loss, decreased vision, ocular hyperemia or bloodshot appearance, ocular flashes, ocular shadows, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal vascular disease or bleeding, vitreous detachment or traction, and paramacular edema also have been reported in patients with ED but not directly attributed to sildenafil. Intermittent diplopia occurred in a middle-aged man with ED within 36 hours after a second dose of sildenafil (50 mg within a month of the first dose); pupil-sparing third-nerve palsy developed during the ensuing 12 hours, but based on the short half-life of sildenafil, a causal relationship to the drug has been questioned.

Retinal hemorrhage occurred in 1.4 or 1.9% of patients with PAH receiving recommended (20 mg 3 times daily) or higher than recommended dosages of sildenafil, respectively, in a controlled clinical trial; retinal hemorrhage was not reported in patients receiving placebo. Ocular hemorrhage occurred in 1.4% of patients with PAH receiving sildenafil at recommended or higher dosages or placebo. Patients experiencing these hemorrhagic events had risk factors for hemorrhage, including concurrent anticoagulant therapy.

For additional information on the effects of sildenafil on visual function, see Pharmacology: Ocular Effects.

Otic Effects

Sudden decrease or loss of hearing has been reported in temporal association with use of PDE type 5 inhibitors, including sildenafil. At least 29 cases of such hearing impairment have occurred with or without concomitant vestibular manifestations (e.g., tinnitus, vertigo, dizziness). Reported hearing loss was unilateral in most cases, and temporary in about one-third of the cases. Such otic effects were observed in a few patients during premarket testing of these drugs; deafness, otic pain, and tinnitus were reported in less than 2% of patients receiving sildenafil in controlled clinical trials. In one case, a 44-year-old man experienced permanent, bilateral sensorineural deafness 15 days after initiating therapy with sildenafil 50 mg daily; this patient did not have any prior or current risk factors for ototoxicity.

It is unclear whether these otic effects are directly related to PDE type 5 inhibitors or attributed to other factors (e.g., patient's underlying medical condition, concomitant use of other ototoxic drugs); however, a strong temporal relationship has been observed between the use of PDE type 5 inhibitors and the onset of hearing impairment in the reported cases. (See Otic Precautions and Contraindications under Cautions: Precautions and Contraindications.)

Respiratory Effects

Nasal congestion, including rhinitis, occurred in 4% of the patients receiving sildenafil for the treatment of ED in controlled clinical trials. Nasal congestion appears to be secondary to sildenafil-induced hyperemia of the nasal mucosa, which results from inhibition of mucosal PDE type 5 and resultant local vasodilation.

Epistaxis was reported in 13% of patients with PAH secondary to connective tissue disease, 3% of patients with primary pulmonary hypertension, and 1% of those receiving placebo in controlled clinical trials. The incidence of epistaxis was higher in patients with PAH receiving concomitant warfarin.

Flu-like syndrome and respiratory tract infection occurred in greater than 2% of patients with ED receiving oral sildenafil in controlled clinical trials, but were similarly common in those receiving placebo. Asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased sputum, and increased cough were reported in less than 2% of patients with ED receiving sildenafil in controlled clinical trials but have not been directly attributed to the drug. Respiratory tract disorder also has been reported with the drug for the treatment of ED, but a causal relationship has not been established. Alveolar hemorrhage, accompanied by dyspnea, pulmonary edema, and focal bronchopneumonia and culminating in death, has been reported in a patient with ED receiving sildenafil with a history of pulmonary infiltration and angina controlled by nitroglycerin, diltiazem, and aspirin. Pulmonary hemorrhage has been reported through postmarketing experience receiving sildenafil for the treatment of ED.

Exacerbated dyspnea, rhinitis, and sinusitis have been reported in 7, 4, and 3%, respectively, of patients with PAH receiving sildenafil in a controlled clinical trial.

Genitourinary Effects

Urinary tract infection occurred in 3% of patients receiving sildenafil for ED in controlled clinical trials. Cystitis, nocturia, urinary frequency, urinary incontinence, abnormal ejaculation, genital edema, and anorgasmia were reported in less than 2% of the patients with ED receiving oral sildenafil in controlled clinical trials but have not been directly attributed to the drug. At least one patient in a long-term study discontinued therapy as a result of groin pain, and pelvic musculoskeletal pain was reported in an early clinical trial in patients with ED receiving sildenafil more frequently (25 or 50 mg 3 times daily) than currently recommended. Hematuria has been reported infrequently through postmarketing surveillance.

Although priapism was not reported in clinical trials with sildenafil, prolonged erection (exceeding 4 hours) and priapism (painful erection exceeding 6 hours) were reported infrequently during postmarketing surveillance with the drug. Nearly half of the men who reported priapism or prolonged erections had used sildenafil in combination with other drug therapy for ED (e.g., alprostadil, trazodone). In at least one patient, priapism was associated temporally with subsequent (9 days later) transient renal failure. Because of the risk of penile tissue damage and permanent loss of potency if priapism is not treated immediately, patients should be warned to seek immediate medical attention if an erection persists for longer than 4 hours.(See Genitourinary Precautions and Contraindications under Cautions: Precautions and Contraindications.) Because of differences in the pharmacology and pharmacodynamics of the drugs, sildenafil may be less likely to produce prolonged erections and/or priapism than other currently available vasoactive therapy (e.g., intracavernosal or intraurethral alprostadil, intracavernosal papaverine) for ED.

Hepatic Effects

Abnormal liver function test results occurred in less than 2% of patients with ED receiving sildenafil in controlled clinical trials but have not been directly attributed to the drug.

Dermatologic and Sensitivity Reactions

Rash, including maculopapular rash, has been reported in 2% of the patients with ED receiving sildenafil in controlled clinical trials. Urticaria, herpes simplex virus infection, pruritus, sweating, skin ulcer, contact dermatitis, photosensitivity reaction, allergic reaction, shock, and exfoliative dermatitis have been reported in less than 2% of patients with ED receiving sildenafil in controlled clinical trials, but a causal relationship to the drug has not been established.

Musculoskeletal Effects

Back pain and arthralgia occurred in greater than 2% of patients with ED receiving oral sildenafil in controlled clinical trials, but were similarly common in those receiving placebo. At least one patient with ED discontinued sildenafil therapy because of intolerable leg and back pain. Arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone or unspecified pain, myasthenia, and synovitis were reported in less than 2% of patients with ED receiving oral sildenafil in controlled clinical trials but have not been directly attributed to the drug.

Myalgia has been reported in 7% of patients with PAH receiving sildenafil in a controlled clinical trial. The incidence of myalgias is dose-related, although an obvious pharmacologic explanation for this effect currently is not known. Adverse musculoskeletal effects have not been accompanied by serum creatine kinase (CK, creatine phosphokinase, CPK) or electromyographic changes to date.

Metabolic and Electrolyte Effects

Hyperuricemia, gout, hyperglycemia, hypoglycemic reaction, unstable diabetes mellitus, or hypernatremia was reported in less than 2% of patients with ED receiving oral sildenafil in controlled clinical trials, but a causal relationship to the drug has not been established.

Other Adverse Effects

Accidental injury or fall, chills, and breast enlargement were reported in less than 2% of patients with ED receiving oral sildenafil in controlled clinical trials, but a causal relationship to the drug has not been established. Anemia and leukopenia also were reported in less than 2% of patients with ED receiving the drug orally in controlled clinical trials but also have not been directly attributed to the drug. Elevated neutrophil count was reported in at least one patient.

Pyrexia occurred in 6% of patients with PAH receiving sildenafil in a controlled clinical trial.

Precautions and Contraindications

Cardiovascular Precautions and Contraindications

The manufacturer states that sildenafil is contraindicated in patients receiving organic nitrates or nitrites or nitric oxide donors (e.g., sodium nitroprusside) in any form (e.g., orally, sublingually, transmucosally, parenterally), given regularly or intermittently, since severe, potentially fatal hypotensive episodes can occur. However, the American College of Cardiology (ACC) and American Heart Association (AHA) recognize that use of organic nitrates and nitrites in patients receiving sildenafil for ED may not be completely avoidable, provided sufficient time has elapsed between use of sildenafil and administration of the nitrate or nitrite.(See Drug Interactions: Organic Nitrates and Nitrites.) In patients with mildly recurring angina after sildenafil use, substitution of non-nitrate antianginal agents, such as β-blocking agents, should be considered so that the possibility of inadvertent combined use with an organic nitrate or nitrite within a 24-hour period (which is contraindicated) can be avoided. In patients with unstable angina who are not receiving a long-acting nitrate and who have short-acting nitrate or nitrite use as the only contraindication to sildenafil therapy but do not appear to require nitrate or nitrite therapy consistently, the risks and benefits of sildenafil therapy should be weighed carefully by the clinician and patient. For patients requiring nitrates or nitrites for mild to moderate exercise limitation, sildenafil therapy probably should be avoided since it is likely that the stress of sexual activity could precipitate an ischemic episode requiring use of the drugs for symptom relief and such combined use with sildenafil would be contraindicated. Organic nitrate and nitrite therapy also should be avoided in patients who develop myocardial infarction or unstable angina during sildenafil use.

Clinicians unfamiliar with their patients' drug history, especially those involved in emergency care (e.g., for presumed myocardial infarction or ischemia), should take a careful history so that concomitant use of organic nitrates or nitrites with sildenafil can be avoided. All patients receiving organic nitrates or nitrites should be warned about the potential interaction between the drugs and sildenafil, even if they currently are not receiving sildenafil, since there is substantial potential for patients to receive the drug from another clinician, from a friend, with little or no clinical intervention (e.g., via the Internet), or illicitly. Similarly, all patients taking either sildenafil or organic nitrates or nitrites must be warned of the potential consequences of taking sildenafil within 24 hours of taking a nitrate- or nitrite-containing preparation.

A degree of cardiac risk (e.g., increase in cardiac work, heart rate, blood pressure, and myocardial oxygen demand similar to that produced by moderate exercise) is associated with sexual activity in men with cardiovascular disease; therefore, clinicians should assess the cardiovascular and cerebrovascular status (including use of organic nitrates and nitrites) of their patients prior to initiating any treatment for ED. Conversely, patients with ED and risk factors for cardiovascular disease should discuss the cardiovascular risk of sexual activity with their clinician. In patients with coronary artery disease, ECG changes indicating ischemia and arrhythmias and symptoms of angina have occurred during coitus; myocardial infarction has occurred rarely within 2 hours of coitus. Therapy for ED, including sildenafil, generally should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. Patients who experience symptoms such as angina pectoris, dizziness, or nausea during sexual activity should be advised to refrain from further activity until they have discussed the episode with their clinician.

Although conclusive data are lacking, baseline treadmill testing to assess the possible presence of stress-induced ischemia in patients with overt or covert coronary artery disease can guide the patient and clinician regarding the relative risk of cardiac ischemia during sexual intercourse. For patients who are physically active and can achieve levels of moderate exercise (e.g., 5-6 metabolic equivalents [METS; a measure of oxygen uptake]) on an exercise treadmill test (ETT) without demonstrating ischemia, the risk of ischemia during coitus with a familiar partner, in a familiar setting, and without the added stress of heavy meal or alcohol ingestion probably is low. It should be recognized that the physical and emotional stresses of sexual intercourse can be excessive in certain individuals, particularly those who have not performed this activity in some time and who are not in good condition. Such stresses themselves may produce acute ischemia or precipitate myocardial infarction. Therefore, patients should be advised to use common sense and to moderate their physical exertion and emotional expectations once they begin their experience with sildenafil.

Cardiac and metabolic expenditures during sexual intercourse will vary depending on the type of sexual activity. In controlled settings, healthy males with their usual female partners achieved an average heart rate of 110 beats/minute with female-on-top coitus and an average heart rate of 127 beats/minute with male-on-top coitus. When oxygen uptake was measured in these men, an average metabolic expenditure during stimulation of 2.4 or 3.3 METS for female- or male-on-top coitus, respectively, was exhibited. However, substantial interindividual variation (2-5.4 METS) in cardiovascular responses for male-on-top coitus was observed, and thus simply equating a level of cardiac or metabolic expenditure during sexual intercourse to activity such as climbing 1 or 2 flights of stairs may underestimate the individual cardiovascular response.

Should an acute cardiac event occur in a patient receiving intermittent sildenafil, the clinician should attempt to establish a temporal relationship between drug use and onset of symptoms. Although definitive evidence currently is lacking, it is possible that a precipitous reduction in blood pressure may occur over the initial 24 hours following a dose of sildenafil; the duration of this risk may be prolonged in patients with hepatic dysfunction (e.g., cirrhosis), severe renal impairment (creatinine clearance less than 30 mL/minute), geriatric patients, or patients receiving potent hepatic cytochrome P-450 (CYP) microsomal isoenzyme 3A4 inhibitors (e.g., erythromycin).(See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.) Although plasma concentrations of sildenafil at 24 hours following dosing are much lower than peak plasma concentrations (peak plasma concentrations of 440 ng/mL versus 2 ng/mL at 24 hours after dosing), information is limited regarding whether organic nitrates and nitrites can be safely administered at this point. Patients who inadvertently receive sildenafil concomitantly with an organic nitrate or nitrite or receive one of these drugs within 24 hours after administration of sildenafil should be observed for possible additive hypotensive effects. Nitrate/nitrite therapy should be withheld and supportive and symptomatic treatment initiated as necessary, including administration of IV fluids and placement of the patient in Trendelenburg's position. Vasopressors (e.g., an α-adrenergic agonist such as phenylephrine) should be used judiciously to treat hypotension. For additional information on the management of sildenafil-induced hypotension, see Acute Toxicity: Treatment.

Most clinical trials with sildenafil for the treatment of ED excluded patients with recent (less than 6 months) myocardial infarction, stroke, life-threatening arrhythmia, or uncontrolled hypertension (blood pressure exceeding 170/110 mm Hg), and only a small fraction of the patients studied had heart disease (e.g., heart failure, coronary artery disease, unstable angina). No clinical trial data are available on the safety and efficacy of sildenafil in patients with PAH and coexisting recent (within 6 months) myocardial infarction, stroke, or life-threatening arrhythmia; coronary artery disease causing unstable angina; or hypertension (blood pressure exceeding 170/110 mmHg). If sildenafil is used for the treatment of PAH in such patients, caution is advised. Patients with PAH should inform their clinician of coexisting chest pain or recent (within 6 months) myocardial infarction, stroke, or arrhythmias prior to initiation of sildenafil.

Because of the potential cardiovascular effects of sildenafil and the lack of safety information on use of the drug in patients with severe or unstable heart disease, the drug should be used with caution in patients with active coronary ischemia who are not receiving nitrates or nitrites, with congestive heart failure and borderline low blood pressure or low blood volume, with left-ventricular outflow obstruction, with diseases (impaired hepatic or renal function) that may alter the excretion of sildenafil, and in those receiving a complex multidrug antihypertensive regimen or drugs (e.g., erythromycin, cimetidine) that may alter the elimination of sildenafil. Patients with coexisting renal or hepatic impairment should inform their clinician prior to initiation of treatment with sildenafil.(See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.) Because there are no controlled clinical data establishing the safety and efficacy of sildenafil in the following subpopulations of patients with ED, the drug should be used with caution in those with a recent (within 6 months) myocardial infarction, stroke, or life-threatening arrhythmia; in those with resting hypotension (systolic/diastolic blood pressure less than 90/50 mm Hg) or hypertension (systolic/diastolic blood pressure exceeding 170/110 mm Hg); and in those with cardiac failure or coronary artery disease causing unstable angina. Patients with ED should inform their clinician of any heart disease (e.g., angina, chest pain, heart failure, arrhythmias, myocardial infarction, aortic valve disease), stroke, high or low blood pressure, or poor circulation prior to initiation of treatment with sildenafil.

Clinicians should consider whether patients with underlying cardiovascular disease could be affected adversely by the vasodilatory activity of selective PDE type 5 inhibitor therapy, especially in combination with sexual activity. The possibility of a hypotensive reaction in patients receiving a selective PDE type 5 inhibitor concomitantly with antihypertensive drug therapy, particularly those receiving multidrug regimens, should be considered, and patients should be informed of this possibility.(See Drug Interactions: Antihypertensive and Hypotensive Agents.) Some experts state that monitoring of blood pressure during initiation of sildenafil therapy may be useful in identifying patients who may have an undesirable hypotensive response to the drug and is recommended for patients receiving a multidrug antihypertensive regimen and in those with congestive heart failure who have a borderline low blood volume because of concern about the potential consequences on blood pressure. In patients with severe renal impairment, concomitant use of sildenafil and antihypertensive agents should be undertaken with caution.

Rarely, serious, potentially fatal effects (e.g., severe cardiovascular events) have been reported temporally in association with sildenafil use, but the contribution of the drug to a fatal outcome is unclear. (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)

Pulmonary vasodilators may worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Because there currently are no clinical data on the use of sildenafil in patients with veno-occlusive disease, the manufacturer states that use of the drug in such patients is not recommended. Patients with PAH should inform their clinician of coexisting PVOD prior to initiation of sildenafil. The possibility of underlying PVOD should be considered in any patient exhibiting manifestations of pulmonary edema during sildenafil therapy.

Genitourinary Precautions and Contraindications

Sildenafil should be used with caution in patients with anatomic deformation of the penis that may make erections painful and/or sexual intercourse painful or difficult (such as angulation, cavernosal fibrosis, or Peyronie's disease) and in patients who have conditions that may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia). Patients should inform their clinician if they have anatomic deformations of the penis, history of prolonged erections, or such blood diseases. Patients should be warned that prolonged erections (exceeding 4 hours in duration) and priapism (painful erection exceeding 6 hours), while reported infrequently with sildenafil to date, are possible. Priapism is a medical emergency that could result in penile tissue damage and permanent loss of potency if not treated immediately, and therefore, patients should be advised to seek immediate medical attention if an erection that persists longer than 4 hours or that is extremely painful occurs.

Because safety and efficacy have not been established, combined use of sildenafil with other therapies for ED currently is not recommended by the manufacturer.

Patients should be advised that use of sildenafil provides no protection against sexually transmitted diseases, including intercurrent cystitis or human immunodeficiency virus (HIV) infection, and they should be counseled regarding protective measures to guard against such transmission.

The possibility of potentiation of systemic vasodilation by sildenafil in patients with lower urinary tract symptoms (e.g., benign prostatic hyperplasia) being treated with an α-adrenergic blocking agent should be considered.(See Drug Interactions: Antihypertensive and Hypertensive Agents.)

Ocular Precautions and Contraindications

Nonarteritic anterior ischemic optic neuropathy (NAION) has been reported in temporal association with the use of all PDE type 5 inhibitors; patients should discontinue sildenafil and contact a clinician immediately if sudden vision loss or decreased vision occurs in one or both eyes. Patients taking or considering taking a PDE type 5 inhibitor should inform their health-care professionals if they have ever had severe loss of vision, which might reflect a prior episode of NAION. Clinicians should advise patients of the increased risk of NAION in individuals who have already experienced NAION in one eye and potential effects of vasodilators such as PDE type 5 inhibitors on the development of NAION in the second eye.

Because sildenafil can cause visual disturbances (e.g., blue/green vision, changes in light sensitivity), particularly at high doses, patients should be advised about the potential for such effects and about the importance of not exceeding recommended doses or frequency of use. Because information concerning persistent or unexpected vision abnormalities reported with sildenafil use is limited, patients should be advised to remain alert for the possibility of such changes.

Patients should inform their clinician of the presence of retinitis pigmentosa or history of severe vision loss. Sildenafil should be used with caution in patients with retinitis pigmentosa, a retinal disorder that may be accompanied by a genetic disorder of retinal phosphodiesterases in some patients, since data establishing the safety and efficacy of the drug in these patients currently are lacking. Pending accumulation of such data, other clinicians suggest that sildenafil not be used at all in these patients or be used with particular or extreme caution and at the lowest possible dose; such precautions also have been suggested for patients with other retinal conditions such as macular degeneration or diabetic retinopathy. However, the manufacturer states that patients with age-related macular degeneration were included in clinical trials with sildenafil, and long-term treatment with the drug was not associated with a deterioration in vision. The theoretical possibility that heterozygote carriers of a PDE 6 gene defect also may have an accentuated risk for adverse visual effects of sildenafil should be considered. Some clinicians suggest periodic retinal exams in patients with retinal abnormalities.

The risk, if any, of persistent and/or serious retinal changes with long-term sildenafil use or with use in older patients remains to be elucidated but the possibility should be considered. Although current evidence suggests that the retinotoxic risk of sildenafil probably is low when used as recommended in otherwise healthy adults, some clinicians suggest that retinal function be monitored periodically in patients receiving the drug. However, in the light of current evidence, other clinicians and the manufacturer question the need for such routine monitoring in patients with normal baseline retinal function. Such monitoring is recommended for patients with ocular manifestations suggestive of retinal effects and in those at risk.

Patients should be warned that sildenafil-associated visual effects may impair their ability to perform certain tasks such as flying or operating a motor vehicle. It has been suggested that at least 6 hours elapse between use of sildenafil in pilots and engagement in flying. In addition, there are theoretical concerns that regular use of sildenafil may be incompatible with safe flight by pilots, air traffic controllers, or others who rely on fluorescent video terminal displays. It has been suggested that blue/green color discrimination impairment could lead to pilot error in detecting taxiway, tower, and runway lights or in detecting color differences in video terminal displays. Because of the possibility of sustained or residual erection if adequate time has not elapsed since taking the drug, full attention to instrument scanning and the flight task may be compromised (cockpit distraction).

Otic Precautions and Contraindications

Because sudden decrease or loss of hearing has been reported in temporal association with use of PDE type 5 inhibitors, including sildenafil, patients should be advised about the potential for such effects. Clinicians should instruct patients to discontinue sildenafil and any other PDE type 5 inhibitor and seek medical attention immediately if sudden hearing loss or decreased hearing occurs.

Other Precautions and Contraindications

Patients with ED should be instructed to visit their clinician for assessment of therapeutic benefit, including the need for possible dosage adjustment, and for monitoring of potential adverse effects of sildenafil therapy. Occasionally, it may be possible to discontinue sildenafil therapy because normal erectile function returns.

In patients with bleeding disorders or active peptic ulcers, sildenafil should be used with caution since safety of the drug has not been established. Patients with such conditions should inform their clinician prior to initiation of treatment with sildenafil.

The possibility that sildenafil could potentiate the effects of certain other drugs exhibiting antiplatelet activity should be considered.(See Drug Interactions: Platelet-Aggregation Inhibitors.)

Rarely, serious, potentially fatal effects (e.g., severe cardiovascular events) have been reported temporally in association with sildenafil use. The contribution of sildenafil to a fatal outcome in these cases is unclear, in part because of the high prevalence of underlying risk factors for sudden cardiac death in these patients and the additional risk associated with sexual activity, and the incidence of severe cardiovascular events (e.g., stroke, myocardial infarction) in clinical trials was similar in patients receiving sildenafil or placebo. The risk of mortality observed with sildenafil increases in association with certain risk factors, such as strenuous sexual activity in the presence of cardiovascular disease or serious drug interactions with organic nitrates or nitrites. Because ED and cardiovascular disease share several common risk factors (e.g., dyslipidemias, hypertension, diabetes mellitus, smoking), a number of deaths, mostly involving cardiac events (myocardial infarction, cardiac arrest, coronary artery disease, severe hypotension), have occurred in middle-aged men (average age: 64 years) who had one or more of these risk factors while receiving sildenafil.

The deaths reported with sildenafil have occurred with the expected background frequency in a population of older men with various concomitant diseases and risk factors. In a small number of patients who had no previously identified heart disease or other risk factor, severe coronary artery disease was detected at autopsy. Of the reported deaths that noted dosage and timing of the event, most patients had received the recommended dosage, and over a third of the fatalities occurred within 4-5 hours of sildenafil use, during or after sexual intercourse. A small number of these deaths were associated with concomitant use of organic nitrates or nitrites, which is contraindicated with sildenafil.(See Drug Interactions: Organic Nitrates and Nitrites.)

Sildenafil is contraindicated in patients with hypersensitivity to any component of the drug formulations; rare cases of hypersensitivity, including anaphylaxis and anaphylactoid reactions, have been reported in patients receiving the drug. Patients should inform their clinician of such hypersensitivity reactions.

Pediatric Precautions

The manufacturer states that safety and efficacy of sildenafil in children have not been established. Although sildenafil has been used effectively in a limited number of children for the symptomatic treatment of PAH, use of the drug currently is not recommended for treatment of PAH in pediatric patients younger than 18 years of age, particularly for chronic therapy. This recommendation is based on findings from a randomized, controlled, dose-ranging study that demonstrated an increased risk of mortality in children with PAH receiving high dosages of sildenafil and a lack of benefit from low dosages of the drug. FDA currently states that this recommendation is not intended to suggest that sildenafil should never be used in pediatric patients; there may be situations in which the risk-benefit profile may be acceptable in individual children (e.g., when other treatment options are limited and sildenafil can be used with close monitoring).

In the dose-ranging study in children and adolescents, patients 1-17 years of age with PAH (idiopathic, familial, or PAH associated with connective tissue or congenital heart disease) received placebo or sildenafil at a low, medium, or high dosage for 16 weeks; after completion of the placebo-controlled portion of the study, patients were enrolled in an ongoing extension phase during which all patients received sildenafil therapy. Although sildenafil at the medium or high dosage levels resulted in clinical improvements (e.g., exercise capacity, hemodynamic parameters, WHO functional class) compared with placebo, a higher rate of mortality was observed in patients who received the high versus low dosage of the drug during the long-term portion of the trial (hazard ratio of 3.5 at a mean follow-up period of 3 years). Deaths were observed after about 1 year and continued to occur at a fairly constant rate thereafter; in most cases, the cause of death was disease progression.

Geriatric Precautions

While safety and efficacy of sildenafil in geriatric patients have not been established specifically, 21-23% of patients who received the drug for ED in clinical trials were 65 years of age and older. Pooled data from 8 controlled clinical trials indicate that sildenafil is comparably effective in geriatric men 65 years of age and older compared with younger men with ED. However, because pharmacokinetic studies revealed decreased clearance of sildenafil and increased (by 40%) area under the plasma concentration-time curve (AUC) in healthy geriatric individuals(see Pharmacokinetics: Elimination), it is recommended that therapy with the drug be initiated in geriatric patients at a lower dosage than in younger adults.(See Initial Dosage under Dosage: Erectile Dysfunction, in Dosage and Administration.)

Clinical studies of sildenafil for PAH did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger adults. Other reported clinical experience has not identified differences in response between geriatric and younger patients with PAH. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly should be considered in dosage selection for the treatment of PAH.

Mutagenicity and Carcinogenicity

Sildenafil did not exhibit evidence of mutagenicity in vitro in bacterial and Chinese hamster ovary cell assays. The drug also did not exhibit clastogenic potential in vivo in the mouse micronucleus test or in an in vitro mammalian (human lymphocytes) test system.

Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (as determined by area under the plasma concentration-time curve [AUC]) for unbound sildenafil and its major metabolite of 29- and 42-times, for male and female rats, respectively, the exposures observed in human males given the maximum recommended human dose of 100 mg for the treatment of ED. The drug also was not carcinogenic when administered to mice for 18-21 months at dosages up to the maximum tolerated dose of 10 mg/kg daily, which is approximately 0.6 times the maximum recommended human dose on a mg/m basis.

Pregnancy, Fertility, and Lactation

Pregnancy

No adequate and well-controlled studies have been performed using sildenafil in pregnant women. Sildenafil should be used in pregnant women only when clearly needed. Women with PAH should inform their clinician if they are or plan to become pregnant prior to initiation of treatment with sildenafil.

The safety and efficacy of sildenafil during labor and delivery have not been established.

No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in rats and rabbits receiving up to 200 mg/kg daily of sildenafil during organogenesis. These doses in rats and rabbits represent, respectively, about 20 and 40 times the maximum recommended human dose for the treatment of ED on a mg/m basis in a 50-kg patient or 32 and 68 times the recommended human dose for the treatment of PAH. In a prenatal and postnatal development study in rats receiving 30 mg/kg daily for 36 days (about 20 times the AUC observed in humans), no adverse effects were observed.

Fertility

Reproduction studies (36 days in female rats and 102 days in male rats) revealed no evidence of impaired fertility at sildenafil dosages up to 60 mg/kg daily, a dosage representing more than 25 times the human male AUC. Such dosage represents 19 and 38 times for males and females, respectively, the recommended human dosage for the treatment of PAH. No effect on sperm motility or morphology was noted after single 100-mg oral sildenafil doses in healthy human adults.

Lactation

No adequate and well-controlled studies have been performed using sildenafil in nursing women. Since it is not known whether sildenafil and/or its metabolites are distributed into breast milk, the drug should be used with caution in nursing women.

Drug Interactions

Organic Nitrates and Nitrites

Cardiovascular Nitrates and Nitrites

Sildenafil and other phosphodiesterase (PDE) type 5 inhibitors (e.g., tadalafil, vardenafil) profoundly potentiate the vasodilatory effects (e.g., a systolic blood pressure reduction exceeding 25 mm Hg with sildenafil) of organic nitrates and nitrites (e.g., nitroglycerin, isosorbide dinitrate), and potentially life-threatening hypotension and/or hemodynamic compromise can result. Nitrates and nitrites promote the formation of cyclic guanosine monophosphate (cGMP) by stimulating guanylate cyclase, and PDE type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) act to decrease the degradation of cGMP via PDE type 5 by inhibiting this enzyme, resulting in increased accumulation of cGMP and more pronounced smooth muscle relaxation and vasodilation than with either PDE type 5 inhibitors or nitrates/nitrites alone. This interaction probably occurs with any organic nitrate, nitrite, or nitric oxide donor (e.g., nitroprusside) regardless of their predominant hemodynamic site of action.

PDE type 5 inhibitors also may potentiate the hypotensive effects of inhaled nitrites (e.g., amyl or butyl nitrite, sometimes referred to as poppers), which may be misused (recreational use) during sexual activity for purported effects in enhancing the sexual experience. Because these agents are used recreationally, patients may be unaware of their pharmacologic effects and potential risks and may not report their use to clinicians. Concurrent use of PDE type 5 inhibitors with poppers, which dilate blood vessels with a rapid onset of action, could result in sudden and marked blood pressure reduction and potentially serious or even fatal effects. Interactions with organic nitrates and nitrites may be even more pronounced in patients who also are taking certain HIV protease inhibitors concomitantly.(See Antiretroviral Agents under Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.) Homosexual males may be at particular risk because of the greater likelihood of recreational inhaled nitrite use and antiretroviral therapy in this population.

Because of the serious risk of concomitant use of PDE type 5 inhibitors and organic nitrates or nitrites, such combined use is contraindicated. At least 19 deaths have been reported in patients who may have taken sildenafil and who took or were given nitroglycerin or another nitrate/nitrite or who were found with nitroglycerin in their possession. The manufacturers of PDE type 5 inhibitors state that these drugs are contraindicated in any patient receiving organic nitrates or nitrites, either regularly or intermittently and in any form (e.g., orally, sublingually, transmucosally, parenterally). However, the American College of Cardiology (ACC) and American Heart Association (AHA) recognize that use of organic nitrates and nitrites in patients receiving sildenafil may not be completely avoidable, provided sufficient time has elapsed between use of sildenafil and administration of the nitrate or nitrite. Although it is not known how much time must elapse between use of sildenafil and administration of a nitrate or nitrite, pharmacokinetic data suggest that these latter agents should not be given within 24 hours of sildenafil administration because an exaggerated hypotensive response is likely; plasma sildenafil concentrations are substantially lower 24 hours after a dose than peak concentrations. The point at which nitrates or nitrites can be given safely is unclear, and therefore the drugs should be avoided unless, in the view of the treating clinician, the benefits outweigh the risks.

If consideration is given to administering a nitrate or nitrite beyond 24 hours after sildenafil use, the response to the initial doses must be monitored carefully and proper facilities for fluid and vasopressor (e.g., α-adrenergic agonists) support must be readily available to prevent acute ischemic episodes. In patients in whom clearance of sildenafil and/or its metabolites may be prolonged (e.g., those with hepatic [e.g., cirrhosis] or severe renal impairment [e.g., creatinine clearance less than 30 mL/minute], those receiving a potent inhibitor of cytochrome P-450 [CYP] isoenzyme 3A4, geriatric patients older than 65 years of age), a more extended period of time between use of sildenafil and administration of a nitrate or nitrite may be necessary. In either case, a short-acting nitrate formulation that can be titrated readily (e.g., IV nitroglycerin) would be preferred and such use should be accompanied by close hemodynamic monitoring.

Patients who develop an acute myocardial infarction or unstable angina should be managed according to current guidelines, except that nitrates and nitrites should not be used. After 24 hours have elapsed, nitrates and nitrites can be administered judiciously, if needed, provided close monitoring is instituted and facilities are available for fluid and vasopressor support. In patients who were receiving sildenafil concomitantly with a nitrate or nitrite, the possibility that the acute myocardial infarction may have resulted from low diastolic perfusion pressure in coronary circulation should be considered; blood pressure support may be sufficient to prevent further myocardial damage, provided an acute plaque rupture is not present. There currently is no evidence to preclude use of heparin, β-adrenergic blockers, calcium-channel blockers, thrombolytic agents, opiate agonists, or aspirin if indicated.

All patients receiving either sildenafil or an organic nitrate or nitrite should be warned about the contraindications and the potential consequences of taking sildenafil within 24 hours of nitrate or nitrite use, even sublingual nitroglycerin. Patients should inform their clinician if they are taking nitrates. Although sublingual nitroglycerin is relatively short-acting, any use during the previous 24 hours suggests that it may be needed again after sildenafil-enhanced sexual activity. In addition, the presence of even trace amounts of nitrates or nitrites may have unknown effects in combination with sildenafil.

Because sildenafil may be obtained without the knowledge of the physician and/or pharmacist, including via the Internet or illicitly, all patients prescribed nitrates or nitrites should be warned of the potential consequences of combined use with sildenafil. The possibility of recreational use of inhaled nitrites (''poppers'') also should be considered whenever sildenafil is prescribed, particularly in homosexual males.

Nitric Oxide and Its Donors

In addition to the hypotensive effect, in vitro studies indicate that sildenafil, by inhibiting PDE type 5, potentiates the inhibitory effect of nitric oxide and sodium nitroprusside (a nitric oxide donor) on platelet aggregation. Sildenafil is likely to have little or no effect on platelet function in the absence of such donors.

Sildenafil has been reported to both augment and prolong the pulmonary cardiovascular effects (e.g., reduced pulmonary arterial pressure and vascular resistance, increased cardiac index) of inhaled nitric oxide in patients with pulmonary arterial hypertension (PAH). In addition, sildenafil ameliorates the rebound pulmonary vasoconstriction precipitated by withdrawal of nitric oxide inhalation therapy. Because nitric oxide can increase intracellular cGMP concentrations with resultant smooth muscle relaxation, the gas has been used via inhalation as a pulmonary vasodilator in the management of pulmonary hypertension and respiratory failure. Abrupt withdrawal of nitric oxide therapy may be complicated by life-threatening events (e.g., rebound pulmonary hypertension, oxygen desaturation), and PDE type 5 activity may play a role in this phenomenon. In several infants who were treated with inhaled nitric oxide and could not be weaned successfully from the gas, oral administration of sildenafil 70-90 minutes prior to another attempted withdrawal of nitric oxide therapy was associated with a near doubling of circulating cGMP concentrations and substantial attenuation of rebound increases in pulmonary artery pressure. It was postulated that nitric oxide inhalation therapy is associated with negative-feedback inhibition of nitric oxide synthase activity, resulting in a rapid decrease in pulmonary vascular smooth muscle cGMP when the gas is withdrawn abruptly. By inhibiting PDE type 5, sildenafil can increase intracellular and circulating cGMP, thus potentiating the pulmonary vasodilatory effect of nitric oxide, and prevent rapid depletion of cGMP and associated deleterious pulmonary effects when the gas is withdrawn.

Nitrous Oxide

Because inhaled nitrous oxide does not form nitric oxide in humans and does not directly activate guanylate cyclase, no apparent contraindication to concomitant use with sildenafil exists. In addition, nitrous oxide does not undergo detectable biotransformation and is rapidly (within minutes) eliminated unchanged, principally via the lungs.

Dietary Sources

Dietary sources of nitrites, nitrates, and l-arginine (precursor to nitric oxide) do not contribute to circulating concentrations of nitric oxide in humans, and are unlikely to interact with sildenafil.

Alcohol

Although patients have been advised (e.g., in some clinical studies) not to consume more than 2 alcoholic drinks within 1 hour of anticipated sexual activity and sildenafil use, sildenafil 50 mg did not potentiate the hypotensive effect of alcohol in healthy individuals (mean maximum blood alcohol concentrations of 0.08%). However, the possibility that heavy alcohol ingestion could add to the stress of sexual activity and the risk of cardiac ischemia during coitus should be considered. In addition, the possibility that alcohol consumption could contribute to erectile dysfunction (ED) should be considered.

Platelet-Aggregation Inhibitors

There currently is no evidence precluding aspirin use in patients receiving sildenafil. In a clinical trial combining a single dose of sildenafil (50 mg) and aspirin (150 mg), sildenafil did not potentiate the aspirin-induced increase in bleeding time. Dosage adjustments are not required when the drugs are used concomitantly.

Sildenafil can potentiate the inhibitory effect of nitric oxide donors (e.g., sodium nitroprusside) on adenosine diphosphate (ADP)-induced platelet aggregation.(See Nitric Oxide and Its Donors under Drug Interactions: Organic Nitrates and Nitrites.)

Specific drug interaction studies have not been conducted with sildenafil and other platelet-aggregation inhibitors such as dipyridamole, ticlopidine, or clopidogrel. Dipyridamole is a nonspecific inhibitor of phosphodiesterases, increasing cyclic adenosine-3',5'-monophosphate (cAMP) in platelets, and therefore a theoretical possibility for a drug interaction with sildenafil exists.(See Drug Interactions: Phosphodiesterase Inhibitors.) However, the manufacturer makes no specific recommendations concerning combined use of the drugs. Ticlopidine and clopidogrel inhibit platelet aggregation through other mechanisms (e.g., inhibition of ADP-mediated platelet activation).

Antihypertensive and Hypotensive Agents

Sildenafil has systemic vasodilatory effects and may augment the blood pressure-lowering effect of other antihypertensive agents. Nitric oxide plays an important role in the regulation of basal systemic vascular resistance and blood pressure in healthy individuals secondary to nitric oxide-induced activation of guanylate cyclase with resultant increases in cGMP formation in target tissues. By acting on this pathway, exogenously administered organic nitrates and nitrites can decrease blood pressure substantially and produce postural hypotension. Since sildenafil does not directly activate guanylate cyclase, but does enhance the response to nitric oxide, the drug has been shown to exhibit only modest, transient vasodilating properties and blood pressure effects when administered alone.(See Pharmacology: Cardiovascular and Cerebrovascular Effects.) However, profound hypotensive effects can occur if sildenafil is administered concomitantly with a nitrate or nitrite.(See Drug Interactions: Organic Nitrates and Nitrites.)

Exaggerated hypotensive responses secondary to sildenafil use in patients receiving antihypertensive therapy has not been observed in retrospective analyses of numerous clinical trials. In some patients, however, the possibility that even the modest sildenafil-induced reduction in blood pressure may have adverse consequences (e.g., certain patients with underlying cardiovascular disease), particularly when combined with sexual activity, should be considered. (See Cardiovascular Precautions and Contraindications under Cautions: Precautions and Contraindications.) Blood pressure should be monitored in patients receiving concomitant therapy with sildenafil and an antihypertensive agent.

Retrospective analysis of patients receiving sildenafil and antihypertensive agents (e.g., β-adrenergic blocking agents; thiazide, loop, or potassium-sparing diuretics; calcium-channel blocking agents; angiotensin-converting enzyme [ACE] inhibitors) concomitantly did not reveal evidence of an increase in blood pressure-related adverse effects nor any systematic enhancement of the blood pressure-lowering effect of the antihypertensives. However, pharmacokinetic and hemodynamic interactions have been reported occasionally in patients receiving sildenafil and certain antihypertensive agents concomitantly (i.e., loop and potassium-sparing diuretics, nonspecific β-adrenergic blocking agents, amlodipine, α-adrenergic blocking agents), and there is a concern that the risk of a hypotensive reaction may be increased in sildenafil-treated patients receiving multiple drugs that include antihypertensive therapy and an inhibitor of the CYP3A4 metabolic pathway.

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. However, they consider it prudent to advise any patient who is receiving sildenafil concomitantly with antihypertensive therapy, particularly multiple drugs, of the possibility of a hypotensive reaction. Because sildenafil can cause both venous and arterial vasodilation, monitoring of blood pressure during initiation of sildenafil therapy may be useful in identifying patients with an undesired hypotensive blood pressure response. The risk of an undesired hypotensive response is of particular concern in patients with congestive heart failure and a borderline low blood volume and low blood pressure status as well as in patients with left-ventricular outflow obstruction, those with severely impaired autonomic control of blood pressure, and in those who are receiving a complex, multidrug antihypertensive regimen.

The area under the plasma concentration-time curve (AUC) of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific β-adrenergic blocking agents and clearance of the active metabolite was reduced by 31 and 54%, respectively; however, the increased active metabolite concentrations are not expected to be clinically important. A number of the patients receiving sildenafil and β-adrenergic blocking agents also were receiving CYP3A4 inhibitors that may have contributed to the effects observed.(See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Additive hypotensive effects may be anticipated when PDE type 5 inhibitors are administered concurrently with α-adrenergic blocking agents (e.g., terazosin, doxazosin, tamsulosin). Stepwise increases in the dosage of the α-adrenergic blocking agent may further lower blood pressure when a PDE type 5 inhibitor is administered concurrently. In several placebo-controlled crossover studies in patients with benign prostatic hyperplasia receiving doxazosin (4 or 8 mg daily) under steady-state conditions, administration of a single dose of sildenafil (50 or 100 mg) resulted in symptomatic hypotension (e.g., dizziness, lightheadedness, nausea, headache, fatigue) in some patients, occurring within approximately 0.5-4 hours of sildenafil administration. Supine blood pressure (systolic and diastolic) decreased by an additional 7/7, 9/5, and 8/4 mm Hg when sildenafil at dosages of 25, 50, and 100 mg, respectively, was administered simultaneously with doxazosin (4 or 8 mg). In addition, standing blood pressure was reduced by an additional 6/6, 11/4, and 4/5 mm Hg, respectively, at these sildenafil dosages. Although symptomatic hypotension occurred in a few patients who received sildenafil 50 or 100 mg, syncope was not reported during these drug interaction studies. Caution is advised when PDE type 5 inhibitors are used concomitantly with an α-adrenergic blocking agent. Patients should be hemodynamically stable on α-adrenergic blocking therapy prior to initiating therapy with a PDE type 5 inhibitor. Patients who demonstrate hemodynamic instability on α-adrenergic blocking therapy are at increased risk of symptomatic hypotension with concomitant use of PDE type 5 inhibitors. In patients who are hemodynamically stable on α-adrenergic blocking therapy, PDE type 5 inhibitors should be initiated at the lowest recommended dose. Conversely, in patients taking an optimized dose of a PDE type 5 inhibitor, therapy with an α-adrenergic blocking agent should be initiated at the lowest recommended dosage. Safety of combination therapy with an α-adrenergic blocking agent may be affected by other variables, including intravascular volume depletion and concomitant use of other antihypertensive agents. Clinicians should advise patients of the potential for sildenafil to augment the blood pressure-lowering effects of α-adrenergic blocking agents and other antihypertensive agents.(See Cautions: Cardiovascular and Cerebrovascular Effects.)

Concomitant administration of sildenafil and doxazosin resulted in either no change or a slight increase in plasma concentrations of doxazosin depending on the dose of sildenafil administered (25, 50, or 100 mg).

Following administration of single 100-mg sildenafil doses in hypertensive patients whose blood pressure was controlled with amlodipine 5 or 10 mg daily, mean supine blood pressure was reduced (systolic by 8 mm Hg, diastolic by 7 mm Hg); the additional reduction in blood pressure is of a similar magnitude to that seen when sildenafil is administered alone to healthy individuals, indicating an additive effect. The greatest decreases in supine systolic and diastolic blood pressures following sildenafil administration were in patients with the highest baseline blood pressures and vice versa, suggesting that the likelihood of a hypotensive episode during combined use with amlodipine is low.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Sildenafil metabolism is mediated principally by CYP isoenzymes 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors or inducers of these isoenzymes may reduce or increase sildenafil clearance, respectively. The possibility that any drug that is metabolized by, induces, or inhibits CYP3A4 may interact with sildenafil should be considered. In some cases, a reduction in sildenafil dosage is recommended, while in other cases, concomitant use of the drugs should be avoided.

Although pooled data from a retrospective analysis of subgroups of patients who received sildenafil and CYP3A4 inhibitors (e.g., cimetidine, ketoconazole, erythromycin) in several clinical studies indicated that the incidence, severity, and duration of adverse cardiovascular effects were similar to those in patients not receiving such inhibitors concomitantly, pharmacokinetic interactions have been reported. Population pharmacokinetic analyses have shown an approximate 30% reduction in sildenafil clearance when the drug was administered concomitantly with mild to moderate CYP3A inhibitors. In specific drug interaction studies with some CYP3A inhibitors, exposure to sildenafil was increased by fivefold.

Concomitant administration of potent CYP3A inducers (e.g., bosentan) is expected to cause substantial decreases in sildenafil plasma concentrations. Population pharmacokinetic analyses from clinical trials have shown an approximate threefold increase in sildenafil clearance when administered concomitantly with mild CYP3A inducers. Clinically important pharmacokinetic interactions also have been reported with several antiretroviral agents that inhibit CYP3A4 (e.g., ritonavir, saquinavir) and potentially could result in an increase in sildenafil-associated adverse effects.

In vitro studies indicate that sildenafil is a weak inhibitor of the CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. Because peak plasma sildenafil concentrations achieved with recommended doses for ED are well below the concentrations necessary for in vitro inhibition of these CYP isoenzymes, the manufacturer states that it is unlikely that sildenafil will alter the clearance of drugs metabolized by these isoenzymes.

Antiretroviral Agents

Combination antiretroviral therapy usually includes one or more HIV protease inhibitors that are inhibitors of CYP3A4 and/or CYP2C9, and the possibility for an interaction with sildenafil clearance resulting in an increased likelihood of sildenafil-associated adverse effects such as headache, flushing, visual changes, priapism, and possibly hypotension and syncope exists. Patients should inform their clinician if they are taking antiretroviral therapy.

While reported experience with use of sildenafil in HIV-infected patients receiving antiretroviral therapy is limited, clinically important pharmacokinetic interactions have been demonstrated when the drug was used concomitantly with ritonavir and saquinavir. Pretreatment with saquinavir (1200-mg liquid-filled capsules [no longer commercially available in the US] 3 times daily) or ritonavir (500 mg twice daily) followed by a single dose of sildenafil (100 mg) increased sildenafil's AUCs by 210 or 1000%, respectively, and the peak plasma concentrations by 140 or 300%, respectively. In these patients receiving ritonavir and sildenafil, plasma concentrations at 24 hours were approximately 200 ng/mL compared with 5 ng/mL when sildenafil was given alone. Ritonavir is a potent inhibitor of both the major (CYP3A4) and minor (CYP2C9) metabolic pathways for sildenafil, while saquinavir is a relatively weak inhibitor of CYP3A4 (compared with ritonavir, indinavir, or nelfinavir), with little inhibitory activity against CYP2C9. Sildenafil is only a weak inhibitor of CYP3A4 and CYP2D6 isoenzymes and single doses of the drug had no effect on steady-state saquinavir or ritonavir pharmacokinetics in healthy adults.

A decrease in sildenafil clearance and a substantial increase in sildenafil concentrations also is expected with amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir in fixed combination with ritonavir, nelfinavir, and tipranavir or darunavir in combination with low-dose ritonavir, and with delavirdine, a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has been shown to inhibit both CYP3A4 and CYP2C9.

In a study in a limited number of patients, pretreatment with etravirine followed by a single dose of sildenafil (50 mg) decreased plasma concentrations of sildenafil and its active N-desmethyl metabolite. Etravirine is an NNRTI that has been shown to induce CYP3A4 and inhibit CYP2C9 and 2C19. Etravirine and sildenafil may be administered concomitantly without dosage adjustments; however, the dosage of sildenafil may need to be increased based on clinical effect.

Sildenafil should be used with caution for the treatment of ED in patients receiving concomitant therapy with any HIV protease inhibitor or delavirdine. Patients receiving these antiretroviral agents should be advised that they may be at increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual changes, syncope, priapism) and cautioned to promptly report any symptoms to their clinician. The antiretroviral manufacturers and some experts recommend that patients receiving these antiretrovirals receive sildenafil at a dosage not exceeding 25 mg every 48 hours for the treatment of ED. The possibility of recreational use of inhaled nitrites (''poppers'') that could further exacerbate this interaction also should be considered.(See Cardiovascular Nitrates and Nitrites under Drug Interactions: Organic Nitrates and Nitrites.)

Concomitant use of sildenafil with ritonavir or other HIV protease inhibitors that are potent inhibitors of CYP3A is not recommended in patients with PAH. Concomitant use of ritonavir-boosted tipranavir is contraindicated in patients receiving sildenafil for the treatment of PAH; safe and effective dosages for concomitant use of these drugs have not been established. If saquinavir is used in patients receiving sildenafil for the treatment of PAH, the manufacturer states that no dosage adjustments are necessary.

Azole Antifungals

Concomitant use of ketoconazole or itraconazole, which are potent CYP3A4 inhibitors, is expected to substantially increase systemic exposure to sildenafil. Population pharmacokinetic analysis of data from clinical trials indicates that sildenafil clearance is reduced when the drug is administered concomitantly with CYP3A4 inhibitors such as ketoconazole.

Because of the possibility of increased efficacy and adverse effects, it is recommended that a lower initial sildenafil dose (25 mg) be considered in patients with ED receiving potent CYP3A4 inhibitors such as ketoconazole or itraconazole. Concomitant use of sildenafil and these potent CYP3A4 inhibitors is not recommended in patients with PAH; such patients should inform their clinicians if they are taking ketoconazole or itraconazole.

Cimetidine

Plasma sildenafil concentrations increased by approximately 56% in healthy individuals who received a single 50-mg oral dose of the drug concomitantly with a single oral dose of cimetidine (800 mg), a nonspecific inhibitor of the cytochrome P-450 mixed-function oxidase system. Population pharmacokinetic analysis of data from clinical trials indicates that cimetidine reduces sildenafil clearance when these drugs are administered concomitantly. Some clinicians recommend that a lower initial sildenafil dose (25 mg) be considered in patients with ED receiving cimetidine. No adjustment of sildenafil dosage is necessary when the drug is used concomitantly with cimetidine in patients with PAH.

Macrolides

Pretreatment with erythromycin (500 mg twice daily for 5 days), a specific CYP3A4 inhibitor, increased the AUC of a single 100-mg dose of sildenafil by 182%. It is recommended that a lower initial sildenafil dose (25 mg) be considered in patients with ED receiving potent CYP3A4 inhibitors such as erythromycin. No adjustment of sildenafil dosage is necessary when the drug is used concomitantly with erythromycin in patients with PAH.

No pharmacokinetic interaction has been observed to date between azithromycin (which does not inhibit CYP3A4) and sildenafil. Therefore, no dosage adjustments are required in patients receiving these drugs concomitantly.

Rifamycins

The possibility that concomitant administration of rifampin, a potent CYP3A4 inducer, could decrease plasma concentrations of sildenafil should be considered. Because rifabutin is a less potent inducer of CYP3A4 than rifampin, rifabutin theoretically is less likely to interact with sildenafil.

Other CYP3A4 Inducers

Concomitant use of sildenafil with potent CYP3A4 inducers is expected to cause substantial decreases in plasma concentrations of sildenafil.

Bosentan, a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19, can increase sildenafil clearance and decrease plasma sildenafil concentrations. In one study in healthy men, concomitant use of bosentan (125 mg twice daily) and sildenafil (80 mg 3 times daily) resulted in a 63% decrease in AUC and a 55% decrease in peak plasma concentrations of sildenafil at steady state; AUC and peak plasma concentrations of bosentan were increased by 50 and 42%, respectively. In patients with PAH in another study, bosentan also decreased peak plasma concentrations and AUC of sildenafil. However, the clinical importance of this pharmacokinetic interaction is unclear. The manufacturer states that no dosage adjustments are required when bosentan is used in conjunction with sildenafil.

Other Drugs

A minor route of metabolism of sildenafil is through the CYP2C9 isoenzyme. Although some clinicians state that the possibility of an interaction between sildenafil and drugs metabolized via CYP2C9 and resultant increased plasma concentrations of the concomitantly administered drug should be considered, there was no evidence of appreciable inhibition of CYP2C9-mediated (e.g., tolbutamide, warfarin) or CYP3A4-mediated (e.g., ritonavir, saquinavir) metabolism by sildenafil in clinical studies. Although no appreciable pharmacokinetic interaction between sildenafil and warfarin was observed in patients with PAH receiving the drugs concomitantly, the incidence of epistaxis was higher (9%) than in those receiving sildenafil alone (2%).

Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics with CYP2D6 inhibitors (such as selective serotonin-reuptake inhibitors [SSRIs], or tricyclic antidepressants).

Antacids

Single doses of an aluminum and magnesium hydroxide-containing antacid did not affect the oral bioavailability of sildenafil. No dosage adjustments are necessary with concomitant use of the drugs.

Atorvastatin

Concomitant administration of sildenafil and atorvastatin did not substantially alter pharmacokinetics of either drug. No dosage adjustments are necessary with concomitant use of the drugs.

β-Adrenergic Blocking Agents

Population pharmacokinetic analyses have shown an approximate 34% reduction in sildenafil clearance when the drug was administered with β-blockers.

Epoprostenol

Concomitant administration of sildenafil (80 mg 3 times daily) and epoprostenol resulted in a slight decrease (28%) in sildenafil exposure and an approximate 22% decrease in mean steady-state sildenafil concentrations; these reductions are not considered clinically important. The effect of sildenafil on epoprostenol pharmacokinetics is not known.

Oral Contraceptives

Pharmacokinetics of sildenafil were not affected by concomitant administration of an oral contraceptive containing ethinyl estradiol and levonorgestrel; plasma concentrations of the estrogen and progestin hormone also were not substantially altered. No dosage adjustments are necessary when sildenafil is used in patients receiving ethinyl estradiol-levonorgestrel oral contraceptives.

Riociguat

Additive hypotensive effects can occur if riociguat is used concomitantly with PDE type 5 inhibitors. In a study in patients with PAH who were receiving stable dosages of sildenafil (20 mg 3 times daily), administration of single doses of riociguat resulted in additive hemodynamic effects. A high rate of drug discontinuance generally has been observed among patients receiving combination therapy with sildenafil and riociguat; at least one death, possibly related to the combined use of these drugs, has been reported.

Because of the risk of hypotension, concomitant use of sildenafil and riociguat is contraindicated.

Therapies for Erectile Dysfunction

The safety and efficacy of sildenafil in combination with other treatments for ED have not been established, and therefore such combined therapy currently is not recommended by the manufacturer.

Phosphodiesterase Inhibitors

Studies currently are under way to evaluate the potential of other PDE inhibitors, such as dipyridamole and theophylline, to affect the action of sildenafil, a specific PDE type 5 inhibitor (which is not present in myocytes). Because cGMP is known to inhibit PDE type 3, which hydrolyzes cAMP, sildenafil may increase cAMP-mediated effects in tissues with PDE type 3, such as increased inotropic effects in cardiac muscle, vascular smooth muscle relaxation, and platelet-aggregation inhibition. However, increased cGMP concentrations also may stimulate PDE type 2, which reduces cAMP concentrations. Limited data from ex vivo studies in certain tissues (e.g., coronary arteries, corpus cavernosum) showed that sildenafil did not increase tissue cAMP concentrations appreciably. Thus, while the risk of precipitating a cardiotoxic, hypotensive, or hemorrhagic event after administration of sildenafil with specific or nonspecific PDE inhibitors currently is not known, it appears unlikely.

Safety and efficacy of sildenafil (Revatio) in combination with sildenafil (Viagra) or other PDE type 5 inhibitors have not been studied. Patients should be informed not to take Revatio and Viagra concomitantly or with other PDE type 5 inhibitors.

Vitamin K Antagonists

Concomitant administration of sildenafil and an oral vitamin K antagonist (acenocoumarol or phenprocoumon) did not substantially alter the international normalized ratio (INR). However, an increased incidence of bleeding (epistaxis) was observed with concomitant use of an oral vitamin K antagonist and sildenafil in patients with PAH. No pharmacokinetic interaction has been observed between warfarin, a CYP2C9 substrate, and sildenafil. Dosage adjustments are not necessary when sildenafil is used concomitantly with a vitamin K antagonist.

Other Drugs

Concomitant administration of sildenafil and heparin in anesthetized rabbits had an additive effect on bleeding time. Although the possibility of a similar interaction in humans has not been studied specifically to date, there currently is no evidence that would preclude the use of heparin in sildenafil-treated patients if indicated.

Safety and efficacy of sildenafil did not appear to be affected by concomitant administration of antidepressants or antipsychotics in clinical trials.

Pharmacokinetics

Absorption

Sildenafil is rapidly and almost completely absorbed following oral administration. Bioequivalence has been established between the 20-mg tablet and the 10-mg/mL oral suspension when administered as a single oral dose of 20 mg. Although single-dose studies indicate that more than 90% of an oral sildenafil dose is absorbed from the GI tract, the drug undergoes extensive metabolism in the GI mucosa during absorption and on first pass through the liver, with only about 40% of a dose reaching systemic circulation unchanged. Pharmacokinetics of the drug (as determined by peak plasma concentrations or area under the plasma concentration-time curve [AUC]) are dose proportional over the single-dose range of 1.25-200 mg. Peak plasma concentrations of sildenafil and its active N-desmethyl metabolite are achieved within 30-120 (median: 60) minutes following oral administration in fasting adults. Plasma concentrations of the active N-desmethyl metabolite are approximately 40% of those seen for sildenafil, and the metabolite reportedly accounts for about 20% of sildenafil's pharmacologic activity. The drug is unlikely to accumulate appreciably with repeated once-daily dosing.

Administration with a high-fat meal delays GI absorption of sildenafil, with a reduction in peak plasma concentrations of about 30% and a delay in time to peak plasma concentrations of about 60 minutes; the extent of absorption is not affected.

Plasma concentrations of sildenafil are increased in geriatric patients and in patients with hepatic or severe renal impairment.(See Pharmacokinetics: Elimination.) AUCs for total sildenafil and its N-demethylated metabolite in geriatric individuals are approximately 84 and 107% higher, respectively, than those observed in healthy younger adults (i.e., 18-45 years of age). Free plasma sildenafil concentrations are increased by about 45% in healthy geriatric individuals (i.e., older than 65 years of age) compared with younger adults as a result of decreased clearance (i.e., resulting from age-related differences in plasma protein binding); plasma concentrations of the N-demethylated metabolite also are increased.(See Pharmacokinetics: Elimination.)

Limited published information currently is available on the onset and duration of the erectile effect of sildenafil. In the largest clinical study published to date, the onset and duration of action of oral sildenafil were not reported. In most other placebo-controlled studies in which improvement in erection was determined by penile plethysmography, the erectile effect was determined at a fixed time of 60 minutes after an oral dose of the drug. In a study in which sildenafil was combined with visual sexual stimulation in patients with erectile dysfunction (ED) that was not of established organic cause, the median time to onset of penile erectile activity was 19 minutes (range: 12-33 minutes) after oral administration of a single 50-mg dose; visual stimulation was initiated 10 minutes after dosing. In another study in such patients, the onset of penile erectile activity was approximately 30-40 minutes after 50-mg dosing, but visual sexual stimulation was not initiated until 30 minutes after dosing in this study.

Although the duration of erectile responsiveness (i.e., the time period in which adequate sexual stimulation can produce an erection) with oral sildenafil has been reported to be approximately 2 hours, with some penile responsiveness persisting for up to 4 hours after oral administration, the duration of penile rigidity of a given erection sufficient for sexual penetration is substantially shorter in most patients. Some patients have reported decreased latency in achieving an erection for up to 12 hours after a dose. Following oral administration of 50 mg of sildenafil in patients with impotence secondary to diabetes mellitus or with no known organic cause of ED, the duration of penile rigidity sufficient for sexual penetration (greater than or equal to 60% at the base of the penis as assessed via penile plethysmography) during visual sexual stimulation was 5.9-31.8 minutes. In a study in patients with ED of no established organic cause who received single doses of 10, 25, or 50 mg, the duration of penile rigidity exceeding 80% at the base was dose related, averaging 3.5, 8, and 11.2 minutes, respectively, with visual sexual stimulation; the duration of this level of rigidity at the tip of the penis averaged 7.4 minutes for the 50-mg dose. However, the relevance of these findings to use of sildenafil with actual sexual activity is unclear. In a study in patients with ED secondary to radical prostatectomy, the estimated duration of vaginal intercourse achieved with a 100-mg sildenafil dose averaged about 7 minutes.

The 10-mg IV dose of sildenafil is predicted to produce pharmacologic effects of sildenafil and its N-desmethyl metabolite equivalent to the 20-mg oral dose.

Distribution

Sildenafil appears to be widely distributed in the body, with a reported volume of distribution at steady state averaging 105 L. It is not known whether sildenafil is distributed into milk. Sildenafil and its major circulating N-desmethyl metabolite are each approximately 96% bound to plasma proteins; protein binding reportedly is independent of plasma concentration over the range of 0.01-10 mcg/mL. Plasma protein binding of the drug in geriatric adults older than 65 years of age is slightly greater (97%) than that observed in individuals younger than 45 years of age (96%).

Sildenafil is distributed to a limited extent in semen following oral administration, with less than 0.001% of a single dose appearing in semen 90 minutes after dosing in healthy individuals Such concentrations are unlikely to cause any effects in sexual partners exposed to the semen.

Elimination

Plasma sildenafil concentrations appear to decline in a biphasic manner following oral administration, with a terminal elimination half-life of about 4 hours (range: 3-5 hours). Following oral administration of the drug in healthy males, plasma clearance of sildenafil averages 41 L/hour. It is likely that sildenafil undergoes renal tubular reabsorption.

Sildenafil appears to be completely metabolized in the liver to up to 16 metabolites, most of which represent only a small fraction of a dose; little or no unchanged drug is detectable in urine or feces following oral or IV administration. Sildenafil is metabolized principally via hepatic cytochrome P-450 (CYP) microsomal isoenzymes 3A4 (major route) and 2C9 (minor route), and potent inhibitors of CYP3A4 can substantially reduce sildenafil clearance.(See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.) Hepatic metabolism of sildenafil is complex, generally involving the piperazine ring, N,N-de-ethylation (ring opening) or N-demethylation of the piperazine ring and aliphatic hydroxylation; the drug and its metabolites do not appear to undergo conjugation. The N-demethylated metabolite, the major circulating metabolite, has a phosphodiesterase selectivity profile similar to that of sildenafil and an in vitro potency for PDE type 5 of approximately 50% of the parent drug. The N-demethylated metabolite is further metabolized to an N-dealkylated N,N-de-ethylated) metabolite. The drug also undergoes N-dealkylation followed by N-demethylation of the piperazine ring.

Sildenafil is eliminated mainly in the feces as metabolites. In healthy adults and those with ED, approximately 80% of an oral dose is excreted as metabolites in feces and 13% is excreted in urine. In feces, the N-dealkylated, hydroxylated, N-demethylated, and N-dealkylated/demethylated metabolites of sildenafil comprise about 22, 13, 3, and 3% of total fecal excretion. In healthy individuals, sildenafil is excreted in urine mainly as the hydroxylated metabolite, with this metabolite representing about 41% of total urinary excretion of the drug.

Sildenafil clearance is reduced in geriatric adults 65 years of age and older and in adults with severe renal or hepatic impairment. Free (unbound) plasma drug concentrations in healthy geriatric adults are approximately 45% greater than those in healthy younger adults (18-45 years). Such age-related reductions in clearance of the drug do not appear to be attributable to age-related declines in creatinine clearance but result from age-related differences in plasma protein binding. In patients with mild (creatinine clearance ranging from 50-80 mL/minute) or moderate (creatinine clearance ranging from 30-49 mL/minute) renal impairment, the pharmacokinetics of a single 50-mg oral dose of sildenafil are not altered. However, in patients with severe (creatinine clearance less than 30 mL/minute) renal impairment, sildenafil clearance is reduced, resulting in AUCs and peak plasma concentrations of the parent drug that are approximately double those in age-matched healthy adults. In addition, AUCs and peak plasma concentrations of the N-demethylated metabolite are 200 and 79% greater, respectively, than those in individuals with normal renal function.

In patients with hepatic cirrhosis (Child-Pugh class A or B), sildenafil clearance also is reduced, resulting in increased AUCs (by 85%) and peak plasma concentrations (by 47%) compared with values observed in age-matched healthy adults. The effect of severe hepatic impairment on the pharmacokinetics of sildenafil has not been evaluated to date.