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Use of Sildenafil (Viagra) in Patients With Cardiovascular Disease

The pharmaceutical preparation sildenafil citrate (Viagra) is being widely prescribed as a treatment for male erectile dysfunction, a common problem that in the United States affects between 10 and 30 million men. The introduction of sildenafil has been a valuable contribution to the treatment of erectile dysfunction, which is a relatively common occurrence in patients with cardiovascular disease. This article is written to appropriately caution and not to unduly alarm physicians in their use of sildenafil in patients with heart disease.

Reported cardiovascular side effects in the normal healthy population are typically minor and associated with vasodilatation (ie, headache, flushing, and small decreases in systolic and diastolic blood pressures). However, although their incidence is small, serious cardiovascular events, including significant hypotension, can occur in certain populations at risk. Most at risk are individuals who are concurrently taking organic nitrates. Organic nitrate preparations are commonly prescribed to manage the symptoms of angina pectoris. The coadministration of nitrates and Viagra significantly increases the risk of potentially life-threatening hypotension. Therefore, Viagra should not be prescribed to patients receiving any form of nitrate therapy.

Although definitive evidence is currently lacking, it is possible that a precipitous reduction in blood pressure with nitrate use may occur over the initial 24 hours after a dose of Viagra. Thus, for patients who experience an acute cardiac ischemic event and who have taken Viagra within the past 24 hours, administration of nitrates should be avoided. In the event that nitrates are given, especially within this critical time interval, it is essential to have the capability to support the patient with fluid resuscitation and -adrenergic agonists if needed. In patients with recurring angina after Viagra use, other nonnitrate antianginal agents, such as ß-blockers, should be considered.

Other patients in whom the use of Viagra is potentially hazardous include those with active coronary ischemia; those with congestive heart failure and borderline low blood volume and low blood pressure status; those with complicated, multidrug, antihypertensive therapy regimens; and those taking medications that may affect the metabolic clearance of Viagra. With respect to patients following complicated multidrug, antihypertensive programs, the randomized studies included a large number of hypertensive patients. However, most patients were controlled with 1 antihypertensive agent, and only a small number were controlled with 3 antihypertensive agents. Until adequate studies are done in these subgroups of patients, sildenafil should be prescribed with caution.

Viagra acts as a selective inhibitor of cyclic GMP (cGMP)–specific phosphodiesterase type 5, resulting in smooth muscle relaxation, vasodilatation, and enhanced penile erection. Although the cardiovascular effects of sildenafil reported in available randomized, controlled clinical trials were relatively minor, heart disease patients represented only a small fraction of studied patients, and patients with heart failure, patients with myocardial infarction or stroke within 6 months, or patients with uncontrolled hypertension were not included in these studies. Thus, there are possible problems in the use of Viagra in these patients that have not been adequately studied.

Given the increasing reports of deaths in which the use of Viagra may be implicated, clinicians need to exercise caution when advising their patients with heart disease about taking this medication. Specific recommendations regarding sildenafil (Viagra) and the cardiac patient are summarized in the following Table.

I. Preamble

The present document is an expert consensus. This type of document is intended to inform practitioners, payers, and other interested parties of the opinion of the American College of Cardiology (ACC) concerning evolving areas of clinical practice and/or technologies that are widely available or are new to the practice community. Topics chosen for coverage by Expert Consensus Documents are so designated because the evidence base and experience with the technology or clinical practice are not sufficiently well developed to be evaluated by the formal ACC/American Heart Association (AHA) Practice Guidelines process. Thus, the reader should view the Expert Consensus Documents as the best attempt of the ACC to inform and guide clinical practice in areas in which rigorous evidence is not yet available. Where feasible, Expert Consensus Documents will include indications and contraindications. Some topics covered by Expert Consensus Documents will be addressed subsequently by the ACC/AHA Practice Guideline process.

A. Sildenafil (Viagra) Use for Erectile Dysfunction
Male erectile dysfunction defined as "the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance"1 is a common problem in the United States affecting between 10 and 30 million men.2 3 Sexual dysfunction in men after the diagnosis of coronary artery disease or a myocardial infarction is common. Most is due to fear that the exertion of sexual activity will precipitate another myocardial infarction, but 10% to 15% is due to organic causes of impotence.4 Approximately 5.5 million men take nitrates on a regular basis for angina pectoris,5 and another half a million will experience a heart attack annually and are potential candidates for nitrate therapy.6 Sildenafil is potentially contraindicated in as many as 6 million patients.

The introduction of sildenafil citrate (Viagra), a drug that acts as a selective inhibitor of cGMP–specific phosphodiesterase type 5 (PDE5), which results in smooth muscle relaxation, vasodilatation, and enhanced penile erection, has been a major advancement in the treatment of erectile dysfunction.7 The vasodilating action of sildenafil affects both the arteries and the veins, so the most frequent side effects of sildenafil are headache and facial flushing.8 Sildenafil causes small decreases in systolic and diastolic blood pressures, but clinically significant hypotension is rare. Studies of sildenafil and nitrates taken together show much greater drops in blood pressure. For that reason, it is contraindicated to use sildenafil in patients who take long-acting nitrates or who use short-acting, nitrate-containing medications.

In the phase II/III studies completed before Food and Drug Administration (FDA) approval, >3700 patients received sildenafil and almost 2000 received placebo in double-blind and open-label studies. None were taking long-acting nitrates, although patients with coronary artery disease were not excluded. Approximately 25% of the patients had hypertension and were taking antihypertensive medications, and 17% were diabetic. In these studies, the incidence of serious cardiovascular adverse effects was similar in the double-blind sildenafil group, the double-blind placebo group, and the open-label group. There were 28 patients who had a myocardial infarction. When adjusted for patient-years of exposure, there were no differences in myocardial infarction rate between the sildenafil group and the placebo group, and no deaths were attributed to treatment. The incidence of myocardial infarction was 1.7/100 patient-years (95% CI, 0.8 to 2.6) in the sildenafil group and 1.4/100 patient-years (95% CI, 0.2 to 2.6) in the placebo group.9 In the subsequent analysis done in May 1998, sildenafil exposure had increased to 4913 patient-years (693 double-blind sildenafil; 4220 open-label extensions), and 26 deaths had been reported, for an incidence rate of 0.53/100 patient-years. The incidence for placebo remained the same (ie, 2 deaths or 0.57/100 patient-years).5

There have now been >3.6 million prescriptions10 written for sildenafil, and 4500 patients taking sildenafil have been followed up without any change in the above conclusions. A total of 69 deaths have been reported to the FDA as of August 26, 1998, in patients who have used Viagra.10 11 Twenty-one were due to unknown causes, 2 due to stroke, and 46 related to probable cardiac events.10 11 Twelve deaths involved a possible interaction between Viagra and nitrates.10 11

Patients with erectile dysfunction are mostly over age 45 and are in general more likely to have risk factors predisposing them to cardiovascular disease, including myocardial infarction and stroke. The vast majority of patients in the clinical development program did not have known coronary disease or congestive heart failure, nor were hypertensive patients taking complicated, multidrug, antihypertensive medical regimens included in the program. Furthermore, 62% of the patients taking Viagra were within the 45- to 64-year-old age category, and only 23% were aged 65 years (Pfizer Inc, unpublished data). Although sildenafil is not presently indicated in women, the cautions referred to in this document should probably apply to both men and women, pending studies performed specifically in women.

B. Development of an ACC Expert Consensus Document
In July 1998, responding to inquiries from both concerned physicians and the press, ACC president Spencer King asked the ACC Technology and Practice Executive Committee (TPEC) to supervise the writing of a press release, summary statement, and Expert Consensus Document on sildenafil (Viagra). This article was written to appropriately caution and not to unduly alarm physicians in their use of sildenafil in patients with heart disease.

Dr King and TPEC chair Dr James Forrester selected a group of physicians with specific expertise to prepare the document. Drs Melvin Cheitlin and Adolph Hutter, Jr, were chosen as cochairs of the Writing Group, on the basis of their status as well-recognized senior clinical cardiologists and their experience in producing clinical practice guidelines. Other members were selected for specific expertise: Dr Brindis (managed care), Dr Ganz (vascular reactivity), Dr Kaul (nitric oxide donors), and Dr Zusman (pharmacology of antihypertensive agents). Dr King also invited the AHA to jointly author the document. Dr Richard Russell (critical care cardiology) was appointed to the Writing Group by AHA president Dr Valentin Fuster. All members of the Writing Group were asked to carefully review any potential conflicts of interest they might have regarding their industry relationships. Those writers who indicated conflicts are identified in the byline.

The Writing Group reviewed both the limited published data on Viagra and unpublished data provided by the manufacturer of Viagra, Pfizer Inc. With respect to the unpublished data, all members of the Writing Group who had access to these documents signed statements that they would not distribute this information outside of the Writing Group until such time as it became public information. Members of the Writing Group were instructed to channel all communications with Pfizer through ACC professional staff to eliminate the appearance of bias.

After completion of the document, 10 external referees reviewed the text. A copy of the draft was also provided to Pfizer and to the FDA for comment. The comments from external review, which were kept anonymous, were provided to the Writing Group, which made revisions as they deemed appropriate. The Expert Consensus Document was approved by vote of the TPEC for presentation to the ACC Board of Trustees, which voted to approve its publication in the Journal of the American College of Cardiology. The AHA Scientific Advisory Committee also reviewed and approved this document for publication in Circulation.

II. Background

A. Physiology of Erection
Penile erection is accomplished by engorgement of cavernous spaces within the corpora cavernosa under near-arterial pressures and involves dilation of arterial inflow, relaxation of corpora cavernosa smooth muscle, and constriction of venous outflow.12 The blood flow to the penis is supplied by the cavernosal arteries and their branches, the helicine arteries, which empty directly into the cavernous spaces.12 Erection is initiated by dilation of helicine arteries, resulting in marked augmentation of blood inflow and transmission of arterial pressures to the cavernosal spaces. Relaxation of smooth muscle trabeculae surrounding cavernosal spaces facilitates blood pooling and engorgement. Restriction of venous outflow is also essential to entrapment of blood in the corpora cavernosa and is caused by compression of venules by the expanding smooth muscle trabeculae against the thick tunica albuginea.12

B. Role of Nitric Oxide and cGMP
The relaxation of the penile arterial smooth muscle, the corporal smooth muscle, and therefore erection is under the control of the autonomic nervous system.13 The principal neural mediator of penile smooth muscle relaxation is nitric oxide (NO).13 14 NO and its derivatives have received much attention because they also account for the biological activity of the endothelium-derived relaxation factor and of organic and inorganic nitrate vasodilators. Three isoforms of NO synthase (NOS) that convert L-arginine to NO have been identified: neuronal (nNOS; type I NOS), inducible (iNOS; type II NOS), and endothelial (eNOS; type III NOS). Terminals containing nNOS densely innervate the corpus cavernosum and its arterial supply.13 14 NO derived from the endothelium lining penile arteries and cavernosal sinuses also participates in the erectile response. The arterial dilator actions of NO and its relaxant effect on the smooth muscle of the corpus cavernosum are mediated by the activation of soluble guanylate cyclase and production of cGMP, which acts as a second messenger.13 14 Accumulation of cGMP leads to a reduction in intracellular calcium and smooth muscle relaxation. The degradation of cGMP into its inactive form, GMP, is catalyzed by cyclic nucleotide phosphodiesterase enzymes.15 16 The predominant isoform of this enzyme in the corpus cavernosum is PDE5.12 15 Inhibitors of the activity of this enzyme prevent the breakdown of cGMP, resulting in enhanced penile erection.

III. Sildenafil

A. Introduction and Mechanism of Action
Sildenafil belongs to a class of compounds called PDE inhibitors. PDEs comprise a diverse family of enzymes that hydrolyze cyclic nucleotides (cAMP and cGMP) and therefore play a critical role in the modulation of second-messenger signaling pathways.15

Sildenafil is a potent and selective inhibitor of cGMP-specific PDE5 (Pfizer, unpublished data), the predominant isozyme that metabolizes cGMP in the corpus cavernosum of the penis. cGMP is the second messenger of NO and a principal mediator of smooth muscle relaxation and vasodilatation in the penis. By inhibiting the hydrolytic breakdown of cGMP, sildenafil prolongs the action of cGMP. This results in augmented smooth muscle relaxation and hence prolongation of the erection. Prior production of cGMP by NO, released primarily from the nonadrenergic, noncholinergic (nitroxidergic) cavernosal nerves in response to sexual stimulation, is required for sildenafil to be effective.13 14

Relatively high levels of PDE5 are found in the human corpus cavernosum; in vascular, visceral, and tracheal smooth muscle; and in platelets.15 Sildenafil is a potent inhibitor of PDE5, with favorable selectivity (>1000-fold) for human PDE5 over human PDE2 (isozyme found predominantly in the adrenal cortex),15 PDE3 (found predominantly in smooth muscles, platelets, and cardiac tissue),15 and PDE4 (found predominantly in the brain and lung lymphocytes)15 and moderate selectivity (>80-fold) over PDE1 (a cGMP-hydrolyzing isozyme found predominantly in the brain, kidney, and smooth muscle).15 Sildenafil is only 10-fold as potent for PDE5 as for PDE6 (an enzyme found in the photoreceptors of the human retina); this lower selectivity is presumed to be the basis for abnormalities related to color vision observed with higher doses or plasma levels of sildenafil (Pfizer, unpublished data). The 4000-fold greater selectivity for PDE5 over PDE3 is important because inhibitors of PDE3 (the isozyme involved in regulation of cardiac contractility), such as milrinone, vesnarinone, and enoximone, that have been used in patients with heart failure are generally associated with increased incidence of cardiac arrhythmias and other serious side effects.17

B. Pharmacokinetics and Metabolism
Sildenafil is rapidly absorbed after oral administration, with absolute bioavailability of 40%. Plasma concentrations peak within 30 to 120 minutes (median, 60 minutes) of oral dosing in the fasted state. Sildenafil is primarily metabolized by the cytochrome P450 3A4 (major route) and 2C9 (minor route) hepatic microsomal isoenzymes, which convert it to an active N-desmethyl metabolite that has been shown to possess 50% of the parent drug's potency for inhibiting PDE5. Plasma concentrations of this metabolite are 40% of those seen for sildenafil, so that the metabolite accounts for 20% of the pharmacological effects of sildenafil. Sildenafil and its active metabolite are both highly bound to plasma proteins (96%), and their terminal half-lives are 4 hours each. The mean steady-state volume of distribution for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil is excreted as metabolites predominantly in the feces (80% of administered oral dose) and to a lesser extent in the urine (13% of the administered oral dose). Less than 0.001% of the administered dose appears in the semen; this dose is very unlikely to have any effects in the partners of patients taking sildenafil. Plasma levels of sildenafil are increased in patients aged >65 years (40% increase) and in patients with hepatic impairment (eg, cirrhosis; 80% increase), severe renal impairment (creatinine clearance <30 mL/min; 100% increase), and concomitant use of potent cytochrome P450 3A4 inhibitors (eg, macrolide antibiotics such as erythromycin [200% increase] and clarithromycin; cimetidine; and antifungal agents such as ketoconazole and itraconazole).18 Protease inhibitors such as indinavir, ritonavir, nelfinavir, and saquinavir have not been formally studied but, being potent 3A4 inhibitors, are anticipated to have similar effects on sildenafil metabolism (Pfizer, unpublished data).

C. Pharmacodynamics
The pharmacodynamic end points that have been investigated with sildenafil reflect the distribution of PDE5 in different tissues, ie, human corpus cavernosum (penile tumescence), vascular smooth muscle (vasodilatation), and platelets (antiplatelet function).

1. Effects on Penile Tumescence
The efficacy of sildenafil in enabling patients with erectile dysfunction due to a broad spectrum of causes, including vasculogenic (diabetes), neuroreflexogenic (spinal cord injury), and psychogenic (nonorganic), to achieve and maintain erection sufficient for satisfactory sexual intercourse has been demonstrated in all 21 double-blind, randomized, placebo-controlled, multicenter studies (Pfizer, unpublished data).

2. Cardiovascular Effects
a. Effects on Cardiac Contractility
Unlike cAMP-specific PDE3 inhibitors (milrinone, vesnarinone, and enoximone) that increase long-term mortality in patients with heart failure,17 19 sildenafil is highly selective (>4000-fold) for human PDE5 over human PDE3 and has not been found to elevate cAMP (Pfizer, unpublished data). The cardiotoxic effects of PDE3 inhibitors are thought to be related to increases in intracellular cAMP in the myocardium.15 19 20 Furthermore, PDE5 is not present in cardiac myocytes, and sildenafil has been shown to have no direct inotropic effects on dog trabeculae muscle (Pfizer, unpublished data). However, sildenafil has not been investigated extensively in heart failure patients.

b. Effects on Blood Pressure and Heart Rate
Sildenafil produces a transient modest reduction in systolic (8 to 10 mm Hg) and diastolic (5 to 6 mm Hg) blood pressures, with peak effects evident at 1 hour after the dose (coincident with peak plasma concentrations) and returning to baseline values by 4 hours after the dose (Pfizer, unpublished data). No significant effects are observed on heart rate. The hypotensive effects of sildenafil are neither age dependent (similar reductions in blood pressure in patients aged <65 years compared with those >65 years) nor dose related (over the range of 25 to 100 mg) and rarely result in reports of orthostatic effects. Doses as high as 800 mg have been well tolerated in some healthy volunteers.13

c. Effects on Central Hemodynamics and Peripheral Vasculature
In normal volunteers, no significant changes in cardiac index were evident up to 12 hours after the dose for oral sildenafil (100 to 200 mg) or intravenous sildenafil (20 to 80 mg) (Pfizer, unpublished data). Significant decreases in systemic vascular resistance index were reported at the end of intravenous sildenafil infusion (20 to 80 mg), when plasma concentrations were highest (Pfizer, unpublished data). Sildenafil has both arteriodilator and venodilator effects on the peripheral vasculature (Pfizer, unpublished data). In 8 patients with stable angina, intravenous sildenafil reduced systemic and pulmonary arterial pressures and cardiac output by 8%, 25%, and 7%, respectively, consistent with its mixed arterial (systemic and pulmonary hypotension) and venous (drop in stroke volume secondary to decreased preload) vasodilator effects.14

In conclusion, consistent with the anticipated effects resulting from an increase in cGMP levels in vascular smooth muscle, sildenafil possesses vasodilatory properties, which result in mild, generally clinically insignificant decreases in blood pressure when taken alone.

d. Platelet Effects
Sildenafil has no direct effects on platelet function but will modestly potentiate the inhibitory effect of the NO donor sodium nitroprusside on ADP-induced platelet aggregation ex vivo, consistent with the requirement for an NO drive for sildenafil to produce its pharmacological effects (Pfizer, unpublished data). No effects on bleeding or prothrombin times were seen in healthy subjects receiving sildenafil alone or concurrently with aspirin or warfarin. In addition, no adverse bleeding episodes have been reported with the use of sildenafil (Pfizer, unpublished data). However, because the effects of sildenafil have not been evaluated in patients with bleeding disorders or in patients taking nonaspirin antiplatelet agents (eg, ticlopidine, clopidogrel, or dipyridamole), caution should be exercised when the drug is administered in these clinical settings.

3. Effects on Visual Function
Transient visual abnormalities (mostly color-tinged [blue-green] vision, increased perception of light, and blurred vision) have been reported in patients taking sildenafil, especially at high oral doses (>100 mg) (Pfizer, unpublished data). These visual effects appear to be related to the weaker inhibiting action of sildenafil on PDE6, which regulates signal transduction pathways in the retinal photoreceptors. Sildenafil is 10-fold selective for PDE5 over PDE6 (Pfizer, unpublished data). In patients with inherited disorders of retinal PDE6, such as retinitis pigmentosa, sildenafil should be administered with extreme caution (Pfizer, unpublished data).

4. Adverse Effects
The adverse effects of sildenafil reflect its pharmacological activity of inhibition of PDE5 in various tissues and can be broadly classified into 4 major adverse reactions:

Vasodilatory effects resulting in headache (16%), flushing (10%), and rhinitis (4%) (the latter presumably as a result of hyperemia of nasal mucosa where PDE5 is present). Dizziness (2%), hypotension (<2%), and postural hypotension (<2%) have been reported rarely and occur at a similar rate in sildenafil- and placebo-treated patients (Pfizer, unpublished data).
Gastrointestinal effects resulting in dyspepsia and burning sensation from reflux due to relaxation of lower esophageal sphincter (7%) (Pfizer, unpublished data).
Visual abnormalities resulting in blue-green color-tinged vision, increased perception of light, and blurred vision (3%), especially at higher doses (Pfizer, unpublished data).
Musculoskeletal effects resulting in myalgias, especially with multiple daily doses. No treatment-related changes in serum creatine kinase or electromyogram have been observed, however (Pfizer, unpublished data). There is no obvious pharmacological explanation for this effect.
IV. Drug-Drug Interactions and Concomitant Disease States

A. Interaction With Nitrates
The vasodilator actions of nitrates are profoundly amplified with concomitant use of sildenafil, resulting in major hemodynamic compromise and potentially fatal events (Pfizer, unpublished data). This interaction likely applies to all nitrates and NO donors, irrespective of their predominant hemodynamic site of action (see Appendix A for a list of commonly used nitrates). Sildenafil may also potentiate the hypotensive effects of an inhaled form of nitrate, such as amyl nitrate or nitrite, also known as "poppers," and therefore is contraindicated. Poppers act by dilating blood vessels, and the concurrent recreational use of poppers and sildenafil could result in sudden and marked lowering of blood pressure, which can be potentially serious or even fatal. This interaction may be even more pronounced in patients taking protease inhibitors concurrently (eg, indinavir [Crixivan], ritonavir [Norvir], nelfinavir [Viracept], or saquinavir [Invirase]).

Dietary sources of nitrites, nitrates, and L-arginine (the substrate from which NO is synthesized) do not contribute to the circulating levels of NO in humans and therefore are unlikely to interact with sildenafil. The anesthetic agent nitrous oxide does not undergo any detectable biotransformation and is eliminated unchanged from the body, mostly via the lungs, usually within minutes of its administration. Because it does not form NO in the human body and does not itself activate guanylate cyclase, there is no contraindication to its use after administration of sildenafil.

It is not known how much time must elapse from the time at which a patient takes sildenafil before a nitrate-containing medication might be given without the marked hypotensive effect being produced. On the basis of the pharmacokinetic profile of sildenafil, it can be assumed that the coadministration of a nitrate within the first 24 hours is likely to produce an exaggerated hypotensive response and is therefore contraindicated unless the benefits are determined to far outweigh the risks. After 24 hours, the administration of a nitrate may be considered, but once again, the response to initial dosages must be monitored carefully. In patients in whom the half-life of sildenafil may be prolonged (see below), a more extended period of time from sildenafil administration to nitrate administration may be required. The preferred form of nitrate therapy in this setting would be short-acting intravenous nitroglycerin infusion under close hemodynamic monitoring.

Similarly, all patients taking either sildenafil or nitrates must be warned of the contraindications and the potential consequences of taking sildenafil in the 24-hour interval after taking a nitrate preparation, including sublingual nitroglycerin. Although sublingual nitroglycerin is very short-acting, its need in the previous 24 hours suggests that it may be needed again after sildenafil-enhanced sexual relations. Furthermore, the presence of even trace amounts of nitrates may have unknown effects in combination with sildenafil. The administration of sildenafil to a patient who has taken a nitrate in the preceding 24 hours is contraindicated.

Appendix A is a listing of nitrate preparations available in the United States. Other preparations may be available in other countries. A careful history of the medications taken by a patient who has taken sildenafil is essential before treatment of the patient for presumed myocardial ischemia or infarction is initiated.

B. Interaction With Antiplatelet Agents
A clinical trial combining sildenafil with aspirin showed no pharmacokinetic interaction between the 2 medications and no additional effect of sildenafil on bleeding time. Dipyridamole is believed to exert antiplatelet effects by at least 2 mechanisms. Its nonspecific PDE action increases platelet cAMP, and it increases plasma adenosine by blocking its reuptake by erythrocytes.21 Ticlopidine and clopidogrel produce antiplatelet aggregatory activity by inhibiting ADP-mediated platelet activation.22 No specific interaction studies have been conducted between sildenafil and dipyridamole, ticlopidine, or clopidogrel.

C. Interaction With Other PDE Inhibitors
PDEs are considered to be major mediators of cross talk between different second-messenger signaling pathways,15 eg, cGMP is known to inhibit PDE3, which hydrolyzes cAMP, thereby resulting in enhanced cAMP levels.15 20 This increase in cAMP levels can potentially augment cAMP-mediated effects in various tissues where PDE3 is localized, ie, Ca2+ current (ICa) and inotropy in cardiac myocytes,23 vascular smooth muscle relaxation,24 and platelet inhibition.25 The risk of precipitating a cardiotoxic, hypotensive, or hemorrhagic event secondary to combining sildenafil with specific PDE3 inhibitors (such as milrinone, vesnarinone, or enoximone) or with nonspecific PDE inhibitors (such as theophylline, dipyridamole, papaverine, and pentoxifylline) is currently unknown, but such effects are unlikely.17

D. Drug-Drug Interactions Affecting Metabolic Clearance of Sildenafil
Sildenafil is an inhibitor of the cytochrome P450 2C9 metabolic pathway. It is possible that the administration of sildenafil could result in a significant increase in the plasma concentrations of other drugs metabolized through this pathway. Although tolbutamide and warfarin are metabolized by the P450 2C9 pathway, there is no evidence to date that the concomitant administration of sildenafil affects the metabolic clearance of these 2 drugs.

Sildenafil is predominantly metabolized by both the P450 2C9 pathway and the P450 3A4 pathway (a low-affinity but high-capacity system). Thus, potent inhibitors of the P450 3A4 pathway may increase the plasma concentrations of sildenafil and therefore its pharmacological effect. Cimetidine and erythromycin are commonly prescribed drugs that inhibit the P450 3A4 pathway. As indicated in the approved product labeling, the simultaneous administration of either of these agents significantly increases the plasma concentrations of sildenafil; a lower initial dose (25 mg) should be considered in the coadministration of sildenafil to patients receiving either of these agents.

Many drugs are metabolized by the P450 3A4 pathway but are not inhibitors of the pathway. The coadministration of 1 of these drugs may lead to a competitive inhibition of the metabolism of sildenafil, although the 3A4 system is a high-capacity enzymatic system. The effects of these agents on the half-life, physiological effects, and side effects of sildenafil are unknown; physicians should be cognizant of the potential interaction of such agents. Appendix B includes a partial listing of commonly prescribed drugs metabolized via the P450 3A4 pathway.

E. Concomitant Administration of Antihypertensive Drugs
Sildenafil administration has been associated with reductions in blood pressure (compared with placebo) of as much as 8/5 mm Hg (systolic/diastolic values). In a drug interaction study of sildenafil and amlodipine, the additional blood pressure reduction in the patient population receiving both sildenafil and amlodipine was not significantly different from the population receiving sildenafil and a placebo (Pfizer, unpublished data). Although formal drug-drug interaction studies have not been conducted with the following medications, no increase in blood pressure–related adverse events or systematic enhancement of the blood pressure–lowering effects of thiazide, loop and potassium-sparing diuretics, ACE inhibitors, calcium channel blockers, or - or ß-adrenergic receptor antagonists have been observed in clinical trials. However, the potential for a hypotensive reaction in patients taking antihypertensive medications as well as sildenafil must be considered and the patient alerted to this possibility. Although not supported by data from the clinical trials, there may be a theoretical concern in a patient receiving multiple medications that include antihypertensive therapy and an inhibitor of the metabolic pathway (cytochrome P450 3A4) of sildenafil.

F. Concomitant Disease States
1. Renal Dysfunction
Patients with severe renal impairment (creatinine clearance <30 mL/min) have a reduced clearance of sildenafil. Plasma levels of the parent drug and of its metabolites in patients with severe renal impairment are approximately twice those found in healthy subjects. Thus, the duration of the effect of sildenafil in these patients will be prolonged and also may be enhanced at any given dosage of the medication. Particular care should be taken in the administration of concomitant medications that may lower blood pressure in patients receiving sildenafil whose renal function is severely impaired. The effects of less-severe degrees of renal dysfunction on the metabolism of sildenafil have been evaluated. There were no significant effects on the metabolism of sildenafil seen in subjects with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal impairment.24 Of note, the plasma creatinine concentration of the elderly patient with a lower body mass may not accurately reflect the patient's creatinine clearance, and thus initiation of therapy at 25 mg rather than 50 mg may be appropriate in the elderly.

2. Hepatic Dysfunction
Patients with hepatic dysfunction have a decreased clearance of sildenafil compared with normal subjects. Plasma concentrations of sildenafil and of its metabolites may be significantly increased in patients with hepatic dysfunction. Under such conditions, the duration of activity of sildenafil may be prolonged and the extent of its effects enhanced. As in patients with renal dysfunction, the initiation of therapy at 25 mg rather than 50 mg may be appropriate in patients with hepatic dysfunction.

V. Cardiovascular Effects of Sexual Intercourse in Patients With Coronary Artery Disease

There is potential for a high incidence of overt and covert coronary artery disease in patients with erectile dysfunction on the basis of the epidemiological profiles of both patient groups. Therefore, when prescribing sildenafil, physicians should consider the potential implications of coronary artery disease in sedentary patients who plan to resume sexual activity. Because nitrates are contraindicated for the management of coronary ischemic syndromes in patients taking sildenafil, review of the patient's ability to tolerate the cardiovascular stresses involved with sexual intercourse, particularly patients with coronary artery disease or at increased risk of coronary artery disease, may aid the treating physician in patient management.

Cardiac and metabolic expenditures during sexual intercourse will vary depending on the type of sexual activity. In a laboratory setting, healthy males with their usual female partners achieved an average peak heart rate of 110 bpm with woman-on-top coitus and an average peak heart rate of 127 bpm with man-on-top coitus.26 When oxygen uptake was measured in these men, an average metabolic expenditure during stimulation and orgasm of 2.5 metabolic equivalents (METS) for woman-on-top coitus and 3.3 METS for man-on-top coitus was attained. There was a significant individual variation of cardiovascular responses among patients ranging from 2.0 to 5.4 METS for man-on-top coitus. Thus, to simply equate a level of cardiac or metabolic expenditure during sexual intercourse to an activity such as "climbing 1 or 2 flights of stairs" may underestimate the level of cardiovascular response in individual patients.

In patients with known coronary artery disease whose antianginal medicines were stopped for study purposes,27 Drory et al compared the electrocardiographic monitoring findings in sexual activity with a near-maximal exercise treadmill test (ETT). Most patients had previous myocardial infarctions and were in New York Heart Association functional class I or II. ECG criteria for ischemia during intercourse were found in one third of the patients; two thirds of the time, this was silent rather than symptomatic ischemia. All patients with ischemia during coitus also demonstrated ischemia at ETT. Drory et al also noted significant variation in heart rate response to coitus, with an average heart rate of 118 bpm but with some patients attaining a heart rate of 185 bpm at orgasm. Other small studies with ECG monitoring during intercourse in patients with coronary artery disease concluded that sexual activity may provoke increased ventricular ectopic activity that is not necessarily elicited by other stimuli.28 Jackson29 found that in 19 patients with ischemic heart disease who developed angina during sexual intercourse, these symptoms were abolished with ß-blockade. The mean maximum heart rate during sexual intercourse with and without use of ß-blockers was 82 and 122 bpm, respectively. This would suggest that these patients may have different hemodynamics while taking antianginal medication that may afford them some protection or lower their risk of ischemia. It should be emphasized that coital death is rare, encompassing only 0.6% of sudden death cases.30 Muller et al31 found by retrospective case-crossover methodology that although sexual activity can trigger the onset of myocardial infarction, the relative risk in the 2 hours after sexual activity is very low (2.5; 95% CI, 1.7 to 3.7). Furthermore, sexual activity was a likely contributor to the onset of myocardial infarction only 0.9% of the time. Additionally, they found that the relative risk of myocardial infarction is not increased in patients with a prior history of cardiac disease and that regular exercise appears to prevent triggering. It should be cautioned that these reassuring data should not be extrapolated to patients taking sildenafil if they perform at higher cardiac and metabolic expenditures during coitus. The hemodynamic changes associated with sexual activity may be far greater with an unfamiliar than with a familiar partner, in unfamiliar settings, and after excessive eating and consumption of alcohol. The person most at risk is usually middle-aged and having extramarital relations.

The ETT can gauge the potential cardiac stress of sexual activity. If a patient can achieve 5 or 6 METS on the ETT without demonstrating arrhythmias or ischemia electrocardiographically, they most likely are not at high risk for developing myocardial ischemia as a result of their normal sexual activities.

VI. Recommendations for Sildenafil and the Cardiac Patient

A. Prescribing Sildenafil to Patients at Clinical Risk

Sildenafil is absolutely contraindicated in patients undergoing any long-acting nitrate drug therapy or using short-acting nitrates because of the risk of developing potentially life-threatening hypotension.
If a patient has stable coronary disease, is not taking a long-acting nitrate, has short-acting nitrate use as the only contraindication to sildenafil, and does not appear to need the nitrate on a consistent basis, the physician and the patient should carefully weigh the risks and benefits of sildenafil treatment. If the patient requires nitrates for mild or moderate exercise limitation, sildenafil should probably not be used.
All patients taking organic nitrates, even if they have not asked for Viagra, should be informed about the nitrate-sildenafil hypotensive interaction. There is a substantial potential for patients to obtain Viagra from another physician, a friend, or through the "black market," circumventing healthcare providers who could offer appropriate caution. Because sildenafil also potentiates the hypotensive effect of an inhaled form of nitrate, such as amyl nitrate or poppers, the concurrent recreational use of poppers and sildenafil could result in sudden and marked hypotensive response that could be serious or fatal. This interaction may be more pronounced in patients taking protease inhibitors concurrently (eg, indinavir, ritonavir, nelfinavir, and saquinavir).
Similarly, patients must be warned of the contraindication of taking sildenafil in the 24-hour time interval after taking a nitrate preparation, including sublingual nitroglycerin. The administration of sildenafil to a patient who has taken a nitrate in any form in the preceding 24 hours is contraindicated.
Although firm data are lacking, pre-Viagra treadmill tests to assess for the presence of stress-induced ischemia in patients with overt and covert coronary artery disease can guide the patient and physician relative to the risk of cardiac ischemia during sexual intercourse. If the patient can achieve 5 to 6 METS on an ETT without demonstrating ischemia, the risk of ischemia during coitus with a familiar partner, in familiar settings, without the added stress of a heavy meal or alcohol ingestion, is probably low. We wish to stress that the physical and emotional stresses of sexual intercourse can be excessive in some people, particularly those who have not performed this activity in some time and who are not in good condition. These stresses themselves may produce acute ischemia or precipitate myocardial infarction. Such patients should be advised to use common sense and to moderate their physical exertion and their emotional expectations as they begin their experience with taking Viagra.
If patients are taking a combination of antihypertensive medications, they should be cautioned about the possibility of sildenafil-induced hypotension. Because both venous and arterial vasodilatation occur with sildenafil, initial monitoring of the blood pressure with the institution of Viagra use would identify patients with an undesired hypotensive blood pressure response. This is an area of particular concern for the patient with congestive heart failure who has a borderline low blood volume and a low blood pressure status as well as for the patient who is following a complicated, multidrug, antihypertensive therapy regimen.
B. Management of Acute Ischemic Syndromes With Patients Taking Sildenafil

The physician should try to establish the time of the last dose of sildenafil. Definitive evidence is currently lacking, but it is possible that a precipitous reduction in blood pressure may occur over the initial 24 hours after a dose of sildenafil. Administration of nitrates in this time interval should be avoided. In the event that nitrates are given after sildenafil administration, it is essential to have the capability to support the patient with fluid resuscitation and -adrenergic agonists if needed. After 24 hours, the administration of a nitrate may be considered, but once again, appropriate caution with careful monitoring of initial dosages must be used. In patients in whom the half-life of sildenafil may be prolonged, such as in renal and hepatic dysfunction or patients concurrently taking a potent CYP 3A4 inhibitor, a more extended period of time from sildenafil administration to the time of nitrate administration may be required. In patients with recurring mild angina after sildenafil use, other nonnitrate antianginal agents, such as ß-blockers, should be considered.
Patients taking sildenafil who have an acute myocardial infarction should be treated in the usual manner as described in the ACC/AHA clinical practice guidelines32 including, where appropriate, primary angioplasty or thrombolytics. The only difference is that nitrates are contraindicated for these patients. If the patient had already used nitrates and sildenafil together, the acute myocardial infarction may have been caused by the low diastolic perfusion pressure of the coronary circulation. Blood pressure support may be sufficient to prevent further myocardial damage if no acute plaque rupture is present.
In patients with unstable angina, therapy should include only nonnitrate antianginal medications but should otherwise adhere to principles established in the clinical practice guideline available from the Agency for Health Care Policy and Research.33 To date, there is no evidence of significant interactions between sildenafil and heparin, ß-adrenergic blockers, calcium channel blockers, narcotics, or aspirin. These agents can be used as appropriate. After 24 hours, nitrates may be administered if close monitoring is provided and proper facilities are available for fluid and vasopressor support.
C. Treatment of the Hypotensive Patient With Inadvertent Sildenafil-Nitrate Combination Effect
In patients who inadvertently received nitrates while taking sildenafil and who manifest a severe hypotensive response, nitrate and nitroprusside (ie, NO donor) therapy should be immediately stopped. Depending on clinical circumstances, any of the following therapies should be considered alone or in combination:

Place the patient in Trendelenburg position.
Provide aggressive fluid resuscitation.
Provide judicious use of an intravenous -adrenergic agonist such as phenylephrine (Neo-Synephrine).
Provide an - and ß-adrenergic agonist (norepinephrine) for blood pressure support, with the realization that this could exacerbate or lead to an acute ischemic syndrome.
Provide intra-aortic balloon counterpulsation.
D. Limitations and Unresolved Issues
Expert Consensus Documents, as noted in the preamble, are often written in circumstances in which the evidence base and experience with the technology or practice are limited. This is clearly the case with Viagra. The evidence base had significant limitations, and many important issues remain unresolved. Of special significance to the current report is the fact that the preapproval clinical trials of Viagra excluded certain high-risk groups of patients with significant cardiac disease (ie, patients with heart failure, patients with myocardial infarction or stroke within 6 months, or patients with uncontrolled hypertension) or patients with blood pressures of <90/50 or >170/100 mm Hg. More research needs to be done to assess the specific risks of Viagra use among these cardiovascular patients.

The authors of this Expert Consensus Document identified a number of other unresolved issues that could affect clinical management of the cardiovascular consequences of sildenafil use, including the following:

Interaction with nonaspirin antiplatelet agents (eg, ticlopidine, clopidogrel, and dipyridamole).
Interaction with other PDE inhibitors, including specific PDE inhibitors (eg, milrinone, vesnarinone, and enoximone) and nonspecific PDE inhibitors (eg, theophylline, dipyridamole, papaverine, and pentoxifylline).
Central nervous system effects of sildenafil (PDE5 is present in the brain).
Hypotensive effects with sildenafil alone in high-risk cardiac patients (severe heart failure).
Musculoskeletal effects (myalgias with chest pains that could be confused with angina).
As more evidence is accumulated, the ACC will consider an update of this Expert Consensus Document.

1 Those authors designated with an asterisk have indicated a potential conflict of interest with respect to the topic of this document. They have excused themselves from discussions or the preparation of the text whence this potential conflict would apply.

Appendix A

List of Representative Organic Nitrates
Nitroglycerin
Deponit Minitran Nitrok Nitro-Bid Nitrocine Nitroderm Nitro Disc Nitro-Dur Nitrogard Nitroglycerin Nitroglycerin T/R Nitroglyn Nitrol ointment Nitrolingual spray Nitrong Nitro-Par Nitropress Nitro SA Nitrospan Nitrostat Nitro-trans system Nitro transdermal Nitro-Time Transiderm-Nitro Tridil

Isosorbide Mononitrate
Imdur ISMO Isosorbide mononitrate Monoket

Isosorbide Nitrate
Dilatrate-SR Iso-Bid Isordil Isordil tembids Isosorbide dinitrate Isosorbide dinitrate LA Sorbitrate Sorbitrate SA

Pentaerythritol Tetranitrate
Peritrate Peritrate SA

Erythrityl Tetranitrate
Cardilate

Isosorbide Dinitrate/Phenobarbital
Isordil w/PB

Illicit Substances Containing Organic Nitrates
Amyl nitrate or nitrite (It is known that amyl nitrate or nitrite is sometimes abused. In abuse situations, amyl nitrate or nitrite may be known by various names, including "poppers.")

Appendix B

Drugs That Are Metabolized by or That Inhibit Cytochrome P450 3A4
Antibiotic/Antifungal
Biaxin (clarithromycin) Clotrimazole Erythromycin Diflucan Sporanox Ketoconazole Miconazole Noroxin Troleandomycin

Cardiovascular
Amiodarone Norvast Digitoxin Diltiazem Disopyramide Plendil (felodipine) DynaCirc (isradipine) Cozaar (losartan) Posicor (mibefradil) Nifedipine Quinidine Verapamil

HMG
Lipitor (atorvastatin) Baycol (cerivastatin) Mevacor (lovastatin) Zocor (simvastatin)

Central Nervous System
Alprazolam Carbamazepine Prozac (fluoxetine) Luvox (fluvoxamine) Imipramine Serzone (nefazodone) Phenobarbital Phenytoin Zoloft Triazolam

Other
Acetaminophen Hismanal (astemizole) Tagamet (cimetidine) Propulsid (cisapride) Cyclosporine Dexamethasone Ethinyl estradiol Naringenin (grapefruit juice) Prilosec (omeprazole) Rifampin Tacrolimus Seldane (terfenadine) Theophylline Rezulin (troglitazone) Viagra (sildenafil) Protease inhibitors: Crixivan (indinavir), Norvir (ritonavir), Viracept (nelfinavir), Invirase (saquinavir)

Biaxin is a registered trademark of Abbott Laboratories. Diflucan, Norvast, and Zoloft are registered trademarks of Pfizer Inc. Sporanox, Hismanal, and Propulsid are registered trademarks of Janssen Pharmaceutica Inc. Noroxin, Cozaar, Mevacor, and Zocor are registered trademarks of Merck & Co, Inc. Plendil and Prilosec are registered trademarks of Astra Merck Inc. DynaCirc is a registered trademark of Norartis Pharmaceuticals Corporation. Posicor is a registered trademark of Roche Pharmaceuticals. Lipitor and Rezulin are registered trademarks of Parke-Davis. Baycol is a trademark of Bayer Corporation. Prozac is a registered trademark of Eli Lilly and Company. Luvox is a registered trademark of Solvay Pharmaceuticals, Inc. Serzone is a registered trademark of Bristol-Myers Squibb Company. Tagamet is a registered trademark of SmithKline Beecham Pharmaceuticals. Seldane is a registered trademark of Hoechst Marion Roussel. Viagra is a trademark of Pfizer Inc.

This summary contains important information about VIAGRA®. It is not meant to take the place of your doctor’s instructions. Read this information carefully before you start taking VIAGRA. Ask your doctor or pharmacist if you do not understand any of this information or if you want to know more about VIAGRA.

This medicine can help many men when it is used as prescribed by their doctors. However, VIAGRA is not for everyone. It is intended for use only by men who have a condition called erectile dysfunction. VIAGRA must never be used by men who are taking medicines that contain nitrates of any kind, at any time. This includes nitroglycerin. If you take VIAGRA with any nitrate medicine your blood pressure could suddenly drop to an unsafe or life threatening level.

What Is VIAGRA?

VIAGRA is a pill used to treat erectile dysfunction (impotence) in men. It can help many men who have erectile dysfunction get and keep an erection when they become sexually excited (stimulated).

You will not get an erection just by taking this medicine. VIAGRA helps a man with erectile dysfunction get an erection only when he is sexually excited.

How Sex Affects the Body

When a man is sexually excited, the penis rapidly fills with more blood than usual. The penis then expands and hardens. This is called an erection. After the man is done having sex, this extra blood flows out of the penis back into the body. The erection goes away. If an erection lasts for a long time (more than 6 hours), it can permanently damage your penis. You should call a doctor immediately if you ever have a prolonged erection that lasts more than 4 hours.

Some conditions and medicines interfere with this natural erection process. The penis cannot fill with enough blood. The man cannot have an erection. This is called erectile dysfunction if it becomes a frequent problem.

During sex, your heart works harder. Therefore sexual activity may not be advisable for people who have heart problems. Before you start any treatment for erectile dysfunction, ask your doctor if your heart is healthy enough to handle the extra strain of having sex. If you have chest pains, dizziness or nausea during sex, stop having sex and immediately tell your doctor you have had this problem.

How VIAGRA Works

VIAGRA enables many men with erectile dysfunction to respond to sexual stimulation. When a man is sexually excited, VIAGRA helps the penis fill with enough blood to cause an erection. After sex is over, the erection goes away.

VIAGRA Is Not for Everyone

As noted above (How Sex Affects the Body), ask your doctor if your heart is healthy enough for sexual activity.

If you take any medicines that contain nitrates – either regularly or as needed – you should never take VIAGRA. If you take VIAGRA with any nitrate medicine or recreational drug containing nitrates, your blood pressure could suddenly drop to an unsafe level. You could get dizzy, faint, or even have a heart attack or stroke. Nitrates are found in many prescription medicines that are used to treat angina (chest pain due to heart disease) such as:

nitroglycerin (sprays, ointments, skin patches or pastes, and tablets that are swallowed or dissolved in the mouth)
isosorbide mononitrate and isosorbide dinitrate (tablets that are swallowed, chewed, or dissolved in the mouth)
Nitrates are also found in recreational drugs such as amyl nitrate or nitrite (“poppers”). If you are not sure if any of your medicines contain nitrates, or if you do not understand what nitrates are, ask your doctor or pharmacist.
VIAGRA is only for patients with erectile dysfunction. VIAGRA is not for newborns, children, or women. Do not let anyone else take your VIAGRA. VIAGRA must be used only under a doctor’s supervision.

What VIAGRA Does Not Do

VIAGRA does not cure erectile dysfunction. It is a treatment for erectile dysfunction.
VIAGRA does not protect you or your partner from getting sexually transmitted diseases, including HIV—the virus that causes AIDS.
VIAGRA is not a hormone or an aphrodisiac.

What To Tell Your Doctor Before You Begin VIAGRA

Only your doctor can decide if VIAGRA is right for you. VIAGRA can cause mild, temporary lowering of your blood pressure. You will need to have a thorough medical exam to diagnose your erectile dysfunction and to find out if you can safely take VIAGRA alone or with your other medicines. Your doctor should determine if your heart is healthy enough to handle the extra strain of having sex.

Be sure to tell your doctor if you:

have ever had any heart problems (e.g., angina, chest pain, heart failure, irregular heart beats, heart attack or narrowing of the aortic valve)
have ever had a stroke
have low or high blood pressure
have a rare inherited eye disease called retinitis pigmentosa
have ever had any kidney problems
have ever had any liver problems
have ever had any blood problems, including sickle cell anemia or leukemia
are allergic to sildenafil or any of the other ingredients of VIAGRA tablets
have a deformed penis, Peyronie’s disease, or ever had an erection that lasted more than 4 hours
have stomach ulcers or any types of bleeding problems
are taking any other medicines

VIAGRA and Other Medicines

Some medicines can change the way VIAGRA works. Tell your doctor about any medicines you are taking. Do not start or stop taking any medicines before checking with your doctor or pharmacist. This includes prescription and nonprescription medicines or remedies:

Remember, VIAGRA should never be used with medicines that contain nitrates (see VIAGRA Is Not for Everyone).
If you are taking alpha-blocker therapy for the treatment of high blood pressure or prostate problems, you should not take a dose of greater than 25 mg of VIAGRA at the same time (within 4 hours) as you take your dose of alpha-blocker.
If you are taking a protease inhibitor, your dose may be adjusted (please see Finding the Right Dose for You).
VIAGRA should not be used with any other medical treatments that cause erections. These treatments include pills, medicines that are injected or inserted into the penis, implants or vacuum pumps.

Finding the Right Dose for You

VIAGRA comes in different doses (25 mg, 50 mg and 100 mg). If you do not get the results you expect, talk with your doctor. You and your doctor can determine the dose that works best for you.

Do not take more VIAGRA than your doctor prescribes.
If you think you need a larger dose of VIAGRA, check with your doctor.
VIAGRA should not be taken more than once a day.
If you are older than age 65, or have serious liver or kidney problems, your doctor may start you at the lowest dose (25 mg) of VIAGRA. If you are taking protease inhibitors, such as for the treatment of HIV, your doctor may recommend a 25 mg dose and may limit you to a maximum single dose of 25 mg of VIAGRA in a 48 hour period. If you are taking alpha-blocker therapy, you should not take a dose of greater than 25 mg of VIAGRA at the same time (within 4 hours) as your dose of alpha-blocker.

How To Take VIAGRA

Take VIAGRA about one hour before you plan to have sex. Beginning in about 30 minutes and for up to 4 hours, VIAGRA can help you get an erection if you are sexually excited. If you take VIAGRA after a high-fat meal (such as a cheeseburger and french fries), the medicine may take a little longer to start working. VIAGRA can help you get an erection when you are sexually excited. You will not get an erection just by taking the pill.

Possible Side Effects

Like all medicines, VIAGRA can cause some side effects. These effects are usually mild to moderate and usually don’t last longer than a few hours. Some of these side effects are more likely to occur with higher doses. The most common side effects of VIAGRA are headache, flushing of the face, and upset stomach. Less common side effects that may occur are temporary changes in color vision (such as trouble telling the difference between blue and green objects or having a blue color tinge to them), eyes being more sensitive to light, or blurred vision.

In rare instances, men have reported an erection that lasts many hours. You should call a doctor immediately if you ever have an erection that lasts more than 4 hours. If not treated right away, permanent damage to your penis could occur (see How Sex Affects the Body).

Heart attack, stroke, irregular heart beats, and death have been reported rarely in men taking VIAGRA. Most, but not all, of these men had heart problems before taking this medicine. It is not possible to determine whether these events were directly related to VIAGRA.

VIAGRA may cause other side effects besides those listed on this sheet. If you want more information or develop any side effects or symptoms you are concerned about, call your doctor.

Accidental Overdose

In case of accidental overdose, call your doctor right away.

Storing VIAGRA

Keep VIAGRA out of the reach of children. Keep VIAGRA in its original container. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

For More Information on VIAGRA

VIAGRA is a prescription medicine used to treat erectile dysfunction. Only your doctor can decide if it is right for you. This sheet is only a summary. If you have any questions or want more information about VIAGRA, talk with your doctor or pharmacist, visit www.viagra.com, or call 1-888-4VIAGRA.

Viagra Success Stories

The impact of ED

Mr. Tomas: Hi, my name is Ronaldo Tomas. I am originally from the Republic of Panama.

Mr. Tomas: I have been in the United States for almost 40 years. I have been diabetic for almost 10 years, and I have had erectile dysfunction for about 5 years.

Mr. D'Amico: Hi. I am Sal D'Amico. I am a retired mechanic.

Mr. D'Amico: I worked for Boys' Market. I retired from there and I had a heart attack.

Mr. Leslie: My name is Robert Leslie. This is my wife, Judy. We have been married for 36 years. I have been in a wheelchair for the last 23.

Mr. Leslie: When I did get hurt, we lost a lot of stuff, you know, that — I couldn't do anymore.

Mrs. Leslie: Going for a walk, holding hands.

Mr. Leslie: Yes, it's just different.

Mrs. Leslie: A walk on the beach, those are all gone, plus your physical, your sexual life is gone. It's not gone, but it's new, it's a new life that you have to learn to live with. And like he used to come up behind me and put his arm around me and kiss me on my neck, little things that people take for granted.

Mr. Tomas: I was a person that was always full of drive, full of wanting to be involved in activities and so on, and when this part of my body started to dysfunction, it put me in a kind of a depression. It was very difficult to deal with the situation where, especially in our home, things about sex were not discussed. But fortunately, when the VIAGRA information came about, I saw the opportunity to maybe see if we could create some kind of alternatives.

Mr. D'Amico: When you are not performing, you wonder if you are doing your job, you know. And maybe they won't say something, you know, but you are always thinking that they will, sooner or later.

Opening up about ED

Mr. D'Amico: And, well, I had a blood clot and he took care of it, and then he recommended a bypass. And any time I have a problem, I can talk to him so easy, and he just helps me right along. He is between a father and a brother.

Mr. Tomas: I am originally from Latin America. And there is a problem within the culture to talk about sexual things, and I think that it's about time that we get off the dime and either, as doctors or as patients, voluntarily provide information about our condition, because sometimes we think we can just forget it, live with something and forget about it. When here, we have an opportunity to get involved and make some real changes and make our lives happier, you know, and why not?

Within the Latino culture, I think that we need to generate more—more thinking to create more awareness that this is nothing to be ashamed of. You know, it's a medical problem, you know, if you are not functioning, you have a medical problem that has a good possibility of being alleviated. So, why keep your mouth shut or why isn't the doctor talking to you about this or why aren't you talking to the doctor about this?

Mr. D'Amico: My wife and I talked about it, and I said, "The only thing I can do is see the doctor and see what he says," because he usually takes care of everything anyway. He is pretty good at what he does. And finally he told me about VIAGRA and I said, "Well, I will try it."

Mr. Leslie: Well, we have been with Dr. Kurtz for the last—

Mrs. Leslie: 15 years.

Mr. Leslie: 15 years. Yeah, I guess about the last 15 years. And he is almost a friend as much as a doctor.

Mrs. Leslie: He is more of a friend.

Mr. Leslie: He is more of a friend, I should say it that way. He is a very caring person. You can almost talk to him, as a friend and not as a doctor. You know, he knows—he knows how to communicate with people.

The VIAGRA experience

Mrs. Leslie: It was like a honeymoon. After 22 and a half years of not being able to have physical relations, it was just like a honeymoon.

Mr. D'Amico: Well, I wasn't too sure it was going to do anything… And then when the doctor prescribed that, we tried it and it worked wonderful.

Mr. Tomas: It was a tremendous change in my entire life. I would like to think that…not that I'd like to think, I know that it gave me a much more positive feeling about myself. And this is one of the reasons I am here today to share this with many of you. It's a thing that we need to talk about, people—doctors need to talk about, patients need to talk about it, because you don't realize what you are doing to yourself by keeping this thing a secret. You have to get out there and at least give yourself a try to see how things can make your life different. And it certainly has made a lot of difference in my life and I would hope that those of you watching would have the opportunity to see that kind of a difference.

I have 4 children, 2 boys, 2 girls, and one living with us now, and he doesn't seem to believe the kind of energy that is floating around the house as a result of…he doesn't really know everything that's going on, but there is a tremendous amount of change in our lives… It’s like a guy who loses an arm and then somebody, by some stroke of some miracle, produces something that makes him have the arm to be useful to him again. You are much more appreciative of something that you have lost when you regain it.

Mrs. Leslie: I was in the office, and he called me in one of the rooms, and he said, the new product had come out. He explained to me what it was, and he said, "I want you to take it and try it" and I said, "But there has been nothing for 22 and a half years." He said, "Just take it and try it." So we decided Friday was date night. So we had a nice dinner, and took the phone off the hook so the kids wouldn't call. And he took the VIAGRA and it worked beautifully....

To be honest, the first night we used it we both ended up crying, because it was so special, and it was beautiful. And we knew each other so well, and yet we were both nervous, because we didn't know what to expect. And after that many years of not having what you would really call an intimate moment, it was...it was beautiful.

Viagra News

Does Your Health Plan Cover Viagra?

Forbes Magazine
William Baldwin, 03.31.03, 12:00 AM ET

Medical costs have made cheats out of us all.
"Defensive medicine," a phrase usually referring to the warding off of lawsuits, is about to take on a new meaning. It's going to apply to the practice of dodging price controls. One battleground will be the $192 billion a year spent on prescription drugs. As Robert Langreth outlines in his story on page 84, the employers who have been paying this bill are desperately coming up with ways to duck it. They want patients to pay more. The patients, in turn, will scheme with their doctors to get around the rules.

For a look at what's in store, visit the Web site for the Tufts Health Plan and look at the "tiers" of pharmacy coverage, with progressively higher hurdles, or stiffer copayments, for drugs that Tufts finds overpriced or unnecessary. The annotation for Viagra says that coverage will be denied for female patients and males under 19. Tufts does not want insured medicine to turn up on the black market, of course, but how it will confirm that an eligible patient actually took the blue pills is hard to picture.

Medical costs have already made cheats out of us all. The politicians cheat hospitals by fixing unfairly low prices for Medicare. The hospitals defend themselves by inflating their reports of what services they are providing or what illnesses they are treating. There's a whole science to such upcoding that dictates how far a hospital can go without running afoul of the 130,000-page rule book.

Families are counseled on how to cheat the government out of nursing home costs by shuffling assets. Drug companies, hardened by years of regulatory lag that cheated them out of the value of their patents, are playing defensive medicine of their own. When a valuable patent expires, cheap generics are supposed to come in, but the patent owners have ways of sabotaging the competition.

Doctors, beaten up first by Medicare and now by HMOs, are getting even, too. I had an interesting look at how during an office visit. The doc explained that drug companies were ripping off the public with their obscene pricing, and so he was doing his part to level the playing field. Drug companies hand out free samples like lollipops, and Dr. Robin Hood solicits, and gets, more than his share. On my way out he handed me a shopping bag full of pills, worth hundreds of dollars. This was, of course, in mitigation of the doc's own bill--$500 for a physical.

How does an erection occur?
What causes ED?
How is ED diagnosed?
How is ED treated?
Hope Through Research
Points to Remember
For More Information

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Erectile dysfunction, sometimes called "impotence," is the repeated inability to get or keep an erection firm enough for sexual intercourse. The word "impotence" may also be used to describe other problems that interfere with sexual intercourse and reproduction, such as lack of sexual desire and problems with ejaculation or orgasm. Using the term erectile dysfunction makes it clear that those other problems are not involved.

Erectile dysfunction, or ED, can be a total inability to achieve erection, an inconsistent ability to do so, or a tendency to sustain only brief erections. These variations make defining ED and estimating its incidence difficult. Estimates range from 15 million to 30 million, depending on the definition used. According to the National Ambulatory Medical Care Survey (NAMCS), for every 1,000 men in the United States, 7.7 physician office visits were made for ED in 1985. By 1999, that rate had nearly tripled to 22.3. The increase happened gradually, presumably as treatments such as vacuum devices and injectable drugs became more widely available and discussing erectile function became accepted. Perhaps the most publicized advance was the introduction of the oral drug sildenafil citrate (Viagra) in March 1998. NAMCS data on new drugs show an estimated 2.6 million mentions of Viagra at physician office visits in 1999, and one-third of those mentions occurred during visits for a diagnosis other than ED.

In older men, ED usually has a physical cause, such as disease, injury, or side effects of drugs. Any disorder that causes injury to the nerves or impairs blood flow in the penis has the potential to cause ED. Incidence increases with age: About 5 percent of 40-year-old men and between 15 and 25 percent of 65-year-old men experience ED. But it is not an inevitable part of aging.

ED is treatable at any age, and awareness of this fact has been growing. More men have been seeking help and returning to normal sexual activity because of improved, successful treatments for ED. Urologists, who specialize in problems of the urinary tract, have traditionally treated ED; however, urologists accounted for only 25 percent of Viagra mentions in 1999.

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How does an erection occur? The penis contains two chambers called the corpora cavernosa, which run the length of the organ (see figure 1). A spongy tissue fills the chambers. The corpora cavernosa are surrounded by a membrane, called the tunica albuginea. The spongy tissue contains smooth muscles, fibrous tissues, spaces, veins, and arteries. The urethra, which is the channel for urine and ejaculate, runs along the underside of the corpora cavernosa.

Erection begins with sensory or mental stimulation, or both. Impulses from the brain and local nerves cause the muscles of the corpora cavernosa to relax, allowing blood to flow in and fill the spaces. The blood creates pressure in the corpora cavernosa, making the penis expand. The tunica albuginea helps trap the blood in the corpora cavernosa, thereby sustaining erection. When muscles in the penis contract to stop the inflow of blood and open outflow channels, erection is reversed.

Figure 1. Arteries (top) and veins (bottom) penetrate the long, filled cavities running the length of the penis--the corpora cavernosa and the corpous sponglosum. Erection occurs when relaxed muscles allow the corpora cavernosa to fill with excess blood fed by the arteries, while drainage of blood through the veins is blocked.

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What causes ED? Since an erection requires a precise sequence of events, ED can occur when any of the events is disrupted. The sequence includes nerve impulses in the brain, spinal column, and area around the penis, and response in muscles, fibrous tissues, veins, and arteries in and near the corpora cavernosa.

Damage to nerves, arteries, smooth muscles, and fibrous tissues, often as a result of disease, is the most common cause of ED. Diseases--such as diabetes, kidney disease, chronic alcoholism, multiple sclerosis, atherosclerosis, vascular disease, and neurologic disease--account for about 70 percent of ED cases. Between 35 and 50 percent of men with diabetes experience ED.

Also, surgery (especially radical prostate surgery for cancer) can injure nerves and arteries near the penis, causing ED. Injury to the penis, spinal cord, prostate, bladder, and pelvis can lead to ED by harming nerves, smooth muscles, arteries, and fibrous tissues of the corpora cavernosa.

In addition, many common medicines--blood pressure drugs, antihistamines, antidepressants, tranquilizers, appetite suppressants, and cimetidine (an ulcer drug)--can produce ED as a side effect.

Experts believe that psychological factors such as stress, anxiety, guilt, depression, low self-esteem, and fear of sexual failure cause 10 to 20 percent of ED cases. Men with a physical cause for ED frequently experience the same sort of psychological reactions (stress, anxiety, guilt, depression).

Other possible causes are smoking, which affects blood flow in veins and arteries, and hormonal abnormalities, such as not enough testosterone.

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How is ED diagnosed? Patient History
Medical and sexual histories help define the degree and nature of ED. A medical history can disclose diseases that lead to ED, while a simple recounting of sexual activity might distinguish between problems with sexual desire, erection, ejaculation, or orgasm.

Using certain prescription or illegal drugs can suggest a chemical cause, since drug effects account for 25 percent of ED cases. Cutting back on or substituting certain medications can often alleviate the problem.

Physical Examination
A physical examination can give clues to systemic problems. For example, if the penis is not sensitive to touching, a problem in the nervous system may be the cause. Abnormal secondary sex characteristics, such as hair pattern, can point to hormonal problems, which would mean that the endocrine system is involved. The examiner might discover a circulatory problem by observing decreased pulses in the wrist or ankles. And unusual characteristics of the penis itself could suggest the source of the problem--for example, a penis that bends or curves when erect could be the result of Peyronie's disease.

Laboratory Tests
Several laboratory tests can help diagnose ED. Tests for systemic diseases include blood counts, urinalysis, lipid profile, and measurements of creatinine and liver enzymes. Measuring the amount of testosterone in the blood can yield information about problems with the endocrine system and is indicated especially in patients with decreased sexual desire.

Other Tests
Monitoring erections that occur during sleep (nocturnal penile tumescence) can help rule out certain psychological causes of ED. Healthy men have involuntary erections during sleep. If nocturnal erections do not occur, then ED is likely to have a physical rather than psychological cause. Tests of nocturnal erections are not completely reliable, however. Scientists have not standardized such tests and have not determined when they should be applied for best results.

Psychosocial Examination
A psychosocial examination, using an interview and a questionnaire, reveals psychological factors. A man's sexual partner may also be interviewed to determine expectations and perceptions during sexual intercourse.

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How is ED treated? Most physicians suggest that treatments proceed from least to most invasive. Cutting back on any drugs with harmful side effects is considered first. For example, drugs for high blood pressure work in different ways. If you think a particular drug is causing problems with erection, tell your doctor and ask whether you can try a different class of blood pressure medicine.

Psychotherapy and behavior modifications in selected patients are considered next if indicated, followed by oral or locally injected drugs, vacuum devices, and surgically implanted devices. In rare cases, surgery involving veins or arteries may be considered.

Psychotherapy
Experts often treat psychologically based ED using techniques that decrease the anxiety associated with intercourse. The patient's partner can help with the techniques, which include gradual development of intimacy and stimulation. Such techniques also can help relieve anxiety when ED from physical causes is being treated.

Drug Therapy
Drugs for treating ED can be taken orally, injected directly into the penis, or inserted into the urethra at the tip of the penis. In March 1998, the Food and Drug Administration approved Viagra, the first pill to treat ED. Taken an hour before sexual activity, Viagra works by enhancing the effects of nitric oxide, a chemical that relaxes smooth muscles in the penis during sexual stimulation and allows increased blood flow.

While Viagra improves the response to sexual stimulation, it does not trigger an automatic erection as injections do. The recommended dose is 50 mg, and the physician may adjust this dose to 100 mg or 25 mg, depending on the patient. The drug should not be used more than once a day. Men who take nitrate-based drugs such as nitroglycerin for heart problems should not use Viagra because the combination can cause a sudden drop in blood pressure.

Additional oral medicines may soon be available to treat ED. Vardenafil and Cialis are being tested for safety and effectiveness. Both of these drugs work like Viagra by increasing blood flow to the penis. A third drug being tested, Uprima, works on the brain and nervous system to trigger an erection.

Oral testosterone can reduce ED in some men with low levels of natural testosterone, but it is often ineffective and may cause liver damage. Patients also have claimed that other oral drugs--including yohimbine hydrochloride, dopamine and serotonin agonists, and trazodone--are effective, but the results of scientific studies to substantiate these claims have been inconsistent. Improvements observed following use of these drugs may be examples of the placebo effect, that is, a change that results simply from the patient's believing that an improvement will occur.

Many men achieve stronger erections by injecting drugs into the penis, causing it to become engorged with blood. Drugs such as papaverine hydrochloride, phentolamine, and alprostadil (marketed as Caverject) widen blood vessels. These drugs may create unwanted side effects, however, including persistent erection (known as priapism) and scarring. Nitroglycerin, a muscle relaxant, can sometimes enhance erection when rubbed on the penis.

A system for inserting a pellet of alprostadil into the urethra is marketed as Muse. The system uses a prefilled applicator to deliver the pellet about an inch deep into the urethra. An erection will begin within 8 to 10 minutes and may last 30 to 60 minutes. The most common side effects are aching in the penis, testicles, and area between the penis and rectum; warmth or burning sensation in the urethra; redness from increased blood flow to the penis; and minor urethral bleeding or spotting.

Research on drugs for treating ED is expanding rapidly. Patients should ask their doctor about the latest advances.

Vacuum Devices
Mechanical vacuum devices cause erection by creating a partial vacuum, which draws blood into the penis, engorging and expanding it. The devices have three components: a plastic cylinder, into which the penis is placed; a pump, which draws air out of the cylinder; and an elastic band, which is placed around the base of the penis to maintain the erection after the cylinder is removed and during intercourse by preventing blood from flowing back into the body (see figure 2).

Figure 2. A vacuum-constrictor device causes an erection by creating a partial vacuum around the penis, which draws blood into the corpora cavernosa. Pictured here are the necessary components: (a) a plastic cylinder, which covers the penis; (b) a pump, which draws air out of the cylinder; and (c) an elastic ring, which, when fitted over the base of the penis, traps the blood and sustains the erection after the cylinder is removed.

One variation of the vacuum device involves a semirigid rubber sheath that is placed on the penis and remains there after erection is attained and during intercourse.

Surgery
Surgery usually has one of three goals:

to implant a device that can cause the penis to become erect

to reconstruct arteries to increase flow of blood to the penis

to block off veins that allow blood to leak from the penile tissues
Implanted devices, known as prostheses, can restore erection in many men with ED. Possible problems with implants include mechanical breakdown and infection, although mechanical problems have diminished in recent years because of technological advances.

Malleable implants usually consist of paired rods, which are inserted surgically into the corpora cavernosa. The user manually adjusts the position of the penis and, therefore, the rods. Adjustment does not affect the width or length of the penis.

Inflatable implants consist of paired cylinders, which are surgically inserted inside the penis and can be expanded using pressurized fluid (see figure 3). Tubes connect the cylinders to a fluid reservoir and a pump, which are also surgically implanted. The patient inflates the cylinders by pressing on the small pump, located under the skin in the scrotum. Inflatable implants can expand the length and width of the penis somewhat. They also leave the penis in a more natural state when not inflated.

Figure 3. With an inflatable implant, erection is produced by squeezing a small pump (a) implanted in a scrotum. The pump causes fluid to flow from a reservoir (b) residing in the lower pelvis to two cylinders (c) residing in the penis. The cylinders expand to create the erection.

Surgery to repair arteries can reduce ED caused by obstructions that block the flow of blood. The best candidates for such surgery are young men with discrete blockage of an artery because of an injury to the crotch or fracture of the pelvis. The procedure is less successful in older men with widespread blockage.

Surgery to veins that allow blood to leave the penis usually involves an opposite procedure--intentional blockage. Blocking off veins (ligation) can reduce the leakage of blood that diminishes the rigidity of the penis during erection. However, experts have raised questions about the long-term effectiveness of this procedure, and it is rarely done.

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Hope Through Research Advances in suppositories, injectable medications, implants, and vacuum devices have expanded the options for men seeking treatment for ED. These advances have also helped increase the number of men seeking treatment. Gene therapy for ED is now being tested in several centers and may offer a long-lasting therapeutic approach for ED.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsors programs aimed at understanding the causes of erectile dysfunction and finding treatments to reverse its effects. NIDDK's Division of Kidney, Urologic, and Hematologic Diseases supported the researchers who developed Viagra and continue to support basic research into the mechanisms of erection and the diseases that impair normal function at the cellular and molecular levels, including diabetes and high blood pressure.

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Points to Remember Erectile dysfunction (ED) is the repeated inability to get or keep an erection firm enough for sexual intercourse.

ED affects 15 to 30 million American men.

ED usually has a physical cause.

ED is treatable at all ages.

Treatments include psychotherapy, drug therapy, vacuum devices, and surgery.

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For More Information Sexual Function Health Council
American Foundation for Urologic Disease
1128 North Charles Street
Baltimore, MD 21201
Phone: 1-800-433-4215 or (410) 468-1800
Email: impotence@afud.org
Internet: www.impotence.org

Finding a Health Care Provider or Counselor
American Urological Association
1120 North Charles Street
Baltimore, MD 21201
Phone: (410) 727-1100
Email: aua@auanet.org
Internet: www.auanet.org

AUA can refer you to a urologist in your area.

American Diabetes Association (ADA)
National Office
1701 North Beauregard Street
Alexandria, VA 22311
Phone: 1-800-DIABETES
Internet: www.diabetes.org

ADA can help you find a doctor who specializes in diabetes care in your area.

American Association of Sex Educators, Counselors, and Therapists (AASECT)
P.O. Box 238
Mount Vernon, IA 52314
Internet: www.aasect.org

Check the AASECT website to find a certified sexuality educator, counselor, or therapist in your area.

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The U.S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this document are used only because they are considered necessary in the context of the information provided. If a product is not mentioned, this does not mean or imply that the product is unsatisfactory.

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National Kidney and Urologic Diseases Information Clearinghouse
3 Information Way
Bethesda, MD 20892-3580
Email: nkudic@info.niddk.nih.gov

The National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC) is a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The NIDDK is part of the National Institutes of Health under the U.S. Department of Health and Human Services. Established in 1987, the clearinghouse provides information about diseases of the kidneys and urologic system to people with kidney and urologic disorders and to their families, health care professionals, and the public. NKUDIC answers inquiries, develops and distributes publications, and works closely with professional and patient organizations and Government agencies to coordinate resources about kidney and urologic diseases.

Publications produced by the clearinghouse are carefully reviewed by both NIDDK scientists and outside experts. This fact sheet was reviewed by Arnold Melman, M.D., Montefiore Medical Center, Bronx, NY; and Mark Hirsch, M.D., U.S. Food and Drug Administration.

This e-text is not copyrighted. The clearinghouse encourages users of this e-pub to duplicate and distribute as many copies as desired.

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NIH Publication No. 03-3923
October 2002

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