Sildenafil, a selective phosphodiesterase (PDE) type 5 inhibitor, is a vasodilating agent.1, 2, 4, 5, 7, 8, 10, 24, 27, 33, 41, 56, 57, 67, 91, 131
Sildenafil citrate (Viagra® and generic equivalents) is used orally for the treatment of erectile dysfunction (ED, impotence).1, 4, 6, 7, 8, 9, 10, 25, 33, 34, 67, 81, 102, 104, 105, 107, 108, 112, 118, 126, 127, 128, 129, 130, 131, 132, 133, 134, 140, 142, 143, 144, 189
A thorough medical, sexual and psychosocial history, physical examination, and selective laboratory testing 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 (e.g., PDE 5 type inhibitor).12, 28, 30, 31, 57, 65, 66, 70, 78, 83, 94, 144, 145, 160, 161, 189, 601, 602, 603 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.12, 28, 70, 81, 118, 144, 161, 602, 603 In instances where substitution therapy is not feasible, concomitant vasoactive therapy with a PDE 5 type inhibitor may promote patient compliance by counteracting ED as an adverse effect.12, 28, 70, 81, 118, 144, 161, 602, 603
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.1, 7, 8, 9, 10, 25, 33, 34, 65, 76, 81, 101, 104, 105, 126, 127, 131, 142, 143, 144 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.1, 8, 9, 33, 126, 130, 131, 155 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, depression, radical prostatectomy, prostate brachytherapy, transurethral resection of the prostate (TURP), spina bifida, spinal cord injury, and in patients taking antidepressants, antipsychotics, diuretics, and antihypertensive agents.1, 25, 30, 33, 34, 93, 101, 102, 104, 105, 107, 108, 112, 118, 126, 127, 128, 129, 130, 131, 132, 133, 134, 140, 144 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.1, 33, 65, 94, 127, 131
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).1, 33, 105, 145 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.33, 34 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.104, 127 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.1, 104 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.76, 127 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.1, 7, 8, 9, 10, 25, 33, 93
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.1, 8, 9, 33, 94, 107, 130, 131, 142 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.1, 8, 33, 131 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.33, 107, 130, 131 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.33, 107, 130, 131
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).143 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.143
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.1, 7, 33, 69, 93, 104, 107, 128, 131, 132, 163, 165
Information on the long-term effects of sildenafil is limited, and thus the optimum duration of therapy is not known.1, 33, 81, 128, 132 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.1 In several long-term and open-label studies, sildenafil remained effective for at least 0.5-4 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).1, 33, 128, 132, 163, 165
The safety and efficacy of sildenafil in combination with other treatments for ED have not been established.1 Such combined therapy may further lower blood pressure and is not recommended by the manufacturer.1
With the availability of orally active and convenient vasoactive (erectogenic) therapies (e.g., selective phosphodiesterase [PDE] type 5 inhibitors such as sildenafil, tadalafil, avanafil, and vardenafil), most experts (e.g., the American Urological Association [AUA]) now consider these drugs to be first-line therapies for a broad range of patients with ED.144, 145, 189, 601
Because PDE type 5 inhibitors are administered orally, they are likely to be more acceptable to men with ED than other vasoactive therapies (e.g., intracavernosal injections, intraurethral suppositories) or mechanical or prosthetic devices.26, 33, 81, 94, 107, 602 Alternative therapies (e.g., intracavernosal or intraurethral vasoactive agents, vacuum constriction devices) 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).144, 155, 161, 189, 601 Ultimately, the choice of therapy for ED should be individualized, taking into account patient 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.33, 65, 81, 101, 189, 601, 602
PDE type 5 inhibitors are effective only in the presence of adequate sexual stimulation.1, 189, 602 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.189, 601, 602 Non-response to PDE type 5 inhibitors is related to factors such as condition severity, medications, and comorbidities (e.g., diabetes mellitus, vascular disease, hypogonadism, psychological factors, neurologic damage [e.g., non-nerve-sparing radical prostatectomy], radiotherapy for prostate cancer).34, 104, 602 Treatment failure may also be attributed to incorrect use of PDE type 5 inhibitor therapy (e.g., lack of sexual stimulation, medication taken with a large meal).189 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 drug.189, 601, 602 Although differences in the pharmacokinetics of these drugs (onset and duration) may exist, data currently are insufficient to support the superiority of one selective PDE type 5 inhibitor over another.189, 601, 602
Administer sildenafil tablets orally without regard to meals; however, administration with a high-fat meal may delay the onset of action.1 117, 131 Administer the drug approximately 1 hour before anticipated sexual activity.1, 28, 33, 81, 91, 93, 94, 102, 105, 118, 130, 132, 161, 602, 603 Sexual stimulation is required for response to therapy.1
Sildenafil tablets should be stored at 20-25°C (excursions permitted to 15-30°C).1
For the treatment of erectile dysfunction (ED), the recommended initial dosage of sildenafil is 50 mg orally as needed approximately 1 hour before anticipated sexual activity.1, 28, 33, 81, 91, 93, 94, 102, 105, 118, 130, 132, 161 The maximum recommended dosing frequency is once per day.1 The dose may be taken anywhere from 4 hours to 30 minutes before sexual activity.1 Peak plasma concentrations are achieved within 30-120 minutes (median 60 minutes) when taken on an empty stomach; the erectile response is diminished at 4 hours compared with 2 hours after administration.1, 91, 127, 132
Based on effectiveness and tolerance, the dose subsequently may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg (maximum frequency once per day).1, 28, 33, 91, 93, 94, 105, 161 Evidence from dose-ranging studies indicates that erectile response is greater at 50- or 100-mg doses than at 25 mg.1, 28, 33, 130, 131
Dosage of sildenafil, including both the dose and frequency of use, must be individualized carefully according to the patient's tolerance and erectile response.1, 33, 67, 81
Dose Adjustments for Drug Interactions
Concomitant use with an α-adrenergic blocking agent: When sildenafil is coadministered with an α-adrenergic blocking agent, patients should be stable on the α-adrenergic blocking agent before initiating sildenafil, and sildenafil should be initiated at the lowest dose (25 mg).1
Concomitant use with cytochrome P-450 (CYP) 3A4 inhibitors: An initial sildenafil dose of 25 mg is recommended in patients receiving strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, cobicistat) or the moderate CYP3A4 inhibitor erythromycin.1, 200
Concomitant use with protease inhibitors (e.g., ritonavir): An initial sildenafil dose of 25 mg is recommended in patients receiving protease inhibitors.1, 200 When used concomitantly, do not exceed a maximum single sildenafil dose of 25 mg in a 48 hour period and monitor for adverse effects.1, 200
In patients with hepatic impairment (e.g., cirrhosis), consider reducing the initial dose of sildenafil to 25 mg.1
In patients with severe renal impairment (creatinine clearance <30 mL/minute), consider reducing the initial dose of sildenafil to 25 mg.1
In patients ≥ 65 years of age, consider reducing the initial dose of sildenafil to 25 mg.1
There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease.1 Therapy for erectile dysfunction (ED), including sildenafil, generally should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.1 The evaluation of ED should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.1
Sildenafil doses of 25-100 mg reduce the maximum supine systolic/diastolic blood pressure by an average of about 8.4/5.5 mm Hg within 1-2 hours after administration of the drug in healthy adults, returning to baseline values within 4-8 hours after a dose.1, 29, 31, 67
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.1, 67, 154
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 (blood pressure less than 90/50 mm Hg) or hypertension (blood pressure exceeding 170/110 mm Hg); and in those with cardiac failure or coronary artery disease causing unstable angina.1, 31, 101, 127, 144, 154, 155, 159
The possibility of a hypotensive reaction in patients receiving a selective PDE type 5 inhibitor concomitantly with antihypertensive drug therapy should be considered.28, 31, 67 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 (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis), those with severely impaired autonomic control of blood pressure, and in those who are receiving a complex, multidrug antihypertensive regimen.1, 67 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.28, 67, 159 In patients with severe renal impairment, concomitant use of sildenafil and antihypertensive agents should be undertaken with caution.28, 67, 80
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.1, 190, 191, 192, 196, 197 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" optic disc), age (older than 50 years), diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking.1, 191, 192, 196 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 100,000.1 Results of an observational study in patients with recent, episodic PDE type 5 inhibitor use (typical of ED treatment) suggest an approximately two-fold increase in the risk of NAION, with a risk estimate of 2.15 within 5 half-lives of such use.1 A risk estimate of 2.27 was reported in a similar study.1
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).1, 190, 191, 196, 197
If sudden vision loss or decreased vision occurs in one or both eyes while a patient is receiving a PDE type 5 inhibitor, the patient should discontinue the drug and contact a clinician immediately.1
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.1 Sildenafil should be used with caution for the treatment of ED in these patients and only when the anticipated benefits outweigh the risks.1
Although at greater risk for NAION compared to the general population, evidence is insufficient to support screening for "crowded" optic disc in prospective users of PDE type 5 inhibitors for the treatment of ED. 1
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.1, 31, 155
Sudden decrease or loss of hearing, with or without concomitant vestibular manifestations (e.g., tinnitus, dizziness), has been reported in temporal association with use of PDE type 5 inhibitors, including sildenafil.1 It is unclear whether these otic effects are directly related to PDE type 5 inhibitors or attributed to other underlying risk factors for hearing loss, a combination of these factors, or to other factors.1
Patients should discontinue sildenafil and seek medical attention immediately if sudden hearing loss or decreased hearing occurs.1
Prolonged erection (exceeding 4 hours) and priapism (painful erection exceeding 6 hours) have been reported infrequently during postmarketing surveillance with sildenafil.1, 31, 127, 131, 139, 146, 147 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.1, 31
Sildenafil should be used with caution in patients with anatomic deformation of the penis (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).1, 33, 159
Concomitant Administration with Beta-Adrenergic Blocking Agents
Caution is advised when PDE type 5 inhibitors are co-administered with α-adrenergic blocking agents; blood pressure may be lowered significantly and in some patients, symptomatic hypotension (e.g., dizziness, lightheadedness, fainting) may occur.1 Patients who demonstrate hemodynamic instability during therapy with an α-adrenergic blocking agent alone are at increased risk for symptomatic hypotension with concomitant use of a PDE type 5 inhibitor.1
In patients who exhibit hemodynamic instability while receiving an α-adrenergic blocking agent, use caution.1 Patients should be stable on an α-adrenergic blocking agent prior to initiation of sildenafil, and sildenafil should be administered at the lowest possible dose.1 In patients receiving an optimal dose of sildenafil, initiate the α-adrenergic blocking agent at the lowest dose.1
Concomitant Use with Ritonavir
Concomitant administration of ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC).1 Data are limited; decreased blood pressure, syncope, and prolonged erection have been reported in some healthy volunteers exposed to high doses of sildenafil (200-800 mg).1 Use sildenafil with caution in patients receiving ritonavir; reduced sildenafil dosage is recommended to decrease the chance of adverse reactions to sildenafil.1
Bleeding events have been reported in patients taking sildenafil for ED.1 In patients with bleeding disorders or active peptic ulcers, sildenafil should be used with caution since safety of the drug has not been established.1, 27, 33, 67, 131 The possibility that sildenafil could potentiate the effects of certain other drugs exhibiting antiplatelet activity should be considered.1, 27, 67
Combination with other PDE Type 5 Inhibitors or other ED Therapies
Safety and efficacy have not been established for use of sildenafil in combination with other PDE type 5 inhibitors or other treatments for ED; such combinations may further lower blood pressure and are not recommended.1
Counseling Patients about Sexually Transmitted Diseases
Patients should be advised that use of sildenafil provides no protection against sexually transmitted diseases and they should be counseled regarding protective measures to guard against such transmission.1, 26, 68
Sildenafil for ED (e.g., Viagra®) is not indicated for use in females.1 There are no data with use in pregnant women to inform any drug-associated risks for adverse developmental outcomes.1
No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in rats and rabbits receiving up to 200 mg/kg daily of sildenafil during organogenesis.1 These doses in rats and rabbits represent about 16 and 32 times, respectively, the maximum recommended human dose (MRHD) for the treatment of ED on a mg/m2 basis in a 50-kg patient.1 No adverse effects were observed Iin a prenatal and postnatal development study in rats receiving 30 mg/kg daily for 36 days (equivalent to 2-times the MRHD on a mg/m2 basis in a 50-kg subject).1
Sildenafil for ED (e.g., Viagra®) is not indicated for use in females.1 Limited data indicate that sildenafil and its active metabolite are present in human milk.1 There is no information about the effects of sildenafil on the breastfed infant or on milk production.1
Females and Males of Reproductive Potential
Reproduction studies revealed no evidence of impaired fertility at sildenafil dosages up to 60 mg/kg daily (for 36 days in female rats and 102 days in male rats), a dosage representing more than 25 times the human male AUC.1 No effect on sperm motility or morphology was noted after a single 100-mg oral sildenafil dose in healthy human adults.1
Sildenafil for ED (e.g., Viagra®) is not indicated for use in pediatric patients.1 The manufacturer states that safety and efficacy of sildenafil in children have not been established.1
The AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45 and 57% higher, respectively, in healthy volunteers ≥65 years of age compared to healthy volunteers 18-45 years of age.1 Clinical studies included patients ≥65 years of age (18%) and ≥75 years of age (2%); no overall differences in safety and efficacy were observed between older (≥65 years of age) and younger (<65 years of age) patients1 Because higher plasma levels may increase the incidence of adverse reactions, consider reducing the initial sildenafil dosage to 25 mg in older patients.1
In patients with hepatic cirrhosis (Child-Pugh class A or B), sildenafil clearance is reduced, resulting in increased AUC (by 85%) and peak plasma concentrations (by 47%) compared with values observed in age-matched healthy adults.1, 31, 131 The effect of severe hepatic impairment on the pharmacokinetics of sildenafil has not been evaluated to date.1
In patients with any degree of hepatic impairment (e.g. cirrhosis), consider reducing the initial dose of sildenafil to 25 mg.1
In patients with mild (creatinine clearance 50-80 mL/minute) or moderate (creatinine clearance 30-49 mL/minute) renal impairment, the pharmacokinetics of a single 50-mg oral dose of sildenafil are not altered.1, 31, 131 However, in patients with severe (creatinine clearance less than 30 mL/minute) renal impairment, sildenafil clearance is reduced, resulting in AUC and peak plasma concentrations of the parent drug that are approximately double those in age-matched healthy adults.1, 31, 67, 131 In addition, AUC and peak plasma concentrations of the N-demethylated metabolite are 200 and 79% greater, respectively, than those in individuals with normal renal function.1
In patients with severe renal impairment (creatinine clearance less than 30 mL/minute), consider reducing the initial dose of sildenafil to 25 mg.1
The most common adverse effects (≥2%) of sildenafil used for the treatment of ED include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash.1
Sildenafil is metabolized principally via hepatic cytochrome P-450 (CYP) microsomal isoenzymes 3A4 (major route) and 2C9 (minor route).1, 91, 131 Inhibitors and inducers of these isoenzymes may reduce or increase sildenafil clearance, respectively.91
In vitro studies indicate that sildenafil is a weak inhibitor of the CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4.1, 26, 67, 250 Sildenafil is not expected to affect the pharmacokinetics of substrates of these CYP enzymes at clinically relevant concentrations.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
The possibility that any drug that inhibits CYP3A4 may interact with sildenafil should be considered.1, 67 In some cases, a reduction in sildenafil dosage is recommended.1
Clinically important pharmacokinetic interactions have been reported with several antiretroviral agents that inhibit CYP3A4 (e.g., ritonavir, saquinavir) and can potentially result in an increase in sildenafil-associated adverse effects.1, 200, 240
The possibility that any drug that induces CYP3A4 may interact with sildenafil should be considered.1, 67, 212
Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics when the drug was used concomitantly with CYP2D6 inhibitors such as selective serotonin-reuptake inhibitors (SSRIs) or tricyclic antidepressants.1
In vitro studies indicate that sildenafil is a weak inhibitor of the CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4.1 26, 67 At clinically relevant concentrations, the manufacturer states that it is unlikely that sildenafil will alter the clearance of drugs metabolized by these isoenzymes.1
A minor route of metabolism of sildenafil is through the CYP2C9 isoenzyme.1, 67, 250 Although some clinicians state that the possibility of an interaction between sildenafil and drugs metabolized by CYP2C9 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.1, 67
Drugs Affecting Gastric Acidity
Antacids:Single doses of an aluminum and magnesium hydroxide-containing antacid did not affect the oral bioavailability of sildenafil.67
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.1, 67 Population pharmacokinetic analysis of data from clinical trials indicates that cimetidine reduces sildenafil clearance when these drugs are administered concomitantly.1, 139 Some clinicians recommend that a lower initial sildenafil dose (25 mg) be considered in patients with ED receiving cimetidine.67
Organic Nitrates, Nitrites, and Nitric Oxide Donors
Concomitant use of any form of organic nitrate (e.g., nitroglycerin), including recreational use of inhaled nitrites (amyl nitrate or nitrite, “poppers”), with sildenafil is contraindicated due to the potential pharmacodynamic interaction (increased hypotensive effect).1
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.67 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.1, 29, 31, 67 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.1, 29, 31, 67, 154
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.67, 159 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 CYP3A4, 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.1, 67, 154 In either case, a short-acting nitrate formulation that can be titrated readily (e.g., IV nitroglycerin) is preferred and such use should be accompanied by close hemodynamic monitoring.67, 159
Sildenafil 50 mg did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy individuals (mean maximum blood alcohol concentrations of 0.08% achieved).1
Antihypertensive and Beta-Adrenergic Blocking Agents
Sildenafil has systemic vasodilatory effects and may augment the blood pressure-lowering effect of other antihypertensive agents.1 Hypotensive responses secondary to sildenafil use in patients receiving antihypertensive therapy have been observed.1, 67
Pharmacokinetic and pharmacodynamic 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.1, 29, 67
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 (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis), those with severely impaired autonomic control of blood pressure, and in those who are receiving a complex, multidrug antihypertensive regimen. 1, 67
The 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; however, the increased active metabolite concentrations are not expected to be clinically important.1
Additive hypotensive effects may be anticipated when PDE type 5 inhibitors are administered concurrently with α-adrenergic blocking agents (e.g., terazosin, doxazosin, tamsulosin).1 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.1 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.1 Although symptomatic hypotension occurred in a few patients who received sildenafil 50 or 100 mg, syncope was not reported during these drug interaction studies.1 Caution is advised when PDE type 5 inhibitors are used concomitantly with an α-adrenergic blocking agent.1 Patients should be hemodynamically stable on α-adrenergic blocking therapy prior to initiating therapy with a PDE type 5 inhibitor.1 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.1 In patients who are hemodynamically stable on α-adrenergic blocking therapy, PDE type 5 inhibitors should be initiated at the lowest recommended dose.1 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.1 Incremental increases in the dosage of the α-adrenergic blocking agent during such concomitant therapy may be associated with a further lowering of blood pressure.1 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.1
Following administration of a single 100-mg sildenafil dose 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).1, 29, 154 The greatest decreases in supine systolic and diastolic blood pressures following sildenafil administration were in patients with the highest baseline blood pressures, suggesting that the likelihood of a hypotensive episode during combined use with amlodipine is low.29
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.1, 240 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 AUC by 210 or 1000%, respectively, and sildenafil peak plasma concentrations by 140 or 300%, respectively.1, 85, 136, 137, 139 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.1, 139 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.1, 26, 67, 139
A decrease in sildenafil clearance and a substantial increase in sildenafil concentrations also is expected with protease inhibitors alone or in combination with ritonavir (e.g., amprenavir , atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, tipranavir, darunavir).26, 67, 139, 200
In patients receiving protease inhibitors alone or in combination with ritonavir or the HIV integrase strand transfer inhibitor (INSTI) elvitegravir in combination with cobicistat (CYP3A4 inhibitor), experts recommended that sildenafil dosage not exceed 25 mg every 48 hours for the treatment of ED.1, 200, 240
The nonnucleoside reverse transcriptase inhibitors efavirenz, nevirapine, and etravirine may decrease sildenafil exposure via CY3A4 (and 2C19 for etravirine) induction, and experts state that sildenafil dose titration based upon clinical effect may be required.200
Ketoconazole or itraconazole, which are potent CYP3A4 inhibitors, inhibit sildenafil metabolism in vitro and concomitant use is expected to substantially increase systemic exposure to sildenafil.1, 250 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 systemic exposure 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.1, 67
Bosentan, a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19, can increase sildenafil clearance and decrease plasma sildenafil concentrations.1, 212, 241 In one study in healthy men, concomitant use of bosentan (125 mg twice daily) and sildenafil at a dose not approved for the treatment of erectile dysfunction (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.1, 241 The clinical importance of this pharmacokinetic interaction is unclear.241
Concomitant administration of sildenafil and heparin in rabbits had an additive effect on bleeding time.1 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.1, 67
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%.1, 69, 239 It is recommended that a lower initial sildenafil dose (25 mg) be considered in patients with ED receiving potent CYP3A4 inhibitors such as erythromycin.1, 67, 239
No pharmacokinetic interaction has been observed to date between azithromycin (500 mg daily for 3 days) and sildenafil.1, 138, 239 Therefore, no dosage adjustments are required in patients receiving these drugs concomitantly.239
Platelet-aggregation Inhibitors
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.1, 65, 67
In an in vitro human platelet study, sildenafil potentiated the antiaggregatory effect of sodium nitroprusside.1, 57, 67, 89
The possibility that concomitant administration of rifampin, a potent CYP3A4 inducer, could decrease plasma concentrations of sildenafil should be considered.1, 69
Additive hypotensive effects can occur if riociguat is used concomitantly with PDE type 5 inhibitors.1, 247 In a study in patients with pulmonary arterial hypertension (PAH) who were receiving stable dosages of sildenafil (20 mg 3 times daily), administration of single doses of riociguat resulted in additive hemodynamic effects.247 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.247
Because of the risk of hypotension, concomitant use of sildenafil and riociguat is contraindicated.1, 247
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.
Concomitant administration of sildenafil and an oral vitamin K antagonist (acenocoumarol or phenprocoumon) did not substantially alter the international normalized ratio (INR).67 No pharmacokinetic interaction has been observed between warfarin, a CYP2C9 substrate, and sildenafil.1, 67
Sildenafil is a selective inhibitor of phosphodiesterases (PDEs), with the greatest selectivity for PDE type 5, the principal isoenzyme of PDE involved in the metabolism of cyclic guanosine monophosphate (cGMP) to GMP in the corpora cavernosa of the penis.1, 2, 4, 5, 7, 8, 10, 24, 27, 33, 41, 42, 54, 56, 57, 67, 87, 88, 91, 131 Sildenafil has no direct relaxant effect on isolated human corpora cavernosa of the penis, but enhances the effect of nitric oxide by inhibiting PDE type 5-mediated hydrolysis of cGMP.1, 2, 4, 5, 7, 8, 10, 33, 41, 42, 127, 131 During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpora cavernosa. 1, 2, 4, 56, 67, 91, 131 By selectively inhibiting PDE type 5, sildenafil causes accumulation of cGMP in various tissues.1, 2, 4, 5, 31, 33, 34, 41, 42, 56, 57, 67, 91, 131 Because sildenafil potentiates the accumulation of cGMP rather than stimulating its production, the drug is effective only when cGMP production in the penis is increased by sexual arousal.34, 91, 131 Sildenafil at recommended doses has no effect on erectile function in the absence of sexual stimulation.1, 4, 33, 34, 91, 127, 130, 131, 132
Sildenafil also exhibits some activity against other PDE isoenzymes.1, 4, 5, 31, 44, 57, 67, 87, 88 In vitro, sildenafil is about 10 times more active against PDE type 5 than against PDE type 6, greater than 70-80 times more active against PDE type 5 than against PDE type 1, greater than 1000 times more active against PDE type 5 than against PDE types 2 and 4, and 4000 times more active against PDE type 5 than against PDE type 3.1, 4, 5, 27, 31, 44, 57, 67, 88, 127, 131 PDE type 3 is involved in cardiac contractility, vascular smooth muscle relaxation (vasodilation), and platelet aggregation, and PDE type 6 (photoreceptor PDE) is found in the retina and involved in phototransduction.1, 4, 27, 31, 45, 52, 55, 57, 67, 87, 88
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.1 In the largest clinical study published to date, the onset and duration of action of oral sildenafil were not reported.33, 34 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.1
Sildenafil is rapidly absorbed following oral administration; the mean absolute bioavailability is 41% (range, 25-63%).1, 4, 56, 67, 91, 116, 249 Although 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.1, 4, 56, 67, 91, 116, 131, 249 Pharmacokinetics of the drug (as determined by peak plasma concentrations or AUC) are dose proportional over the single-dose range of 1.25-200 mg.1, 4, 56, 91, 116, 131 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.1, 4, 91, 127, 130, 249 Administration with a high-fat meal delays GI absorption, with a reduction in peak plasma concentrations of about 29% and a delay in time to peak plasma concentrations of about 60 minutes; the extent of absorption is not affected.1, 131
Sildenafil appears to be widely distributed in the body.1, 4, 67, 116, 131 Sildenafil and its major circulating N-desmethyl metabolite are each approximately 96% bound to plasma proteins; protein binding reportedly is independent of plasma concentration.1, 67, 91, 116, 131 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.1, 67 Such concentrations are unlikely to cause any effects in sexual partners exposed to the semen.67 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).1, 4, 67, 91, 116, 127, 130, 131 Sildenafil is metabolized principally via hepatic cytochrome P-450 (CYP) microsomal isoenzymes 3A4 (major route) and 2C9 (minor route).1, 26, 67, 91, 131 Plasma concentrations of the active N-desmethyl metabolite are approximately 40% of those observed with sildenafil, and the metabolite reportedly accounts for about 20% of sildenafil's pharmacologic activity.1, 67, 131 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.1, 116, 131 Sildenafil is eliminated mainly in the feces as metabolites following oral administration.1, 67, 91, 116, 131 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.1, 67, 116, 131
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 25 mg (of sildenafil)* | Sildenafil Tablets | |
Viagra® | Pfizer | |||
50 mg (of sildenafil)* | Sildenafil Tablets | |||
Viagra® | Pfizer | |||
100 mg (of sildenafil)* | Sildenafil Tablets | |||
Viagra® | Pfizer |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions April 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
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