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P T. 2013;38(7): 407, 414-419
Drug Class Review

Phosphodiesterase-5 (PDE5) Inhibitors In the Management of Erectile Dysfunction

Sharon A. Huang
Janette D. Lie PharmD, BCACP

INTRODUCTION

Erectile dysfunction (ED) is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance.1 According to data from the Massachusetts Male Aging Study, up to 52% of men between the ages of 40 and 70 are affected by ED.2 Based on findings from the 2001–2002 National Health and Nutrition Examination Survey (NHANES), it is estimated that 18.4% of men in the U.S. who are 20 years of age and older have ED.

Although ED is not an inevitable consequence of aging, there is a positive correlation with age. The prevalence of 5.1% in 20- to 39-year-old men increases to 70.2% in men 70 years of age and older. Because the etiology of ED often involves a combination of vascular, neurological, endocrinological, and psychological factors, the condition is not limited to elderly men. Other risk factors such as cardiovascular disease, hypertension, diabetes, hypercholesterolemia, and smoking have been strongly associated with an increased prevalence of ED.3

Historically, a limited understanding of the physiological mechanism of erections restricted the treatment of ED to vacuum-constriction devices, prosthetic implants, intracavernosal injections, and intraurethral suppositories.4 Since its advent, the class of agents known as type-5 phosphodiesterase (PDE5) inhibitors has revolutionized the management of ED. PDE5 inhibitors have become the first-line therapy for ED, as recommended by the American Urological Association (AUA) and the European Association of Urology (EAU).4,5

The four oral PDE5 inhibitors commercially available in the U.S. are sildenafil (Viagra, Pfizer), vardenafil (Levitra and Staxyn, Bayer/GlaxoSmithKline), tadalafil (Cialis, Eli Lilly), and a more recently approved drug, avanafil (Stendra, Vivus). The expansion of this class has allowed for greater flexibility in prescribing based on individual response.

CLASSIFICATION AND HISTORY

Sildenafil, vardenafil, tadalafil, and avanafil are classified as PDE5 inhibitors and are indicated for the treatment of men with ED. Sildenafil, the first PDE5 inhibitor, was introduced in 1998. More than 20 million men were treated with sildenafil in its first 6 years on the market.5 In 2003, vardenafil was approved, offering patients an alternative option. Tadalafil followed several months later and was also approved in 2003. Nicknamed the “weekend pill,” tadalafil’s 36-hour effectiveness offered patients more spontaneity.

In 2010, a 10-mg oral disintegrating tablet (ODT) formulation of vardenafil (Staxyn) was introduced; this ODT discreet formulation is considered more convenient to administer.

Several years after the introduction of tadalfil on the market, researchers toyed with the idea of a chronic, low-dose formulation to further enhance spontaneity. In 2008, Eli Lilly obtained FDA approval for the once-daily administration of tadalafil. In October 2011, tadalafil (Cialis) was also approved to treat benign prostatic hyperplasia (BPH) with or without ED. Avanafil (Stendra) was approved in April 2012, offering an onset of action as early as 15 minutes after administration and further expanding treatment options for men with ED.

Sildenafil and tadalafil are also used to treat pulmonary arterial hypertension (PAH) under the trade names Revatio (sildenafil 20-mg tablets and 10-mg/12.5-mL single-use vial injections) and Adcirca (tadalafil 20-mg tablets).

Although alternative roles exist for these agents, PDE5 inhibitors for the treatment of ED are the focus of this review.

PHARMACOLOGY

During sexual arousal, nitric oxide (NO) is released from nerve terminals and endothelial cells in the corpus cavernosum. NO activates guanylate cyclase to convert guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), triggering a cGMP-dependent cascade of events. The accumulation of cGMP leads to smooth-muscle relaxation in the corpus cavernosum and increased blood flow to the penis.

PDE5 is an enzyme found primarily in the smooth muscle of the corpus cavernosum that selectively cleaves and degrades cGMP to 5′-GMP. PDE5 inhibitors are similar in structure to cGMP; they competitively bind to PDE5 and inhibit cGMP hydrolysis, thus enhancing the effects of NO. This increase in cGMP in the smooth muscle cells is responsible for prolonging an erection.

PDE5 inhibitors lack a direct effect on corpus cavernosum smooth-muscle relaxation. Therefore, after administration, adequate sexual stimulation is necessary for an erection to occur.6,7

Pharmacokinetics

PDE5 inhibitors have been studied to determine their pharmacokinetic characteristics in absorption, distribution, metabolism, and excretion. A summary of the pharmacokinetic activity of these agents is presented in Table 1.

Absorption

As a class, although PDE5 inhibitors can reach maximum observed plasma concentrations (Cmax) in as little as 30 minutes, the median times to maximum concentration (Tmax) are 60 minutes for sildenafil and vardenafil and 2 hours for tadalafil. For avanafil, a median Tmax of 30 to 45 minutes is reported, possibly translating to a quicker onset of action; however, the actual clinical significance has not been determined.

The exact values for vardenafil ODT (Staxyn) have not been reported, but this drug provides a higher systemic exposure compared with the film-coated formulation (Levitra). For this reason, these two formulations are not equivalent milligram for milligram and therefore are not interchangeable. In addition, despite the perception that an ODT formulation would take effect more quickly, both the film-coated tablets and the ODT formulation have similar onsets of action.

A comparison of agents in the PDE5 drug class is presented in Table 2.812

Except for tadalafil, the rate and extent of absorption of PDE5 inhibitors are diminished when they are ingested with high-fat meals. Despite the similar rate and extent of change observed with vardenafil and avanafil, only sildenafil has been found to have clinical significance, according to its manufacturer. Absorption is affected significantly with a mean reduction in Cmax of 29% and a mean delay in Tmax of 60 minutes. Patients are advised to avoid taking sildenafil after a high-fat meal to avoid a possible diminished potency and delay in the onset of effect.8

Unique to vardenafil ODT is the effect of water on the drug’s absorption. When vardenafil was taken with water, the Tmax was shortened by 60 minutes and the area-under-the curve (AUC) concentration was decreased by 29%. To maintain appropriate onset and maximum potency, patients should not take vardenafil ODT with liquids.12

Distribution

High volumes of distribution (Vd) for sildenafil (105 L), vardenafil (208 L), and tadalafil (63 L) suggest extensive tissue binding; data are unavailable for avanafil. All PDE5 inhibitors are highly protein-bound (94%–99%), contributing to the observed high volume of distribution.812 Therefore, disease states that alter protein levels, such as malnutrition and liver disease (e.g., cirrhosis), can be expected to cause variations in the distribution of PDE5 inhibitors.

Metabolism

Each PDE5 inhibitor undergoes metabolism predominantly through the hepatic isoenzyme cytochrome P450 (CYP) 3A4 pathway. Minor pathways include CYP2C9 for sildenafil, CYP3A5 and CYP2C for vardenafil, and CYP2C for avanafil. Because the metabolism of these agents relies primarily on CYP3A4, moderate-to-strong inhibitors, such as erythromycin (Ery-Tab, E-Mycin, Abbott; Eryc, Warner Chilcott), ketoconazole (Nizoral, PriCara/Janssen), itraconazole (Sporanox, Janssen), and ritonavir (Norvir, Abbott) and inducers, such as rifampin, phenytoin (Dilantin, Pfizer) of this isoenzyme can be expected to affect the blood concentrations of PDE5 inhibitors.

Of the four agents available in the U.S., only tadalafil has metabolites that are not pharmacologically active. Sildenafil produces an active metabolite that retains approximately 50% of the potency of the parent drug, contributing to approximately 20% of its total pharmacological activity.8 Vardenafil and avanafil produce active metabolites that contribute to the total pharmacological activity of each of these agents (7% and 4%, respectively).9,11

The precise clinical impact of these active metabolites, particularly in patients with impaired ability to metabolize or eliminate these agents, has not been determined.

Elimination

PDE5 inhibitors are eliminated predominantly as metabolites in the feces and, to a lesser extent, in the urine. Sildenafil, vardenafil, and avanafil share similar mean terminal half-lives of 4 to 5 hours. In contrast, tadalafil has an extended half-life of approximately 17.5 hours, allowing its use as a once-daily agent.812

Renal Impairment

In patients with mild-to-moderate renal impairment or with a creatinine clearance (CrCl) above 30 to 80 mL/minute, the pharmacokinetic properties of sildenafil remain unaltered. However, in patients with severe renal impairment (CrCl, 30 mL/minutes or less), the AUC concentration and the Cmax are doubled. As a precaution, it is recommended that sildenafil be initiated at 25 mg per dose in men with severe renal impairment.8

When vardenafil was studied in patients with moderate and severe renal impairment (CrCl, 50 mL/minute or less), the AUC concentration was increased by 20% to 30% compared with patients with a CrCl exceeding 80 mL/minute, resulting in no need for dosage adjustments. Because pharmacokinetic parameters for vardenafil have not been assessed in patients undergoing dialysis, this drug is not recommended in this population. These renal dosing recommendations also apply to vardenafil ODT.9,12

When avanafil was administered to patients with mild-to-moderate renal impairment (a CrCl of 30–90 mL/minute or more), the AUC concentration and the Cmax increased slightly, resulting in no need for dosage adjustments. However, because avanafil has not been studied in patients with severe renal impairment or in patients on dialysis, it is not recommended for these patient populations.11

When tadalafil was given to patients with mild-to-moderate renal impairment (a CrCl of 30–80 mL/minute or more), the AUC concentration doubled, resulting in changes to the dosing recommendations. Therefore, in patients with moderate renal insufficiency (CrCl, 30–50 mL/minute) who used tadalafil as needed, a starting dose of 5 mg no more than once daily is recommended, with a maximum of no more than 10 mg in 48 hours.

Patients who have severe renal impairment (CrCl, below 30 mL/minute) or men who are receiving dialysis should not take more than 5 mg of tadalafil within 72 hours. The once-daily use of tadalafil is not recommended for men with severe renal insufficiency.10

Hepatic Impairment

Patients with mild-to-moderate hepatic impairment (Child– Pugh class A and B) who received sildenafil experienced increased AUC concentrations (85%) and Cmax (47%). A starting dose of sildenafil 25 mg is recommended for these patients.8

In men with moderate hepatic impairment who received vardenafil, the AUC concentration and the Cmax were increased by 160% and 130%, respectively. Therefore, the recommended starting dose of vardenafil in patients with moderate hepatic impairment is 5 mg with a maximum dose of 10 mg per dose.9 Vardenafil ODT is not recommended for use in men with moderate hepatic impairment.12

When tadalafil is used as needed in patients with mild-to-moderate hepatic impairment, doses exceeding 10 mg are not recommended. Once-daily tadalafil has not been well studied in patients with mild-to-moderate hepatic impairment and should be used with caution.10

In patients with moderate hepatic impairment, avanafil’s AUC concentration was increased by 11% and the Cmax was decreased by 51%. No dosage adjustments are recommended for avanafil in patients with mild-to-moderate hepatic impairment.11

As a result of insufficient data, none of the four agents are recommended for men with severe hepatic impairment (Child–Pugh class C).

Pharmacodynamics

Mammalian phosphodiesterases (PDEs) comprise 11 gene families, which are distributed in different areas of the body. Each PDE family contributes to various physiological functions.13 Because the smooth muscle of the corpus cavernosum expresses type-5 PDEs predominantly, the specificity and selectivity of PDE5 inhibition play a crucial role in prolonging erections and in limiting adverse effects from nonspecific PDE inhibition.

All of the currently available PDE5 inhibitors are highly selective for the type-5 gene family. Sildenafil and vardenafil, however, are less selective against PDE6, which is expressed in the retina.13,14 Patients have reported vision-related adverse effects consistent with PDE6 inhibition, such as dose-related impairment in color discrimination (blue/green) or cyanopsia (objects appearing blue).810 By contrast, although tadalafil is selective against PDE6, it also expresses selectivity against PDE11, which is concentrated in the prostate, testes, and skeletal muscles.13,14 Inhibition of the type-11 PDE isoenzyme has been associated with pain and myalgia.15

DRUG–DRUG INTERACTIONS

CYP3A4 Isoenzymes

Because of their extensive CYP3A4 metabolism, PDE5 inhibitors carry a risk of interacting with potent CYP3A4 inhibitors and inducers. The concomitant use of potent CYP3A4 inhibitors increases plasma concentrations of sildenafil. When sildenafil 100 mg was administered with erythromycin (e.g., Ery-Tab, E-Mycin, Eryc) and saquinavir (Invirase, Hoffman-LaRoche) (both are considered relatively potent CYP3A4 inhibitors), the AUC concentration was increased by 182% and 210%, respectively. More notably, when sildenafil 100 mg was administered with ritonavir (Norvir), a highly potent CYP3A4 inhibitor, the AUC concentration was increased by 11-fold (1,000%). Therefore, a starting dose of 25 mg is recommended in patients initiating sildenafil therapy with the concomitant use of moderate-to-strong CYP3A4 inhibitors such as ketoconazole (Nizoral), itraconazole (Sporanox), erythromycin, and saquinavir. Doses of sildenafil should not exceed 25 mg in 48 hours when it is taken with ritonavir.8

The use of potent CYP3A4 inhibitors with vardenafil has also been studied. A dramatic 49-fold increase in the AUC concentration resulted when vardenafil 5 mg was taken with ritonavir 600 mg twice daily. Coadministration with erythromycin, ketoconazole, and indinavir (Crixivan, Merck) may also lead to an increase in the AUC concentration of vardenafil by four-fold to 16-fold. Consequently, a maximum dose of vardenafil 5 mg per 24 hours is recommended when it is used concomitantly with moderate CYP3A4 inhibitors (e.g., erythromycin, ketoconazole 200 mg, and itraconazole 200 mg).

With potent CYP3A4 inhibitors such as indinavir, saquinavir, atazanavir (Reyataz, Bristol-Myers Squibb), ketoconazole 400 mg, itraconazole 400 mg, and clarithromycin (Biaxin, Abbott), doses of vardenafil 2.5 mg per 24 hours should not be exceeded, except for ritonavir, the dose of which should not exceed 2.5 mg every 72 hours.9

The concomitant use of moderate or potent CYP3A4 inhibitors with vardenafil ODT is not recommended.12

When given with ketoconazole 400 mg daily, a single dose of tadalafil 20 mg increased the AUC concentration of tadalafil by 312%. When ritonavir 500 to 600 mg twice daily or 200 mg twice daily was taken with a single dose of tadalafil 20 mg, tadalafil’s AUC concentration increased by 32% and 124%, respectively. Nonetheless, when tadalafil is prescribed as needed, a maximum dose of 10 mg in a 72-hour period should not be exceeded when used concomitantly with any potent CYP3A4 inhibitor. Similarly, for daily use of tadalafil, a maximum dose of 2.5 mg/day is recommended in patients taking potent CYP3A4 inhibitors.10

The use of both ketoconazole 400 mg daily and ritonavir 600 mg twice daily has been shown to increase avanafil’s AUC concentration by 13-fold. As recommended by the manufacturer, the avanafil dose should not exceed 50 mg/day in patients who are also taking moderate CYP3A4 inhibitors. Avanafil should not be used in patients taking potent CYP3A4 inhibitors.11

Not all interactions with moderate and potent CYP3A4 inhibitors have been studied with each PDE5 inhibitor; however, dosage adjustments and avoiding concomitant use altogether in some cases should be considered.

Alpha Blockers

Coadministration of PDE5 inhibitors with alpha-adrenergic blocking agents can result in additive vasodilatory effects, causing potentially significant reductions in blood pressure (BP).16 PDE5 inhibitor therapy for ED should be initiated only if the patient’s BP is already stable with alpha blockers and at the lowest recommended dose.

Vardenafil ODT (Staxyn) is not recommended for patients who are taking alpha blockers, particularly new users of this combination. Alternatively, low-dose, film-coated vardenafil tablets (Levitra) can be used. Patients taking PDE5 inhibitors and alpha blockers concomitantly should be monitored closely.812

Nitrates

Nitrates such as nitroglycerin increase the production of cGMP. PDE5 inhibitors decrease cGMP degradation. The concomitant use of these agents can cause a significant increase in cGMP accumulation, resulting in a synergistic reduction in BP. Therefore, the use of PDE5 inhibitors with any form of organic nitrates is contraindicated. In emergency situations, if patients have taken a PDE5 inhibitor and experience chest pain requiring treatment, a non-nitrate containing agent (e.g., a calcium-channel blocker or a beta blocker) can be used as an alternative when appropriate.17

A minimum of 24 hours should elapse after the last dose of sildenafil or vardenafil is taken before a nitrate can be used.8,9 A period of at least 12 hours for avanafil and 48 hours for tadalafil should elapse before the patient takes a nitrate.10,11,18 In such an event, nitrates should be administered only under close monitoring.

CLINICAL EFFICACY

Results from clinical trials of PDE5 inhibitors have shown consistent improvement in erectile functioning compared with placebo. Studies commonly use questionnaires based on diaries and event logs to evaluate efficacy and functional improvements.

One of the most extensively used measurements is the mean score derived from the International Index of Erectile Function– Erectile Function domain (IIEF–EF). Scores range from 0 to 30 based on 15 questions. Separate evaluation of responses to Question 3 (successful penile penetration) and Question 4 (maintenance of erection after penetration) are often used to further determine the efficacy of PDE5 inhibitors.

The Sexual Encounter Profile (SEP) is a diary that has also been used to document a patient’s sexual experiences. In particular, responses to Question 2 (SEP2, erection sufficient for penetration) and Question 3 (SEP3, erection sufficient for successful intercourse) are used to measure efficacy outcomes.

The Global Assessment Question (GAQ) asks the patient whether the treatment has improved erectile function and is reported as the percentage of patients responding “yes.”

In a published systematic review and meta-analysis of randomized controlled trials by Tsertsvadze et al., the efficacy of oral PDE5 inhibitors was found to be consistent in the treatment of ED.19 In 16 trials that evaluated sildenafil in men with various comorbidities, the mean per-patient percentage of successful sexual intercourse was 69% with treatment (range, 52%–85%) compared with 35.5% for placebo (range, 19%–68%). Data pooled from four trials reported a 34.4% improvement from baseline in successful intercourse attempts.

In 13 trials evaluating vardenafil in men with various comorbidities using SEP3, the mean per-patient percentage of successful sexual intercourse attempts was 68% for vardenafil (range, 50%–88%) versus 35% for placebo (range, 20%–49%). Data pooled from two trials reported a 33.2% improvement from baseline in successful intercourse attempts.

Fifteen trials that assessed the use of tadalafil in men with various comorbidities were conducted to determine the mean per-patient percentage of successful intercourse attempts. Based on data collected from SEP3, tadalafil was reported as having a success rate of 69% (range, 50%–85%) versus 33% for placebo (range, 23%–52%). Data pooled from five trials revealed a 35.1% improvement from baseline in successful intercourse attempts.19

Data supporting the safety and efficacy of once-daily tadalafil led to the eventual approval of this dosing option. One of the most cited reasons for poor response to the treatment of ED is the lack of spontaneity with on-demand dosing.20 By taking advantage of the prolonged half-life of tadalafil, this new approach to treatment has created more “natural” sexual experiences for patients and has even been referred to as a “cure” for ED.21

Chronic low-dose PDE5 inhibitor therapy has also benefited difficult-to-treat populations such as diabetic, post-prostatectomy, and post-radiotherapy patients and may be an alternative for men who have not responded to other PDE5 inhibitors or to traditional on-demand dosing.22

In a 1- to 2-year open-label extension study by Porst et al., once-daily tadalafil 5 mg was found to be a safe and efficacious option for men with ED. No serious adverse events attributed to the drug were observed. Upon the completion of the study period, 95.7% and 92.1% of patients, respectively, reported positive responses in GAQ1 (improved erections) and GAQ2 (improved ability to engage in sexual activity) scores. Mean IIEF–EF domain scores also increased by 10.8 points from baseline.23

In a multicenter, randomized, double-blind phase 3 trial, 646 men with mild-to-moderate ED received avanafil (50 mg, 100 mg, 200 mg) or placebo. SEP2, SEP3, and IIEF–EF domain scores were evaluated to determine efficacy. After 12 weeks of treatment, patients receiving avanafil showed statistically significant improvements over placebo in all primary endpoints studied. The mean percentage change from baseline for successful vaginal penetration (SEP2) was 54% for placebo vs. 64% to 77% for 50 to 200 mg of avanafil. The mean percentage change from baseline for successful sexual intercourse (SEP3) was 27% for placebo vs. 41% to 57% for 50 mg to 200 mg of avanafil. At the end of treatment, the mean IIEF–EF domain score was 15.3 for placebo versus 18.1 to 22.2 for 50 mg to 200 mg for avanafil. Although all three studied strengths of avanafil were found to be more effective than placebo, doses of 100 mg and 200 mg showed greater benefit over 50 mg. No significant difference was noted between the higher doses.24

Although PDE5 inhibitors have clearly shown efficacy in placebo-controlled trials for the treatment of ED, only a limited number of head-to-head trials have compared the various agents. The evidence is inconclusive regarding the superiority of one agent over another; however, most men in the comparative studies cited tadalafil as the preferred agent because of its extended duration of action.25

SAFETY AND ADVERSE EFFECTS

PDE5 inhibitors are generally well tolerated for the treatment of ED. The most common adverse drug reactions reported include headache, flushing, nasal congestion, nasopharyngitis, and dyspepsia. Rare but serious reports of prolonged erections lasting more than 4 hours and priapism (painful erections lasting more than 6 hours) have been reported with PDE5 inhibitors. Patients should be advised to seek immediate medical attention if they experience these events. Cases of priapism that are not immediately treated can lead to permanent penile tissue damage.812

Visual abnormalities have been reported with PDE5 inhibitors. In July 2005, an FDA alert recommended that men discontinue all such agents and seek immediate medical attention if they experienced a sudden loss of vision.26 Cases of non-arteritic anterior ischemic optic neuropathy (NAION) were reported during postmarketing experience with PDE5 inhibitors.2730 In this condition, blood flow to the optic nerve is blocked. Although evidence of a cause-and-effect relationship is insufficient, caution should be used in prescribing PDE5 inhibitors, particularly for men with pre-existing risk factors for the development of NAION, such as hypertension, diabetes, and hyperlipidemia.

Sudden hearing loss was also reported in postmarketing studies. In October 2007, the FDA requested that this potential risk be displayed more prominently on the labels for PDE5 inhibitors. At the time of the announcement, 29 cases of hearing loss had been reported in postmarketing analyses. Additional cases were identified in a retrospective analysis of the clinical trials. Although the direct association of hearing loss with PDE5 inhibitor use has not been established, patients were advised to discontinue the use of all PDE5 inhibitors and to seek medical attention if they experienced a sudden decrease in or a loss of hearing.31

Back pain and myalgia have been reported with tadalafil. In general, the pain was reported as mild to moderate in severity, occurring 12 to 24 hours after administration and typically resolving within 48 hours without medical treatment. When treatment was necessary, acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) were generally effective in alleviating the reported pain.10

INDICATIONS

Sildenafil, vardenafil, tadalafil, and avanafil are approved for as-needed use in the treatment of ED. In 2008, tadalafil was granted FDA approval for once-daily use in the treatment of ED and in 2011, it was given an indication for BPH with or without ED. Sildenafil and tadalafil are also approved for PAH under the trade names of Revatio and Adcirca, respectively.812

CONTRAINDICATIONS AND PRECAUTIONS

PDE5 inhibitors are contraindicated in patients who are taking any form of organic nitrates, regularly or intermittently. Because these agents modify the cGMP and NO pathways, PDE5 inhibitors, if used with nitrates, may synergistically contribute to hypotensive effects.

Rare but serious hypersensitivity reactions, such as Stevens–Johnson syndrome and exfoliative dermatitis, have been reported with sildenafil and tadalafil. Cases of pruritus and eyelid swelling have been reported with avanafil. All PDE5 inhibitors are contraindicated in patients with a known hypersensitivity to any component of the agents.812

The vardenafil ODT formulation contains phenylalanine and should be used with caution in patients with phenylketonuria. Patients with a rare hereditary intolerance to fructose should also exercise caution with the ODT formulation because of its sorbitol content.12

COST AND ECONOMIC BURDEN

Erectile dysfunction (ED) is a common male sexual disorder, affecting nearly one in five men older than age 20, and the prevalence increases with advancing age. Extrapolating from the National Health and Nutrition Examination Survey (NHANES), the cost of treatment for ED in the U.S. was estimated to be as high as $15 billion if all men with ED were to seek treatment.32 The true burden of ED is unclear because of the various economical and psychological components involved.

With the expansion of this class of agents, men with ED have effective and reliable options. PDE5 inhibitors have gained tremendous popularity, as shown in 2011 worldwide revenues of sildenafil ($1.98 billion), vardenafil ($332 million), and tadalafil ($1.88 billion).3335 Although PDE5 inhibitors are effective, their more widespread use is limited by their high cost (see Table 2).36

CONCLUSION

The currently available PDE5 inhibitors, including the more recently approved avanafil, provide men with ED with a safe, convenient, and effective method for improving erectile function. These agents have become the first-line therapy for ED and are preferred by health care practitioners and patients because of their ease of use, quick onset of action, and tolerability. Given the lack of adequate head-to-head trials, it is difficult to determine the superiority of one agent over another. Further studies comparing these agents are needed to distinguish the possible benefits of each, particularly in specific subsets of patients.

All PDE5 inhibitors allow for flexibility in prescribing and patient preference based on individual response and need. Specific characteristics of each agent (cost, ease of use, and adverse effects) should be used to guide appropriate treatment.

Tables

Phosphodiesterase-5 (PDE5) Inhibitors: Pharmacokinetic Summary

Sildenafil (Viagra) Vardenafil (Levitra) Vardenafil ODT (Staxyn) Tadalafil (Cialis) Avanafil (Stendra)
Bioavailability 41% (mean)
25%–63% (range)
15% (mean)
Tmax 1 hour (median)
0.5–2 hours (range)
1 hour (median)
0.5–2 hours (range)
1.5 hours (median)
0.75–2.5 hours (range)
2 hours (median)
0.5–6 hours (range)
0.5–0.75 hours (range)
Vd 105 L 208 L 208 L 63 L
Protein binding 96% 95% 95% 94% 99%
Metabolism Major: CYP3A4 Minor: CYP2C9 Major: CYP3A4 Minor: CYP3A5, CYP2C Major: CYP3A4
Minor: CYP3A5, CYP2C
CYP3A4 Major: CYP3A4 Minor: CYP2C
Active metabolite (% effect) Yes (20%)
N-desmethylation
Yes (7%)
Desmethylation
Yes (7%)
Desmethylation
No Yes (4%)
Methylation, glucuronidation
Half-life 4 hours 4–5 hours 4–6 hours 17.5 hours 5 hours
Elimination 80% feces
13% urine
91%–95% feces
2%–6% urine
91%–95% feces
2%–6% urine
61% feces
36% urine
62% feces
21% urine
Ingestion with high-fat meals ↓ Cmax 29%
↑ Tmax by 1 hour
Avoid
↓ Cmax 18%–50%
May use (per manufacturer)
↓ Cmax 35%
May use (per manufacturer)
Not affected ↓ Cmax 24-39%
↑ Tmax by 1.12–1.25 hours
May use (per manufacturer)
Additional PDE inhibition PDE1, PDE6 PDE1, PDE6 PDE1, PDE6 PDE11

Cmax = peak concentration; CYP = cytochrome P450; ODT = oral dissolving tablet; Tmax = time to peak concentration.

Data from prescribing information for sildenafil;8 vardenafil;9 tadalafil;10 avanafil;11 and vardenafil ODT.12

Phosphodiesterase-5 (PDE5) Inhibitors: Product Comparison

Sildenafil (Viagra) Vardenafil (Levitra) Vardenafil ODT (Staxyn) Tadalafil (Cialis) Avanafil (Stendra)
Manufacturer Pfizer Bayer/GlaxoSmithKline Bayer/GlaxoSmithKline Eli Lilly Vivus
Year of approval 1998 2003 2010 2003 2012
Usual dosage 25–100 mg/day 5–20 mg/day 10 mg/day 5–20 mg/day (as needed);
2.5–5 mg/day once daily
50–200 mg/day
Administration time 1 hour before sexual activity 1 hour before sexual activity 1 hour before sexual activity At least 0.5 hours before sexual activity 0.5 hours before sexual activity
Time frame of efficacy 0.5–4 hours post dose Up to 36 hours post dose As early as 0.25 hours post dose
Dosage adjustments Renal
CrCl < 30 mL/minute: starting dose 25 mg
Hepatic
Hepatic impairment: starting dose 25 mg
Drug Interactions
  • Potent CYP3A4 inhibitors: starting dose 25 mg
  • Ritonavir: maximum 25 mg/48 hours

Other
>65 years old: starting dose 25 mg
Renal
Do not use in patients receiving hemodialysis
Hepatic
  • Moderate impairment: starting dose 5 mg; maximum 10 mg
  • Severe impairment: do not use

Drug Interactions
  • Moderate CYP3A4 inhibitors: maximum 5 mg/24 hours
  • Potent CYP3A4 inhibitors: maximum 2.5 mg/24 hours
  • Ritonavir: maximum 2.5 mg / 72 hours

Other
≥65 years of age: starting dose 5 mg
Renal
Do not use in patients receiving hemodialysis
Hepatic
Moderate/severe impairment: do not use
Drug Interactions
Moderate/potent CYP3A4 inhibitors: do not use
As-needed use:
Renal
  • CrCl 30–50 mL/minute: starting dose 5 mg/day; maximum 10 mg/48 hours
  • CrCl < 30 mL/minute or if patient is receiving hemodialysis: maximum 5 mg/72 hours

Hepatic
  • Mild/moderate impairment: maximum 10 mg/day
  • Severe impairment: do not use

Drug Interactions
Potent CYP3A4 inhibitors: maximum 10 mg/72 hours
Once-daily use:
Renal
CrCl <30 mL/minute or if on hemodialysis: do not use
Hepatic
  • Mild/moderate impairment: use with caution
  • Severe impairment: do not use

Drug Interactions
Potent CYP3A4 inhibitors: maximum 2.5 mg/day
Renal
Do not use if CrCl < 30 mL/minute or in patients receiving hemodialysis
Hepatic
Severe impairment: do not use
Drug Interactions
  • Moderate CYP3A4 inhibitors: maximum 50 mg/day
  • Potent CYP3A4 inhibitors: do not use
Common adverse reactions Headache, flushing, dyspepsia, nasal congestion, nasopharyngitis, visual abnormalities Headache, flushing, dyspepsia, nasal congestion, nasopharyngitis, visual abnormalities Headache, flushing, dyspepsia, nasal congestion, nasopharyngitis, visual abnormalities Headache, flushing, dyspepsia, nasal congestion, nasopharyngitis, back pain, myalgia Headache, flushing, dyspepsia, nasal congestion, nasopharyngitis
Time required from last dose to administration of a nitrate (e.g., nitroglycerin) 24 hours 24 hours 24 hours 48 hours 12 hours
AWP unit cost $22.49 (100 mg) $21.46 (20 mg) $13.98 (10 mg) $24.48 (20 mg)

AWP = average wholesale price; CrCl = creatinine clearance; CYP = cytochrome P450.

Data from prescribing information for sildenafil;8 vardenafil;9 tadalafil;10 avanafil;11 vardenafil ODT;12 and Red Book Online.36

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