AOPXXX10.1177/1060028013501989The Annals of PharmacotherapyKyle et al

Review Article-New Drug Approvals

Avanafil for Erectile Dysfunction

Annals of Pharmacotherapy 47(10) 1312­–1320 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013501989 aop.sagepub.com

Jeffrey A. Kyle, PharmD, BCPS1, Dana A. Brown, PharmD, BCPS2, and Jerame K. Hill1

Abstract Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of avanafil and evaluate relevant clinical trial data. Data Sources: A MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, and Google Scholar searches (1966 to July 2013) were conducted using the key words: avanafil, erectile dysfunction, and phosphodiesterase type 5 (PDE5) inhibitor. Study Selection and Data Extraction: Articles evaluating avanafil for erectile dysfunction (ED) published in English and using human subjects were selected. Five clinical trials were identified. References cited in identified articles were used for additional citations. Data Synthesis: Avanafil is a highly selective PDE5 inhibitor that is a competitive antagonist of cyclic guanosine monophosphate. Specifically, avanafil has a high ratio of inhibiting PDE5 as compared with other PDE subtypes allowing for the drug to be used for ED while minimizing adverse effects. Absorption occurs quickly following oral administration with a median Tmax of 30 to 45 minutes and a terminal elimination half-life of 5 hours. Additionally, it is predominantly metabolized by cytochrome P450 3A4. As such, avanafil should not be co-administered with strong cytochrome P450 3A4 inhibitors. Dosage adjustments are not warranted based on renal function, hepatic function, age or gender. Five clinical trials suggest that avanafil 100 and 200 mg doses are effective in improving the Sexual Encounter Profile and the Erectile Function Domain scores among men as part of the International Index of Erectile Function. A network meta-analysis comparing the PDE5 inhibitors revealed avanafil was less effective on Global Assessment Questionnaire question 1 while safety data indicated no major differences among the different PDE5 inhibitors. The most common adverse effects reported from the clinical trials associated with avanafil were headache, flushing, nasal congestion, nasopharyngitis, sinusitis, and dyspepsia. Conclusions: Avanafil is a potent PDE5 inhibitor and is an effective treatment option for ED. Keywords avanafil, erectile dysfunction, male sexual dysfunction, phosphodiesterase inhibitor Received July 21, 2013

Introduction Sexual health is an important part of one’s quality of life, which can be compromised by sexual dysfunction. While female sexual dysfunction is not as well characterized, male sexual dysfunction includes diminished libido, abnormal ejaculation, and erectile dysfunction (ED).1 Erectile dysfunction, the most common sexual problem, is defined as the persistent inability to achieve or maintain penile erection sufficient for satisfactory sexual performance.2 It is estimated that more than 150 million men worldwide are affected with ED.3,4 Because of an increasing aging population, approximately more than 300 million men worldwide will be affected with ED by 2025.5 With the increase in the aging population, therapies for treating sexual dysfunction will become higher in demand. Even now, some ED therapies are in the top 200 drugs prescribed in the United States.6,7 Current therapies for ED include phosphodiesterase-5 (PDE5) inhibitors, penile self-injection programs with vasoactive drugs such as alprostadil, vacuum erection devices, and penile prostheses. Because of efficacy, ease of use, and a favorable adverse effect profile, the American Urology

Association along with other national organizations recommend PDE5 inhibitors as first-line agents in the treatment of ED.8-10 Four PDE5 inhibitors are currently on the market: sildenafil, vardenafil, tadalafil, and avanafil. The newest phosphodiesterase inhibitor, avanafil (Stendra) manufactured by Vivus, Inc, was approved in April 2012 by the US Food and Drug Administration for the treatment of ED.11

Data Sources Initial MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, and Google Scholar searches (1966- July


Samford University, Birmingham, AL, USA Palm Beach Atlantic University, West Palm Beach, FL, USA


Corresponding Author: Jeffrey A. Kyle, PharmD, BCPS, Department of Pharmacy Practice, McWhorter School of Pharmacy, Samford University; 800 Lakeshore Drive, Birmingham, AL 35229, USA. Email: [email protected]

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Kyle et al Table 1.  Pharmacokinetic and Cost Comparisons of PDE5 Inhibitors.12,23-26. Pharmacokinetic Parameter/Cost Absorption

Distribution Metabolism

Excretion Cost (AWP unit price as of July 2013)




Cmax 30-45 min If taken with food (specifically high fat): mean reduction in Cmax of 24% to 39%; mean delay of 1.12-1.25 h Vd: not reported Major: CYP 3A4, Minor: CYP 2C Active metabolites: M4, M16 t1/2: 5 h Feces 62% Not yet determined

Cmax 30 min to 2 h If taken with food (specifically high fat): mean reduction in Cmax of 29%; mean delay of 1h Vd: 105 L Major: CYP 3A4, Minor: CYP 2C9 Active metabolite: Ndesmethyl t1/2: 4 h Feces 80% All doses: $29.24


Cmax 30 min to 6 h If taken with food: Cmax not affected

Cmax 30 min to 2 h If taken with food: mean reduction in Cmax of 18% to 50%; median delay of 1 h

Vd: 63 L Major: CYP 3A4 Nonactive metabolite: methylcatechol glucuronide t1/2: 17.5 h Feces 61% 2.5, 5 mg tablets: $5.41 10, 20 mg tablets: $34.84

Vd: 208 L Major: CYP 3A4, Minor: CYP 3A4, 2C Active metabolite: M1 t1/2: 4-5 h Feces 91% to 95% All doses: $28.05

Abbreviations: Cmax, peak serum concentration; Vd, volume of distribution; L, liters; CYP = cytochrome P450; t1/2, terminal half-life; AWP, actual wholesale price.

2013) were conducted for clinical trials with the key words: avanafil, erectile dysfunction, and phosphodiesterase type 5 inhibitor. Clinical trials evaluating the safety and efficacy of avanafil for ED published in English and using human subjects were selected and evaluated.

other PDE5 inhibitors.21,22 This high selectivity minimizes avanafil’s pharmacodynamic impact on other PDE subtypes and improves its adverse effect profile.


Avanafil is quickly absorbed following oral administration with a median Tmax of 30 to 45 minutes (Table 1).12-20 However, its absorption can be affected if taken with a high-fat meal, delaying Tmax up to 1.25 hours and reducing maximum concentrations (Cmax) by approximately 24% (100 mg) and 39% (200 mg) after administration.12,20 Avanafil has a degree of protein binding that is independent of total drug concentrations, age, renal function, and hepatic function. It undergoes hepatic metabolism predominantly by the cytochrome P450 (CYP) 3A4 enzyme and to a minor extent the CYP2C isoform. Among avanafil’s major metabolites, the M4 metabolite has an in vitro inhibitory potency for PDE5 and accounts for 4% of its pharmacologic activity. Avanafil does not accumulate following multiple dosing. The terminal elimination half-life is 5 hours, with 62% excreted in the feces and 21% excreted in the urine.12,13,20 No dosage adjustments are necessary based on renal function, hepatic function, age, or gender. Because of the lack of safety and efficacy data, avanafil should not be used in patients younger than 18 years though use in this population would not be anticipated.

Avanafil is a highly selective inhibitor of PDE5, possessing a unique diaminopyrimidine derived chemical structure.12-20 It is a competitive antagonist of cyclic guanosine monophosphate (cGMP) at the catalytic binding pocket of the phosphodiesterase enzyme. The inhibition of this enzyme allows for an increase in cGMP levels, resulting in a reduction in intracellular calcium. Smooth muscle vasodilatation in the corpus cavernosae occurs, allowing for increased blood flow to the penis, and ultimately an erection. Selectivity for PDE rather than potency, pharmacodynamically differentiates the PDE5 inhibitors. PDE5 selectivity is expressed as a ratio between the inhibitory concentration (IC50) for a given PDE and the IC50 of PDE5. Within the family of phosphodiesterase enzymes, there are 11 subtypes located in different concentrations throughout the body. Inhibition of PDE subtypes 1, 6, and 11 is responsible for many of PDE5 inhibitors’ adverse effects.21 PDE1 is located throughout the vasculature and is correlated with vasodilation, tachycardia, and flushing while PDE6 is involved with phototransduction. PDE11 inhibition has been associated with an increase in myalgia and lower back pain. Avanafil is more selective, in some cases 100-fold more selective, for PDE5 than for PDE1, PDE6, or PDE11 versus


Clinical Trials To date, 4 multicenter, randomized, double-blinded, placebocontrolled clinical trials have been conducted evaluating the

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Annals of Pharmacotherapy 47(10)

Table 2.  Summary of Clinical Trials. Reference


Goldstein et al 12 WK (2012)27 MC, R, DB, PC, PG N = 646

Avanafil Dose

Outcome Measures

A50, A100, or 1. Change in percentage A200 each taken of sexual attempts 30 min prior to when penis was sexual activity inserted into vagina between run-in period and end of treatment period (SEP 2)


2. Change in percentage of sexual attempts in which erection was maintained for successful sexual intercourse between run-in period and end of treatment period (SEP 3)


3. Change from baseline to end of treatment period in IIEF-EF scores

              Zhao et al (2012)28

12 WK MC, R, DB, PC, PG N=200

          Goldstein et al 12 WK MC, R, DB, PC (2012)29 N = 390    

A100 or A200 each taken 30 min prior to sexual activity

A100 or A200 each taken 30 min prior to sexual activity

Mean change from baseline to end of treatment period for IIEF-EF scores

Change from baseline to end of treatment period in IIEF-EF, SEP 2, and SEP 3 scores

Results SEP 2


12 WK

P 47% A50 45% (P < .005 vs placebo) A100 47% (P < .0001 vs placebo; P < .01 vs A50) A200 48% (P < .0001 vs placebo; P < .01 vs A50) SEP 3 BL

54% 64% 74% 77% 12 WK

P 13% A50 13% (P < .005 vs placebo) A100 14% (P < .0001 vs placebo; P < .01 vs A50) A200 12% (P < .0001 vs placebo; P < .01 vs A50) IIEF-EF BL

27% 41% 57% 57% 12 WK

P 12.4 A50 12.6 (P < .005 vs placebo) A100 12.6 (P < .0001 vs placebo; P < .01 vs A50) A200 12.8 (P < .0001 vs placebo; P < .01 vs A50) IIEF-EF

15.3 18.1 20.9 22.2

P A100 (P < .005 vs placebo) A200 (P < .005 vs placebo) IIEF-EF

3.5 8.5




12 WK

P A100

11.3 11.2

13.2 15.8 (continued)

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Kyle et al Table 2. (continued) Reference                               Belkoff et al (2013)31



Avanafil Dose

Outcome Measures

A100 initially, 1. Change in percentage option to between run-in period increase to A200 of original study and end or decrease to of treatment A50 taken 30 period (SEP 2) min prior to sexual activity


Results (P = .002 vs placebo) A200 (P < .001 vs placebo) SEP 2 P A100 (P < .001 vs placebo) A200 (P < .001 vs placebo) SEP 3 P A100 (P < .001 vs placebo) A200 (P < .001 vs placebo) SEP 2

A100 A200 SEP 3 A100 A200

  Mulhall et al (2011)30  

12 WK R, DB, PC N = 298

A100 or A200 each taken 30 min prior to sexual activity



BL 36% 32%

12 WK 42% 54%



BL 10% 8%

12 WK 20% 34%




52 WK

44% 43% BL 13% 11%

83% 79% 52 WK 68% 66%

2. Change in percentage between run-in period of original study and end of treatment period (SEP 3) 3. Mean change from IIEF-EF BL baseline to end of A100 13.6 treatment period for A200 11.9 IIEF-EF scores and end of treatment period (SEP 3) Note: Statistical significance not provided Change from baseline A100 IIEF-EFD, SEP 2, SEP 3 (P < .001) to end of treatment period in IIEF-EFD, SEP 2, and SEP 3 scores A200 IIEF-EFD, SEP 2, SEP 3 (P < .001)

12 WK 22.2 22.7

Abbreviations: WK, week; MC, multicenter; R, randomized; DB, double-blind; PC, placebo controlled; PG, parallel group; A50, avanafil 50 mg; A100, avanafil 100 mg; A200, avanafil 200 mg; min, minutes; P, placebo; SEP 2, Sexual Encounter Profile question 2; SEP 3, Sexual Encounter Profile question 3; IIEF, International Index of Erectile Function (a 15-item standardized questionnaire to assess patient satisfaction and quality of erectile function. A lower score indicates a higher degree of dysfunction); EFD, Erectile Function Domain; BL, baseline; OL, open-label; EXT, extension.

efficacy of avanafil (Table 2).27-30 A fifth trial, which is an open-label extension trial containing patients from two of these studies, was also identified.31 Two studies have evaluated the use of avanafil in specific ED patient populations: one in those with diabetes and the other in those post–radical prostatectomy.29,30 Overall, study designs were similar among all four clinical trials consisting of a 4-week run-in period assessing

sexual attempts followed by a treatment period of 12 weeks. At the end of the run-in period, men with a 50% or greater failure rate in maintaining an erection of sufficient duration to permit successful intercourse and an International Index of Erectile Function–Erectile Function (IIEF-EF) domain score of 5 through 25 and who had made at least 4 attempts at intercourse during those 4 weeks were randomized. Additional

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Annals of Pharmacotherapy 47(10)

Table 3.  Sexual Encounter Profile Questions.32 Question 2 (SEP 2): When you had erections with sexual stimulation, how often were your erections hard enough for penetration? 0 = No sexual activity; 1 = Almost never/never; 2 = A few times (much less than half the time); 3 = Sometimes (about half the time); 4 = Most times (much more than half the time); 5 = Almost always/always Question 3 (SEP 3): When you attempted sexual intercourse, how often were you able to penetrate (enter) your partner? 0 = Did not attempt intercourse; 1 = Almost never/never; 2 = A few times (much less than half the time); 3 = Sometimes (about half the time); 4 = Most times (much more than half the time); 5 = Almost always/always

inclusion and exclusion criteria varied among trials. Primary outcome measures were related to 2 questions from the Sexual Encounter Profile (SEP; Table 3) and IIEF-EF domain scores.32-34 The open-label study was a 52-week treatment extension of patients enrolled in 2 previous clinical studies with the option to increase or decrease the dose of avanafil.31 Goldstein et al27 randomized 646 subjects with mild to severe ED to avanafil 50 mg, 100 mg, 200 mg or placebo. Men aged 18 years and older were eligible if they had at least a 6 month history of mild to severe ED as measured by the IIEF-EF, made at least 4 sexual attempts during the runin period, and experienced 50% or greater failure in maintaining erections that were sufficient to allow for successful sexual intercourse. Additionally, they were required to be in a monogamous, heterosexual relationship for at least 3 months. Exclusion criteria consisted of dose-limited adverse effects or treatment failure during past use of PDE5 inhibitor therapy, administration with CYP 3A4 inhibitors, organic nitrate use, androgen therapy, history of ED as a result of a spinal cord injury or radical prostatectomy, untreated hypogonadism, a penile implant, prostate-specific antigen level >4 ng/mL (or prostate cancer), diabetes, uncontrolled hypertension, hypotension, life-threatening arrhythmia, coronary revascularization within 6 months, myocardial infarction, or stroke. Initiation of α-adrenergic blocker therapy was discouraged; however, patients who started therapy at least 2 weeks before the study were allowed to participate if the dose remained stable. Prior use of PDE5 inhibitors was allowed as long as consistent failure had not occurred. All doses of avanafil demonstrated statistically significant improvement in SEP questions 2 (SEP 2) and 3 (SEP 3), and IIEF-EF scores as compared to placebo. However, the 100 and 200 mg doses of avanafil demonstrated statistically significant results for SEP 2, SEP 3, and IIEF-EF domain scores as compared with the 50 mg dose. Additionally, patients who had been previously treated with PDE5 inhibitors experienced a statistically significant improvement in all 3 primary outcomes with all 3

doses of avanafil (P < .0001 vs baseline). During the study, 300 sexual attempts were made within 15 minutes of dosing avanafil resulting in 64%, 67%, and 71% successful attempts with avanafil 50, 100, and 200 mg, respectively as compared with 27% with placebo. A total of 4066 sexual attempts occurred 15 to 30 minutes postdose. Erection was achieved 52%, 61%, and 58% of the time for 50, 100, and 200 mg doses, respectively, while only 31% of the time for placebo. Although Goldstein et al27 were able to capture data from a large percentage of patients (~70%) with varying degrees of ED severity, the results are limited by the extensive exclusion criteria, including men with diabetes. Thus, they must be interpreted cautiously. Additionally, no P values were provided for the baseline characteristics to determine whether there was homogeneity amongst the groups. Though the investigators used the well-validated SEP to assess outcomes, there is subjectivity in each participant’s definition of “satisfactory sexual intercourse,” which could have affected the scores. Finally, no confidence intervals were provided to assess the clinical differences of the results. Zhao et al28 investigated 200 men older than 20 years with ED for ≥6 months who made at least 4 sexual intercourse attempts during the run-in period in which at least half of the attempts were unsuccessful. Exclusion criteria included use of medications/products (eg, nitrates, anticoagulants, androgens, antiandrogens, trazodone, erythromycin, cimetidine, ketoconazole, indinavir, grapefruit juice); history of active peptic ulcer disease within 1 year; anatomical defects of the penis; spinal cord injuries; radical pelvic surgery; hyperprolactinemia; hypogonadism; inadequately controlled diabetes (ie, A1c >12%); proliferative diabetic retinopathy; major uncontrolled a psychiatric disorder; history of alcoholism or other substance abuse; history of cardiovascular disease, stroke, myocardial infarction, cardiac failure, unstable angina or life-threatening arrhythmia within 6 months prior to study entry; major renal, hepatic or hematologic abnormalities. Prior PDE5 inhibitor use was allowed; however, patients considered non-responders to previous therapy were ineligible. The primary outcome was the change from baseline to 12 weeks posttreatment in the IIEF-EF domain scores. Secondary outcomes included SEP 2 and SEP 3, responses to the Global Assessment Questionaire question 1 (GAQ-1 “Has the treatment you have been taking improved your erectile function?”), and normalization of the IIEF-EF domain score (ie, score ≥26). Following 12 weeks of treatment with avanafil, doses of 100 and 200 mg produced mean changes in the IIEF-EF domain scores of 8.5 and 8.8, respectively, as compared with a score of 3.5 with placebo (P < .001). Similar to the study by Goldstein et al,27 this study did not include patients who failed treatment with previous PDE5 inhibitor therapy, and no confidence intervals were provided. Additionally, there were extensive exclusion criteria. However, this study did allow inclusion of patients with

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Kyle et al diabetes pending the A1c was 9%), ED resulted from a spinal cord injury or radical prostatectomy, blood glucose level greater than 270 mg/dL, and untreated hypogonadism. Participants on average were reported to have ED for at least 6 years and diabetes for at least 11 years. After a 4-week run-in period, patients were randomized to avanafil 100 mg, 200 mg, or placebo, which was were to be taken 30 minutes prior to sexual intercourse for 12 weeks. The primary endpoints were identical to the first trial by Goldstein et al27 (ie, SEP 2, SEP 3, IIEF-EF). At trial end, those randomized to avanafil 100 or 200 mg doses met the primary endpoints compared to placebo regardless of the type of diabetes, duration of diabetes, severity of ED, and duration of ED. No differences were noted between avanafil doses with regards to the primary endpoints. Limitations include an overall small sample size, especially those with type 1 diabetes (n = 41), no reported confidence intervals, and subjectivity of primary endpoints. Though there are no known racial differences in response, inclusion of predominantly white men may limit generalizability of the results. Belkoff et al31 conducted a phase 3, 52-week, open-label extension study of the men participating in either of the studies by Goldstein et al.27,29 A total of 712 men with and without diabetes (32% with a previous diagnosis) who had mild to severe ED (29.1% mild, 33.4% moderate, and 37.5% severe) were given 100 mg of avanafil with the option to increase to 200 mg for efficacy if needed or decrease to 50 mg for tolerability if applicable. Similar to previous studies, they were required to make at least 4 sexual attempts. They were excluded from participation if they required treatment with nitrates, protease inhibitors, or 5-α reductase inhibitors or if they developed a medical condition that could lead to safety concerns with the administration of avanafil. The primary outcomes were changes in SEP 2 and SEP 3 from the run-in period of the original study and the treatment period for this study, and the change in mean IIEF-EF scores from baseline to the end of the treatment period. Of the 712 participants, 171 (24%) received avanafil 100 mg, 536 (75.3%) requested an increase in dose to 200 mg, and 3 (0.4%) requested a dosage reduction. One patient received all 3 doses, and 1 patient did not receive any study drug. The 5 patients requesting a dosage reduction, receiving all 3 doses, and not receiving any study drug were excluded from the intent-to-treat population analysis.

Sexual Encounter Profile question 2 improved from 44.1% at baseline of the original study to 83.3% with treatment of 100 mg of avanafil. Additionally, those receiving a dosage titration to 200 mg experienced an increase in SEP 2 from 43% to 79%. Similarly, improvements in SEP 3 were noted with an increase from 13% to 68% with 100 mg and from 11% to 66% with 200 mg of avanafil. The mean IIEF-EF score increased from 13.6 at baseline to 22.2 with avanafil 100 mg and 11.9 to 22.7.with avanafil 200 mg. Sexual intercourse occurred within 15 minutes for 83% of participants and after 6 hours of dosing in 74% of participants. A subgroup analysis found the higher dose of avanafil (200 mg) to be associated with a greater improvement in SEP 3 as compared to the 100 mg dose (42.4% and 24.6%, respectively, P < .05). The most common side effects noted were headache, flushing, nasopharyngitis, and nasal congestion. An overall discontinuation rate of 30.9% was noted,with 2.8% of these being attributed to adverse effects. Major limitations to this study include the lack of P values and confidence intervals for the majority of the data, including outcomes and baseline characteristics. Thus, although an improvement might be noted based on numerical data, the statistical significance is unknown.31 The fifth clinical trial selected for review, performed by Mulhall et al,30 assessed the effects of avanafil in men with mild to severe ED for at least 6 months following bilateral nerve-sparing radical prostatectomy. Patients aged 18 to 70 years, who underwent a prostatectomy for localized carcinoma ≥6 months prior to screening, had prostate cancer staging ≤pT2 and Gleason score ≤7 (4 + 3), and functional erections without medication assistance prior to diagnosis of prostate cancer were randomized to avanafil 100 mg, 200 mg, or placebo. Exclusion criteria were similar to other studies aforementioned. Out of the 298 patients randomized, at baseline 71.5% of men were categorized as “severe” based on IIEF-EF domain scores and 16.1% were aged ≥65 years. Statistically significant differences were noted with both doses of avanafil within the primary endpoints of SEP 2, SEP 3, and IIEF-EF domain scores (P < .001). In the patients receiving avanafil (both doses), 36.4% and 45.5% of sexual attempts at 15 minutes or less and 6 hours or longer, respectively, were successful compared with 4.5% and 15.4%, respectively, in those patients receiving placebo. It is unclear if the avanafil reported findings are a combined percentage for both doses.

Adverse Effects Based on clinical trial data, avanafil was generally well tolerated as adverse effects were mainly considered to be mild to moderate with no serious adverse events reported.27-31 It appears that the incidence of adverse effects were dose dependent. The most commonly occurring adverse effects reported with the use of avanafil (all doses included) throughout the 5 clinical trials were headache (2.7% to

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12.1%), flushing (1.4% to 13%), nasopharynigitis (0.6% to 5.1%), nasal congestion (0.6% to 4.3%), and back pain (0.6% to 3%).27-31 Infrequently occurring adverse effects were dyspepsia, dizziness, fatigue, upper respiratory infections.12,27-31 While priapism or hearing loss were not reported during the clinical trials, 1 patient experienced visual color disturbance in the open label extension trial.2731 Study discontinuation due to an adverse effect was similar between avanafil and placebo.27-30 Last, there were no clinically relevant effects noted on laboratory parameters, vital signs, or electrocardiograms.27-31

Precautions and Contraindications Similar to other PDE5 inhibitors, avanafil is contraindicated with any form of organic nitrate, both intermittent and/or chronic use, because of the risk of a sudden drop in blood pressure. In a life-threatening situation, nitrates should not be used until 12 hours after the last dose of avanafil. Patients with underlying cardiac conditions should not use avanafil before proper evaluation by a physician. Cautious use of avanafil is recommended for patients with left ventricular outflow obstruction and with vasovagal reflex disorders.12 Avanafil was not studied in patients who had a stroke, myocardial infarction, life-threatening arrhythmias, or coronary revascularization surgery within the past 6 months, patients with resting hypotension (eg, 170/100 mm Hg), those with unstable angina or angina during sexual intercourse, or those with New York Heart Association class 2 or greater heart failure, underlying bleeding disorders, other erectile dysfunction medications.12 Therefore, safety and efficacy has only been established as monotherapy for ED.12 Those with prolonged erections lasting more than 4 hours or experiencing priapism, painful erections lasting greater than 6 hours, should be referred to a physician. Patients should be monitored for any signs of vision changes or sudden hearing loss.

Drug Interactions Avanafil has the potential to have clinically significant pharmacokinetic and pharmacodynamic interactions. Strong CYP P450 3A4 inhibitors, such as ketoconazole, have shown a significant increase in avanafil’s maximum concentration (Cmax) and overall drug exposure area under the curve of 13- and 3-fold, respectively.12 Avanafil should not be used with strong CYP 3A4 inhibitors, and a maximum dose of 50 mg in a 24-hour period is recommended for patients taking moderate CYP 3A4 inhibitors, such as fluconazole.12 α-Adrenergic blockers, other antihypertensives, and alcohol increase the likelihood of hypotension. A baseline blood pressure reading should be considered prior to starting therapy and monitored for changes throughout therapy.

Dosage and Administration Avanafil is available as an oral tablet in 3 strengths: 50, 100, and 200 mg. It is recommended that 100 mg be taken approximately 30 minutes prior to sexual activity and not exceed 1 dose in a 24-hour period.12 The dose may be decreased to 50 mg or increased to a maximum 200 mg based on the patient’s response. Doses may be administered with or without food. Although, fatty foods may affect absorption as aforementioned. For patients with severe renal impairment (estimated creatinine clearance less than 30 mL/min) or those on dialysis, avanafil should be avoided as it has not been studied in these populations. No dose adjustments are necessary in those with mild to moderate renal impairment (estimated creatinine clearance ≥30 to 12 hours after an avanafil dose, if needed for a life-threatening event. Avanafil should be initiated at 50 mg in those taking α-blockers whereas those concomitantly taking moderate CYP 3A4 inhibitors should not exceed 50 mg in a 24-hour period. Tablets should be kept out of the light and stored at room temperature (25°C), with an acceptable range of 20°C to 25°C.12

Discussion Based on the evidence from 5 clinical trials, avanafil is an additional PDE5 inhibitor that is effective and safe for the treatment of ED. It has a high selectivity for the PDE5 enzyme with a Tmax that ranges from 30 to 45 minutes. As such, avanafil is recommended to be taken approximately 30 minutes prior to sexual activities without regard to food, especially fatty foods, since food may delay absorption and reduced drug concentrations.12 No dosage adjustments are required for patients with hepatic and renal impairment. However, the drug has not been studied in patients with severe renal or hepatic dysfunction as well as those on dialysis. Avanafil was generally well tolerated throughout the clinical trials as adverse effects were mainly considered to be mild to moderate.27-31 It is clear that avanafil, even taken at a higher doses (ie, 200 mg), for 1 year was found to be tolerable for most patients.31 Since its major metabolic pathway is through CYP 3A4 enzyme, strong CYP 3A4 inhibitors should be avoided while concomitantly taking avanafil. Avanafil’s place in therapy and advantage over other existing PDE5 inhibitors can only be theorized as direct comparative studies are lacking. It is known that PDE5 inhibitors are considered first line therapy for ED.8-10 A comparative network meta-analysis of the PDE5 inhibitors

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Kyle et al concluded tadalafil may be the most effective PDE5 inhibitor for ED followed by vardenafil.35 These results were based on the the primary endpoints of the GAQ-1 and change from baseline to study end on the IIEF-EF domain score.35 Because of inadequate reporting, avanafil was only included in the GAQ-1 portion of the primary outcome. On this portion of the primary outcome, avanafil was assocated with lower GAQ-1 positive responses compared with other PDE5 inhibitors.35 However, the inherent limitations of a network meta-analysis should lend caution to its conclusions. No clinical conclusions can be drawn about the use of avanafil for patients not responding to other PDE5 inhibitors. In fact, participants with prior PDE5 inhibitors use were included in the studies by both Zhao et al28 and Goldstein et al,27 but those who failed prior PDE5 inhibitor treatment were ineligible. Based on the the trial by Mulhall et al,30 a specific place in therapy for avanafil might be in men with ED following radical prostatectomy. Comparing avanafil’s pharmacodynamic and pharmacokinetic profile to others within the PDE5 inhibitor class may be more helpful when assessing its potential advantages (Table 1). Its high potency and selectivity for PDE5 allows for an effective treatment option for ED without causing severe hypotension and myalgia that has been associated with this class of medications.16,22,36 Given its Cmax, the close proximity of drug administration to engagement in sexual activities may allow for sexual spontaneity. In fact, Goldstein et al27 found that more than half of sexual attempts made between 15 and 30 minutes after avanafil administration were successful, occurring with all 3 doses of avanafil studied.27 This has also been evident in the other clinical trials.28-31 As with new medications on the market, the initial cost of the drug tend to be a disadvantage. Although avanafil is approved by the Food and Drug Administration, as of July 2013, the drug has not reached the US market and thus cost for the drug has yet to be determined. Nevertheless, when this medication does reach the market and is prescribed in clinical practice, more evidence with regard to its place in therapy and advantages may manifest. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Avanafil for erectile dysfunction.

To review the pharmacology, pharmacokinetics, safety, and efficacy of avanafil and evaluate relevant clinical trial data...
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