National Drug Abbreviated Monograph

Avanafil Monograph

Avanafil (STENDRA)

National Drug Abbreviated Monograph

December 2013

VA Pharmacy Benefits Management Services,
Medical Advisory Panel, and VISN Pharmacist Executives

The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.

Introduction1

Erectile dysfunction is defined as the consistent or recurrent inability to attain or maintain an erection sufficient for satisfactory intercourse or other sexual expression. ED is reported to affect 52% of men between the ages of 40 to 70 years and 67% of men 70 years and older.

Causes of ED are often categorized as organic or psychological. Several risk factors have been identified for ED, the most significant being aging although ED is not an inevitable consequence of aging. Other risk factors include diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, conditions associated with endothelial dysfunction, trauma (either localized or to the spinal cord), medications, and depression. Cigarette smoking and chronic alcohol abuse are associated with ED. Surgeries such as radical prostatectomy and lumbarectomy can result in ED.

The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating avanafil for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA.

Pharmacology/Pharmacokinetics1, 2

The release of nitric oxide by nerves and endothelial cells in the penis in response to sexual stimulation results in the formation of cyclic guanosine monophosphate (cGMP). The increase in cGMP results in the relaxation of smooth muscles in the corpus cavernosum, leading to an inflow of blood, which can produce an erection. Phosphodiesterase type 5 is the predominant PDE isozyme in penile tissue and is responsible for the metabolism of cGMP. All the PDE5 inhibitors selectively inhibit PDE5, thus preventing the breakdown of cGMP and enhancing or restoring the natural erectile response. Other types of PDE, 1 – 11, are found throughout the body and provide a number of different functions. In vitro, avanafil selectively inhibits the PDE5 isoenzyme and >100-fold more potent to PDE5 than other PDE isoenzymes. The 50% inhibitory concentrations (IC50) for the marketed PDE5 inhibitors are shown in Table 1.

Table 1 IC50 Values PDE5 Inhibitors for PDE5Isozyme

PDE Isozyme / IC50 value, nmol/L
Avanafil / Sildenafil / Vardenafil / Tadalafil
PDE5 / 4.3-5.2 / 3.5 / 0.14 / 6.74

Like the other marketed PDE5 inhibitors, avanafil is highly bound to plasma proteins and metabolized primarily by CYP3A4 (Table 2). Its half-life, onset of action and duration of action are similar to those of sildenafil and vardenafil (Tables 2 and 3).

Table 2 Pharmacokinetics of PDE5 Inhibitors

Agent / Absolute
Bioavailability / Protein
Binding / Metabolism / Active
Metabolite / Half-life / Excretion
Avanafil / ND / 99% / CYP3A4 and 2C9 / Yes (minor) / 5 hrs / 62% fecal
21% renal
Sildenafil / 40% / 96% / CYP3A4 and 2C9 / Yes / 4 hrs / 80% fecal
13% renal
Vardenafil / 15% / 95% / CYP3A4 / Yes / 4 hrs / 91%-95 % fecal; ~2-6% renal
Tadalafil / ND / ND / CYP3A4 / No / 17.5 hrs / ~61% fecal
~36% renal

ND - Not determined

Table 3 Pharmacodynamics of PDE5 Inhibitors in Erectile Dysfunction

Agent / Effect of Food / Onset of Action (median) / Duration of Action
Avanafil / High fat meal decreased Cmax 39% and delayed Tmax to ~1.2 hours. AUC was decreased <4%. / <30 minutes / 4 to >6 hours
Sildenafil / High fat decreases rate of absorption, delaying Tmax to 60 minutes and decreasing Cmax 29% / 27 minutes / 4 hours
Vardenafil / High fat meal decreases Cmax 18%-50% / 26 minutes / 4 hours
Tadalafil / No effect / 45 minutes / 36 hours

FDA Approved Indication1

Treatment of erectile dysfunction

Potential Off-label Uses

Post-prostatectomy penile rehabilitation

Current VA National Formulary Alternatives

Sildenafil, an oral PDE 5-type inhibitor

Alprostadil, intraurethral pellet or injection

Dosage and Administration1

• Usual initial dose is 100 mg taken 30 minutes prior to sexual activity; no more than once daily.
• The dose can be increased to 200 mg or decreased to 50 mg based on response and tolerability.
• Patients taking a moderate CYP 3A4 inhibitor should take no more than 50 mg in one day.
• An initial dose of 50 mg is recommended for patients taking a stable dose of an alpha-blocker prior to starting avanafil.
• Patients taking a strong CYP 3A4 inhibitor should not take avanafil.
• Avanafil can be taken without regard to meals.
• Avanafil should not be taken by patients with severe renal (CrCl <30 mL/min) or severe hepatic impairment.
• No dosage adjustment is need for patients with mild or moderate renal (CrCl 30 mL/min) or hepatic dysfunction (Pugh Class A or B).
• No dosage adjustment is recommended for geriatric patients

Efficacy3-5

Efficacy Measures

Assessment and Outcome Measures

The International Index of Erectile Dysfunction (IIEF) has been the main measure used in clinical trials to assess the efficacy of the PDE5 inhibitors. The IIEF is a validated, self-administered 15-question, questionnaire that assesses erectile function, orgasmic function, sexual desire, satisfaction with intercourse, and overall sexual satisfaction. Questions are answered on a scale of 0 (no attempt), 1 (almost never or never) to 5 (almost always). The scores of questions 1 through 5 and question 15 are frequently summed (range 1 – 30) and reported as the erectile function domain score. Men who score 0 to 10 are rated as having severe ED, those scoring 11 to 25 as mild to moderate ED, and men scoring 26 to 30 are not considered to have ED (i.e., normal erectile function. Treatment efficacy is also assessed by evaluating Questions 3 and 4 separately, which ask the man about frequency he was able to penetrate his partner and the frequency he was able to maintain an erection after penetration in the preceding 4-weeks, respectively.

Patients in some clinical trials were asked to keep Sexual Encounter Profile (SEP) diaries to record their sexual experiences. The changes from baseline to endpoint in the mean proportions of “yes” responses to questions 2 (SEP-Q2) and 3 (SEP-Q3), respectively are often used as co-primary efficacy outcome measures. SEP-Q2 asks, “Were you able to insert your penis into your partner’s vagina? (yes or no),” while SEP-Q3 asks, “Did your erection last long enough to have successful intercourse? (yes or no).”

A frequently used secondary outcome measures are the mean IIEF Intercourse Satisfaction score and the overall mean IIEF Satisfaction score.

Summary of trial design

Five clinical trials with avanafil were identified: three Phase 3 and one Phase 2 trials from the United States and two trials conducted in North Korea. This review will focus on the findings of the three U.S. Phase 3 trials: one excluding men with diabetes or a history of radical prostatectomy, another in men with diabetes, and the third in men post bilateral nerve sparing radical prostatectomy without a history of diabetes. The three studies share the following study design:

• Prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group design
• Men 18 years and older were eligible if they had a history of mild to severe ED for 6 months or longer and were in a monogamous, heterosexual relationship for 3 months of longer.
• Key exclusion criteria included a history of dose-limiting adverse events or consistent treatment failure with PDE5 inhibitors, or use of a CYP3A4 inhibitor 28 days before randomization or during the trial.
• Included a 4-week run-in period without treatment after which only men with a 50% or greater failure rate in maintaining an erection sufficient duration to permit successful intercourse and in IIEF-EF domain score of 5 through 25 who had made a least 4 attempts at intercourse during the 4 weeks were randomized.
• Subjects were stratified by ED severity to avanafil 50 mg (one trial), 100 mg, or 200 mg, or placebo in 1:1:1:1 ratio.
• Avanafil’s efficacy and safety were evaluated over 12-weeks with clinic visits every 4-weeks after randomization.
• Subjects were instructed to take study medication 30 minutes prior to sexual activity and were allowed to take 2 doses within 24 hours provided they were separated by 12 hours.

Summary of efficacy findings

The primary outcome findings for the 3 clinical trials are shown in Table 3. In each trial all doses of avanafil differed statistically from placebo in each outcome measure. These findings did not vary when subjects were stratified by ED severity at baseline with the exception of those assigned to avanafil 100 mg in post-prostatectomy trial. Avanafil 100mg and 200 mg was statistically different from avanafil 50 mg. The presence of diabetes did not affect response, while the magnitude of the treatment effect was greater when diabetes had existed for 60 months.

Table 4 Primary Outcome Efficacy Findings from U.S. Phase 3 Trials

Trial, Population Studied
& Primary Outcome / A50 mg / A100 mg / A200 mg / Placebo
Goldstein, et al. 2012a
No DM or prostatectomy
% Successful
SEP2 baseline
End of Tx
SEP3 baseline
12 weeks
End of Tx
IIEF-EF score
Baseline
End of Tx / n = 154
45.0
64.0
13.0
41.0
12.6
18.1 / n = 157
47.0
74.0
14.0
57.0
12.6
20.9 / n = 156
48.0
77.0
12.0
57.0
12.8
22.2 / n = 155
47.0
54.0
13.0
27.0
12.4
15.3
Goldstein, et al. 2012b
DM, no prostatectomy
% Successful
SEP2 baseline
End of Tx
SEP3 baseline
12 weeks
End of Tx
Change in IIEF-EF score / Dose
Not
Studied / n = 126
32.5
54.0
8.2
34.4
4.5 / n = 126
41.5
63.5
8.0
40.0
5.4 / n = 127
36.0
42.0
10.0
20.5
1.8
Muhall, et al 2013
Post prostatectomy, no DM
% Successful (estimates)
SEP2 baseline
End of Tx
SEP3 baseline
12 weeks
End of Tx
IIEF-EF score
Change in score, baseline – Wk 12
% who improved / Dose
Not
Studied / n = 95
~18.0
~32.0
~5.0
~23.0
3.6
40.0 / n = 100
~20.0
~41.0
~5.0
~25.0
5.2
55.0 / n = 99
~20.0
~20.0
~4.0
~9.0
0.1
1.0

A – Avanafil

Changes in individual IIEF domain scores improved significantly with all doses of avanafil compared to placebo. For all degrees of ED severity the proportion of subjects in each avanafil group achieving a normal IIEF-EF score was significantly greater than placebo.

Among those who attempted intercourse within 30 minutes of dosing, approximately twice as many subjects assigned to avanafil 100 mg and 200 mg reported successful intercourse than those assigned to placebo. Subjects with or without diabetes, but without prostatectomy attempting intercourse more than 6 hours after dosing reported successful intercourse 50% to 83% of the time with avanafil and <25% of the time with placebo. In men post-prostatectomy, avanafil did not demonstrate a difference in success rate compared to placebo 6 hours after a dose.

Adverse Events (Safety Data) 2-5

Deaths and Other Serious Adverse Events

In one trial less than 2% of subjects experienced syncope. Priapism and other cardiovascular events were not reported in the trials. No other serious adverse events were attributed to study drug. There was on study death due to a gunshot wound that was not attributed to the study medication.

Common Adverse Events

The common adverse events reported in trials with avanafil are similar to what has been reported with other PDE5 inhibitors and for the most part are consistent with their vasodilator properties (Tables 5 and 6)

Table 5 Adverse Events Reported by 2% of Subjects in Phase 3 Clinical Trials

Adverse Event / A50mg / A100mg / A200mg / Placebo
Headache / 5.1% / 6.9% / 10.5% / 1.7%
Flushing / 3.2% / 4.3% / 4.0% / 0.0%
Nasal congestion / 1.8% / 2.9% / 2.0% / 1.1%
Back pain / 3.2% / 2.0% / 1.1% / 1.1%

Table 6 Adverse Events Reported by >2% of Subjects Post-bilateral Nerve Sparing Prostatectomy

Adverse Event / A100mg / A200mg / Placebo
Headache / 8.1% / 12.1% / 1.0%
Flushing / 5.1% / 10.1% / 0.0%
Nasopharyngitis / 3.0% / 5.1% / 0.0%
Upper respiratory infect. / 2.0% / 3.0% / 0.0%
Nasal congestion / 3.0% / 1.0% / 1.%
Back pain / 3.0% / 2.0% / 1.0%
ECG abnormal / 1.0% / 3.0% / 0.0%
Dizziness / 1.0% / 2.0% / 0.0%

Tolerability

The proportion of patients assigned to avanafil 50 mg, 100 mg or 200 mg who discontinued study participation secondary to adverse effects were 1.4%, 2.0%, and 2.0%, respectively, compared to 1.7% assigned to placebo.

Contraindications2

• Nitrates - administration of any form of organic nitrates, either regularly and/or intermittently
• Hypersensitivity to any component of the tablet

Warnings and Precautions2

• Treatments for ED, including avanafil, should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status
• Avanafil has systemic vasodilator properties and may augment the blood pressure-lowering effect of anti-hypertensive medications. Avanafil 200 mg resulted in transient decreases in sitting blood pressure in healthy volunteers of 8.0 mmHg systolic and 3.3 mmHg diastolic, with the maximum decrease observed at 1 hour after dosing
• The safety and efficacy of combinations of STENDRA with other treatments for ED has not been studied. Therefore, the use of such combinations is not recommended
• The safety of avanafil is unknown in patients with bleeding disorders and patients with active peptic ulceration. In vitro studies with human platelets indicate that avanafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide [NO] donor)

See also Adverse Effects and Drug-Drug Interactions

Special Populations

Use in Pregnancy: Category C

Sentinel Events

No data

Look-alike / Sound-alike (LA / SA) Error Risk Potential

As part of a Joint Commission standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from three four data sources (Lexi-Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion:

LA/SA for generic name avanafil: sildenafil, tadalafil, vardenafil

LA/SA for trade name STENDRA: None identified

Drug Interactions2

Drug-Drug Interactions

• Organic nitrates, e.g., nitroglycerin. See Contraindications
• Alpha-blockers - caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. See Dose and Administration
• Antihypertensive medications - potentiation of the blood pressure-lowering effects. See Warnings and Precautions
• Substantial consumption of alcohol (e.g., greater than 3 units) in combination with avanafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache
• Use with strong CYP3A4 inhibitors such as ketoconazole and ritonavir will significantly decrease the metabolism and increase exposure of avanafil. Concomitant use is contraindicated
• Use with moderate CYP3A4 inhibitors, e.g., erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil will decrease the metabolism and increase exposure of avanafil. The maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours for patients taking concomitant moderate CYP3A4 inhibitors
• Use with other CYP3A4 substrates is likely todecrease the metabolism and increase exposure of avanafil.
• Use of avanafil with CYP3A4 inducers has not been studied and concomitant use is not recommended.

Acquisition Costs

Refer to VA pricing sources for updated information.

Conclusions

Avanafil is a PDE5 inhibitor that has demonstrated safety and efficacy in the treatment of mild, moderate and severe ED in the general male population, those with diabetes and those post bi-lateral nerve sparing prostatectomy. Although there are no comparative trials to other PDE5 inhibitors, none of the available evidence suggests that avanafil offers a substantial advantage over the other PDE 5 inhibitors.

References

1. VA Drug Class Review: Phosphodiesterase Type 5 Inhibitors with 2011 Addendum. Washington, DC: Pharmacy Benefits Management Services, Medical Advisory Panel and VISN Pharmacist Executives, Veterans Health Administration, Department of Veterans Affairs; March 2011.
2. STENDRA (avanafil) package label, October 2012.
3. Goldstein I, McCullough AR, Jones LA, et al. A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction. J Sex Med 2012;9:1122-33.
4. Goldstein I, Jones LA, Belkoff LH, et al. Avanafil for the treatment of erectile dysfunction: A multicenter, randomized, double-blind study in men with diabetes mellitus. Mayo Clin Proc 2012;87:843-52.
5. Mulhall JP, Burnett AL, Wang R, et al. A phase 3, placebo-controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy. J Urology 213;189:2229-36.

Prepared December 2013. Contact person: Todd Semla, MS, PharmD, BCPS, FCCP, AGSF

Updated version may be found at or / 1