Avanafil tablets are a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction in adult males.

Avanafil tablet is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction ( 1)

• The starting dose is 100 mg taken as early as approximately 15 minutes before sexual activity, on an as needed basis ( 2.1)
• Take avanafil tablet no more than once a day ( 2.1).
• Based on efficacy and/or tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity or decreased to 50 mg taken approximately 30 minutes before sexual activity. Use the lowest dose that provides benefit ( 2.1).
• Avanafil tablet may be taken with or without food ( 2.2)
• Do not use avanafil tablet with strong CYP3A4 inhibitors ( 2.3)
• If taking a moderate CYP3A4 inhibitor, the dose should be no more than 50 mg in a 24-hour period ( 2.3).
• In patients on stable alpha-blocker therapy, the recommended starting dose of avanafil tablet is 50 mg ( 2.3).

The recommended starting dose is 100 mg. Avanafil tablets should be taken orally as needed as early as approximately 15 minutes before sexual activity. 

Based on individual efficacy and tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg taken approximately   30 minutes before sexual activity. The lowest dose that provides benefit should be used. 

The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment.

Avanafil tablets may be taken with or without food.

Nitrates

Concomitant use of nitrates in any form is contraindicated [see Contraindications ( 4.1)].

Alpha-Blockers
If avanafil tablet is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating treatment with avanafil tablet, and avanafil tablet should be initiated at the 50 mg dose [see Warnings and Precautions ( 5.6), Drug Interactions ( 7.1) and Clinical Pharmacology ( 12.2)].

CYP3A4 Inhibitors
• For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin), do not use avanafil tablet [see Warnings and Precautions ( 5.2) and Drug Interactions ( 7.2)].
• For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of avanafil tablet is 50 mg, not to exceed once every 24 hours [see Warnings and Precautions ( 5.2) and Drug Interactions ( 7.2)].

• Administration of avanafil tablet to patients using any form of organic nitrate is contraindicated ( 4.1)
• Hypersensitivity to any component of the avanafil tablet ( 4.2)
• Administration with guanylate cyclase (GC) stimulators such as riociguat and vericiguat ( 4.3)

Administration of avanafil tablets with any form of organic nitrates, either regularly and/or intermittently, is contraindicated. Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, avanafil has been shown to potentiate the hypotensive effects of nitrates.

In a patient who has taken avanafil tablets, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil tablets before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring [see Contraindications ( 4.1), Dosage and Administration ( 2.3), and Clinical Pharmacology ( 12.2)].

Avanafil is contraindicated in patients with a known hypersensitivity to any component of the tablet. Hypersensitivity reactions have been reported, including pruritis and eyelid swelling.

Do not use avanafil tablets in patients who are using a GC stimulator, such as riociguat or vericiguat. PDE5 inhibitors, including avanafil tablets may potentiate the hypotensive effects of GC stimulators.

Evaluation of erectile dysfunction (ED) should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.

Before prescribing avanafil, it is important to note the following:

• Patients should not use avanafil if sexual activity is inadvisable due to cardiovascular status or any other reason ( 5.1)
• Use of avanafil with alpha-blockers, other antihypertensives, or substantial amounts of alcohol (greater than 3 units) may lead to hypotension ( 2.3, 5.6, 5.7)
• Patients should seek emergency treatment if an erection lasts greater than 4 hours ( 5.3)
• Patients should stop avanafil and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of Non Arteritic Ischemic Optic Neuropathy (NAION). Avanafil should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a “crowded” optic disc may also be at an increased risk of NAION ( 5.4, 6.2)
• Patients should stop taking avanafil and seek prompt medical attention in the event of sudden decrease or loss of hearing ( 5.5)

There is a potential for cardiac risk during sexual activity in patients with pre-existing cardiovascular disease. Therefore, treatments for ED, including avanafil, should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.

Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of vasodilators, including avanafil.

The following groups of patients were not included in clinical safety and efficacy trials for avanafil, and therefore until further information is available, avanafil is not recommended for the following groups:

• Patients who have suffered a myocardial infarction, stroke, life-threatening arrhythmia, or coronary revascularization within the last 6 months;
• Patients with resting hypotension (blood pressure less than 90/50 mmHg) or hypertension (blood pressure greater than 170/100 mmHg);
• Patients with unstable angina, angina with sexual intercourse, or New York Heart Association Class 2 or greater congestive heart failure.

As with other PDE5 inhibitors avanafil has systemic vasodilatory properties and may augment the blood pressure-lowering effect of other 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 [see Clinical Pharmacology ( 12.2)] , with the maximum decrease observed at 1 hour after dosing. While this normally would be expected to be of little consequence in most patients, prior to prescribing avanafil, physicians should carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.

Avanafil metabolism is principally mediated by the CYP450 isoform 3A4 (CYP3A4). Inhibitors of CYP3A4 may reduce avanafil clearance and increase plasma concentrations of avanafil.

For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin), do not use avanafil [see Drug Interactions ( 7.2)].

For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours [see Drug Interactions ( 7.2)].

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported with other PDE5 inhibitors. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If not treated immediately, penile tissue damage and permanent loss of potency could result.

Avanafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Physicians should advise patients to stop use of all PDE5 inhibitors, including avanafil and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 in males aged ≥ 50.

An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare postmarketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [see Adverse Reactions ( 6.2)].

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including avanafil should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population; however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including avanafil, for this uncommon condition.

Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials for avanafil. and therefore, until further information is available, avanafil is not recommended for use in these patients.

Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus or dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6)] . Patients experiencing these symptoms should be advised to stop taking avanafil and seek prompt medical attention.

Physicians should discuss with patients the potential for avanafil to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications [see Drug Interactions ( 7.1) and Clinical Pharmacology ( 12.2)].

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase type 5 inhibitors, including avanafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).

Consideration should be given to the following:
• Patients should be stable on alpha-blocker therapy prior to initiating treatment with a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose (Avanafil 50 mg).
• In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.

Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs [see Dosage and Administration ( 2) and Drug Interactions ( 7.1)].

Patients should be made aware that both alcohol and PDE5 inhibitors including avanafil act as vasodilators. When vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., greater than 3 units) in combination with avanafil may increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Drug Interactions ( 7.1) and Clinical Pharmacology ( 12.2)].

The safety and efficacy of combinations of avanafil 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 vitrostudies with human platelets indicate that avanafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide [NO] donor).

The use of avanafil offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV), should be considered.

Most common adverse reactions (greater than or equal to 2%) include headache, flushing, nasal congestion, nasopharyngitis, and back pain ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Avanafil was administered to 2215 men during clinical trials. In trials of avanafil for use as needed, a total of 493 patients were exposed for greater than or equal to 6 months, and 153 patients were treated for greater than or equal to 12 months.

In three randomized, double-blind, placebo-controlled trials lasting up to 3 months in duration, the mean age of patients was 56.4 years (range from 23 to 88 years). 83.9% of patients were White, 13.8% were Black, 1.4% Asian, and <1% Hispanic. 41.1% were current or previous smokers. 30.6% had diabetes mellitus.

The discontinuation rate due to adverse reactions for patients treated with avanafil 50 mg, 100 mg, or 200 mg was 1.4%, 2.0%, and 2.0%, respectively, compared to 1.7% for placebo-treated patients.

Table 1 presents the adverse reactions reported when avanafil was taken as recommended (on an as-needed basis) from these 3 clinical trials.

Table 1: Adverse Reactions Reported by Greater Than or Equal to 2% of Patients Treated with Avanafil From 3 Placebo-Controlled Clinical Trials Lasting 3 Months for Avanafil Use as Needed

Adverse reactions reported by greater than or equal to 1%, but less than 2% of patients in any avanafil dose group, and greater than  placebo included: upper respiratory infection (URI), bronchitis, influenza, sinusitis, sinus congestion, hypertension, dyspepsia, nausea, constipation, and rash. 

In an open-label, long-term extension study of two of these randomized, double-blind, placebo-controlled trials, the total duration of treatment was up to 52 weeks. Among the 712 patients who participated in this open-label extension study, the mean age of the population was 56.4 years (range from 23 to 88 years). The discontinuation rate due to adverse reactions for patients treated with avanafil (50 mg, 100 mg, or 200 mg) was 2.8%. 

In this extension trial, all eligible patients were initially assigned to avanafil 100 mg. At any point during the trial, patients could request to have their dose of avanafil increased to 200 mg or decreased to 50 mg based on their individual response to treatment. In total, 536 (approximately 75%) patients increased their dose to 200 mg and 5 (less than 1%) patients reduced their dose to 50 mg.

Table 2 presents the adverse reactions reported when avanafil was taken as recommended (on an as-needed basis) in this open-label extension trial. 

Table 2:  Adverse Reactions Reported by Greater Than or Equal to 2% of Patients Treated With Avanafil in an Open-Label Extension Trial

Adverse reactions reported by greater than or equal to 1%, but less than 2% of patients in the open-label extension study included: upper respiratory infection (URI), influenza, sinusitis, bronchitis, dizziness, back pain, arthralgia, hypertension, and diarrhea. 

The following events occurred in less than 1% of patients in the three placebo-controlled 3-month clinical trials and/or the open-label, long-term extension study lasting 12 months. A causal relationship to avanafil is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use and reports too imprecise to be meaningful. 

Body as a whole — edema peripheral, fatigue 
Cardiovascular — angina, unstable angina, deep vein thrombosis, palpitations 
Digestive — gastritis, gastroesophageal reflux disease, hypoglycemia, blood glucose increased, alanine aminotransferase increased, oropharyngeal pain, stomach discomfort, vomiting
Musculoskeletal — muscle spasms, musculoskeletal pain, myalgia, pain in extremity 
Nervous — depression, insomnia, somnolence, vertigo 
Respiratory — cough, dyspnea exertional, epistaxis, wheezing 
Skin and Appendages — pruritus 
Urogenita l — balanitis, erection increased, hematuria, nephrolithiasis, pollakiuria, urinary tract infection 

In an additional, randomized, double-blind, placebo-controlled study lasting up to 3 months in 298 men who had undergone bilateral nerve-sparing radical prostatectomy for prostate cancer, the mean age of patients was 58.4 years (range 40 to 70). Table 3 presents the adverse reactions reported in this additional study. 

Table 3: Adverse Reactions Reported by Greater than or Equal to 2% of Patients Treated with Avanafil in a Placebo-Controlled Clinical Trial Lasting 3 Months in Patients Who Underwent Bilateral Nerve-Sparing Radical Prostatectomy (Study 3)

A randomized, double-blind, placebo-controlled 2 months study was conducted in 435 subjects with a mean age of 58.2 years (range 24 to 86 years) to determine the time to onset of effect of avanafil, defined as the time to the first occurrence of an erection sufficient for sexual intercourse. Table 4 presents the adverse reactions occurring in ≥ 2% of subjects treated with avanafil. 

Table 4: Adverse Reactions Reported by ≥ 2% of Patients Treated with Avanafil in a Placebo-Controlled Clinical Trial Lasting 2 Months to Determine the Time to Onset of Effect (Study 4)

Across all trials with any avanafil dose, 1 subject reported a change in color vision.

The following adverse reactions have been identified during post approval use of avanafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.

Cardiovascular and cerebrovascular:
Serious cardiovascular and cerebrovascular events, including myocardial infarction, sudden cardiac death, cerebrovascular accident, and subarachnoid hemorrhage, have been reported post-marketing in temporal association with the use of avanafil. All of these patients had preexisting cardiovascular risk factors. The occurrence of sexual activity was not stated in the majority of reports, although events were reported to occur both with and without sexual activity. It is not possible to determine whether these events are related directly to avanafil, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors [see Warnings and Precautions ( 5.1) and Patient Counseling Information ( 17.2)].

Nervous:transient global amnesia

Special senses:

Ophthalmologic:vitreous detachment, visual impairment

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, such as avanafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking [see Warnings and Precautions ( 5.4)].

Otologic:Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, such as avanafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of PDE5 inhibitors such as avanafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions ( 5.5) and Patient Counseling Information ( 17.6)].