avanafil 100 MG Oral Tablet

INDICATIONS AND USAGE 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 )

DOSAGE AND ADMINISTRATION • 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 ). 2.1 Erectile Dysfunction 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. 2.2 Use with Food Avanafil tablets may be taken with or without food. 2.3 Concomitant Medications 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 )].

WARNINGS AND PRECAUTIONS 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 ) 5.1 Cardiovascular Risk 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. 5.2 Concomitant Use of CYP3A4 Inhibitors 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 )]. 5.3 Prolonged Erection 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). 5.4 Effects on Eye 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. 5.5 Sudden Hearing Loss 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. 5.6 Alpha-Blockers and Other Antihypertensives 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

CONTRAINDICATIONS • 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 ) 4.1 Nitrates 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 )]. 4.2 Hypersensitivity Reactions 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. 4.3 Concomitant Guanylate Cyclase (GC) Stimulators 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.

Mechanism of Action The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cGMP, producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Avanafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting PDE5, which is responsible for degradation of cGMP in the corpus cavernosum. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation. Studies in vitro have shown that avanafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (greater than 100-fold for PDE6; greater than 1,000-fold for PDE4, PDE8 and PDE10; greater than 5,000-fold for PDE2 and PDE7; greater than 10,000-fold for PDE1, PDE3, PDE9, and PDE11). Avanafil is greater than 100-fold more potent for PDE5 than PDE6, which is found in the retina and is responsible for phototransduction. In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in these tissues by avanafil may be the basis for the enhanced platelet anti-aggregatory activity of NO observed in vitro and peripheral vasodilatation in vivo .