AVANAFIL Drug Interactions: What You Need to Know
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Drug Interactions (FDA Label)
INTERACTIONS
- Avanafil can potentiate the hypotensive effect of nitrates, alpha-blockers, antihypertensives, and alcohol ( 7.1 )
- CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, erythromycin) increase avanafil exposure ( 7.2 )
7.1 Potential for Pharmacodynamic Interactions with Avanafil Nitrates Administration of avanafil to patients who are using any form of organic nitrate, is contraindicated. In a clinical pharmacology trial, avanafil was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken avanafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring <span class="opacity-50 text-xs">[see Contraindications ( 4.1 ), Dosage and Administration ( 2.3 ), and Clinical Pharmacology ( 12.2 )]</span>. Alpha-Blockers Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 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) <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 ), Dosage and Administration ( 2.3 ), and Clinical Pharmacology ( 12.2 )]</span>. Antihypertensives PDE5 inhibitors, including avanafil, are mild systemic vasodilators. A clinical pharmacology trial was conducted to assess the effect of avanafil on the potentiation of the blood pressure-lowering effects of selected antihypertensive medications (amlodipine and enalapril). Additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single 200 mg dose of avanafil with these agents compared with placebo <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.2 )]</span>.
Alcohol
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. 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 [see Clinical Pharmacology ( 12.2 )].
7.2 Potential for Other Drugs to Affect Avanafil Avanafil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Strong CYP3A4 Inhibitors Ketoconazole (400 mg daily), a selective and strong inhibitor of CYP3A4, increased avanafil 50 mg single-dose systemic exposure (AUC) and maximum concentration (C max) equal to 13-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 9 hours. Other potent inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir and telithromycin) would be expected to have similar effects. Do not use avanafil in patients taking strong CYP3A4 inhibitors <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 ) and Dosage and Administration ( 2.3 )]</span>.
Hiv
Protease inhibitor — Ritonavir (600 mg twice daily), a strong CYP3A4 inhibitor, which also inhibits CYP2C9, increased avanafil 50 mg single-dose C max and AUC equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 9 hours in healthy volunteers. Do not use avanafil in patients taking ritonavir. Moderate CYP3A4 Inhibitors Erythromycin (500 mg twice daily) increased avanafil 200 mg single-dose C max and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours in healthy volunteers. Moderate CYP3A4 inhibitors (e.g., erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. Consequently, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours for patients taking concomitant moderate CYP3A4 inhibitors [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.2 )]. Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice are likely to increase avanafil exposure. Weak CYP3A4 Inhibitors No in vivo drug-drug interaction studies with weak CYP3A4 inhibitors were conducted. CYP3A4 Substrate When administered with avanafil 200 mg, amlodipine (5 mg daily) increased the C max and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The C max and AUC of amlodipine decreased by approximately 9% and 4%, respectively [see Dosage and Administration ( 2.3 )]. Cytochrome P450 Inducers The potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated. The concomitant use of avanafil and CYP inducers is not recommended.
Contraindications
4 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 <span class="opacity-50 text-xs">[see Contraindications ( 4.1 ), Dosage and Administration ( 2.3 ), and Clinical Pharmacology ( 12.2 )]</span>.
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.
Related 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span>. 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span>.
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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )]</span>. 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 )].