Avanafil is an oral phosphodiesterase type 5 (PDE5) inhibitor. It is used for treatment of erectile dysfunction (ED) and is taken prior to anticipated sexual activity. As with other PDE5 inhibitors, avanafil should not be used by men who also take nitrates because the combination can cause a sudden drop in blood pressure that can be dangerous. PDE5 inhibitors are first-line agents for ED according to guidelines. Although associated with high rates of success, approximately 35% of ED patients fail to respond to PDE5 inhibitor therapy. An alternate PDE5 inhibitor may be considered if a patient does not respond to a PDE5 inhibitor trial; a treatment failure may be deemed after at least 4 unsuccessful trials. Those refractory to PDE5 inhibitors for ED should be counseled on appropriate use, potentially modifiable factors (e.g. hormonal abnormalities, food or drug interactions, lack of adequate sexual stimulation, heavy alcohol use, and the patient's relationship with their partner), and the risks and benefits of other therapies. Follow-up visits are necessary to determine whether therapy continues to be effective for ED or if cardiovascular health has significantly changed.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-For erectile dysfunction, may be taken 15 to 30 minutes before sexual activity depending on the dose being prescribed; the maximum dosing frequency is once daily.
-May be administered without regard to meals.
There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) associated with PDE5 inhibitors, such as avanafil. Priapism is considered a medical emergency. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Additional genitourinary (GU) related adverse events reported in less than 1% of patients receiving avanafil in clinical trials include: balanitis, increased erection, hematuria, nephrolithiasis, urinary urgency or increased urinary frequency, and urinary tract infection; a causal relationship to avanafil use could not be determined.
Avanafil safety was evaluated in 3 placebo-controlled trials. Study patients received avanafil as needed for 2 to 3 months at varying doses, 50 mg (n = 217), 100 mg (n = 349), and 200 mg (n = 352). Adverse reactions reported in 2% or more of patients, independent of dose included: headache (5.1% to 10.5%) vs. placebo (1.7%). Headache was also reported among 5.6% of patients receiving avanafil (n = 711) in an open-label extension trial. In a study of men who underwent bilateral nerve-sparing radical prostatectomy, headache was reported in 8.1% to 12.1% of men receiving avanafil; the incidence of headache increased with dose during clinical evaluation. Dizziness was also reported in prostatectomy patients at an incidence of 1% to 2% of treated men and was independent of dose. Additional central nervous system related adverse events reported in less than 1% of patients receiving avanafil in clinical trials include: depression, insomnia, drowsiness (somnolence), and vertigo; a causal relationship to avanafil use could not be determined. In postmarketing experience, transient global amnesia has been reported.
As with other PDE5 inhibitors, avanafil exhibits systemic vasodilatory proprieties and may result in subsequent hypotension. In clinical evaluation, avanafil (200 mg) reduced the sitting blood pressure of healthy subjects by 8 mmHg systolic and 3.3 mmHg diastolic, with the maximum decrease in blood pressure observed at 1 hour after dosing. In most patients, this reduction in blood pressure is transient and is of little clinical consequence. However, patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. Additional lowering of blood pressure by 3 to 5 mmHg can be expected when avanafil is combined with antihypertensive therapies. Syncope, orthostatic hypotension (decrease in standing blood pressure) and other forms of symptomatic hypotension (e.g., dizziness, lightheadedness) appear more likely to occur in patients concomitantly using alpha-blockers or in those patients who consume substantial alcohol during dosing. Hypertension was reported in 1 to 2% of patients in clinical evaluation of avanafil. Additional cardiovascular related adverse events reported in less than 1% of patients receiving avanafil in clinical trials included: angina, unstable angina, deep vein thrombosis, and palpitations; a causal relationship to avanafil use could not be determined. In postmarketing experience with avanafil, myocardial infarction, sudden cardiac death (cardiac arrest), cerebrovascular accident (stroke), and intracranial bleeding (reported as subarachnoid hemorrhage) were reported in patients with pre-existing cardiovascular risk factors. In a placebo-controlled study of men who underwent bilateral nerve-sparing radical prostatectomy, patients received avanafil at varying doses (100 to 200 mg); electrocardiogram (ECG) abnormalities (unspecified) were reported in 1% to 3% of patients vs. none receiving placebo. In clinical evaluation, avanafil administration was not associated with significant QT prolongation at recommended doses. A double-blind, randomized, placebo- and active-controlled (moxifloxacin), thorough QT/QTc trial of avanafil (100 and 800 mg) in healthy male subjects demonstrated that avanafil did not cause any significant changes in QTc interval or ventricular repolarization.
Avanafil safety was evaluated in 3 placebo-controlled trials. Study patients received avanafil as needed for 2 to 3 months at varying doses, 50 mg (n = 217), 100 mg (n = 349), and 200 mg (n = 352). Adverse reactions reported in 2% or more of treated patients included flushing (3.2% to 4.3%). Flushing was also reported among 3.5% of patients receiving avanafil (n=711) in an open-label extension trial. In an additional study of patients with bilateral nerve-sparing radical prostatectomy, flushing occurred in 5.1% to 10.1% of avanafil-treated patients. Rash (unspecified) was also reported in 1 to 2% of patients during clinical trials, and pruritus was reported in less than 1%.
The use of phosphodiesterase type 5 (PDE5) inhibitors may cause visual impairment of various types. Advise patients to stop use of all phosphodiesterase 5 (PDE5) inhibitors, including avanafil and seek medical attention in the event of a sudden visual disturbance in 1 or both eyes. Postmarketing reports with PDE5 inhibitors have included cases of visual disturbances including retinal vein occlusion, visual field defects, reduced visual acuity, vitreous detachment, and loss of vision (temporary or permanent). Patients receiving single oral doses of PDE5 inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. Across all trials with any avanafil dose, 1 patient reported a change in color vision. Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors. It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision (less than 2%) and loss of visual field in 1 or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio ('crowded disc'), age over 50 years, diabetes, high blood pressure, coronary artery disease, hyperlipidemia, and smoking. Additionally, 2 patients had retinal detachment and one patient had hypoplastic optic neuropathy. An observational, case-crossover study evaluated the risk of NAION when PDE5 inhibitor use occurred immediately before NAION onset compared to PDE5 inhibitor use in a prior time period. Results suggest a 2-fold increase in the risk of NAION (risk estimate of 2.15 [95% CI 1.06, 4.34]). A similar study reported consistent results (risk estimate of 2.27 [95% CI 0.99, 5.20]). Other risk factors for NAION may have contributed to the occurrence of NAION in these studies. A causal relationship between PDE5 inhibitor use and the occurrence of NAION cannot be substantiated based on the rare postmarketing reports or these observational studies.
Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing. Twenty-nine reports of sudden changes in hearing including hearing loss or decrease in hearing, usually in 1 ear only, have been reported to the FDA during post-marketing surveillance in patients taking PDE5 inhibitors such as sildenafil, tadalafil, or vardenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Many times, the hearing changes are accompanied by vestibular effects including tinnitus and vertigo. Follow-up has been limited in many of the reports; however, in approximately one-third of the patients, the hearing loss was temporary. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Patients should be instructed to contact their physician if they experience changes in hearing while taking avanafil.
Gastrointestinal (GI) adverse events reported in 1 to 2% of patients in clinical evaluation of avanafil included: dyspepsia, nausea, constipation, and diarrhea. Other GI adverse events reported in less than 1% of patients receiving avanafil in clinical trials include: gastritis, gastroesophageal reflux disease, elevated hepatic enzymes (increased ALT), oropharyngeal pain, abdominal pain (stomach discomfort), and vomiting; a causal relationship to avanafil use could not be determined.
Avanafil safety was evaluated in 3 placebo-controlled trials. Study patients received avanafil as needed for 2 to 3 months at varying doses, 50 mg (n = 217), 100 mg (n = 349), and 200 mg (n = 352). Adverse reactions reported in 2% or more of patients treated with avanafil, independent of dose and at rates higher than with placebo included: nasal congestion (1.8% to 4.1%) and naso-pharyngitis (0.9% to 3.4%). Nasal congestion and naso-pharyngitis were also reported among 2.1% and 3.4% (respectively) of patients receiving avanafil (n = 711) in an open-label extension trial. In an additional study of men with bilateral nerve-sparing radical prostatectomy, avanafil treated patients reported nasal congestion (1% to 3%), naso-pharyngitis (3% to 5.1%), and upper respiratory infection (2% to 3%). Additional respiratory-related adverse events reported in 1% to 2% of patients in clinical trials included: bronchitis, influenza, sinusitis, and sinus congestion; cough, dyspnea exertional, epistaxis, and wheezing were reported in less than 1% of treated patients.
Avanafil safety was evaluated in 3 placebo-controlled trials. Study patients received avanafil as needed for 2 to 3 months at varying doses, 50 mg (n = 217), 100 mg (n = 349), and 200 mg (n = 352). Musculoskeletal adverse reactions reported in 2% or more of treated patients, independent of dose and at higher rates than with placebo included back pain (1.1% to 3.2%); back pain was reported in 1% to 2% of avanafil-treated patients in an open-label extension trial. In a study of men with bilateral nerve-sparing radical prostatectomy, back pain occurred in 2% to 3% of avanafil-treated men. Arthralgia was also reported in 1% to 2% of patients during clinical trials. Additional musculoskeletal related adverse events reported in less than 1% of patients included: muscle cramps, musculoskeletal pain, myalgia, and pain in extremity.
Miscellaneous adverse events reported in less than 1% of patients receiving avanafil in clinical trials include: peripheral edema, fatigue, hypoglycemia, and hyperglycemia. A causal relationship to avanafil use could not be determined.
The safe and effective use of avanafil in combination with other agents for treating erectile dysfunction has not been studied. Therefore, the use of such combinations is not recommended.
Avanafil is contraindicated in individuals who are currently on nitrate/nitrite therapy or those taking guanylate cyclase (GC) stimulators. Review drug interactions. Consistent with its known effects on the nitric oxide/cGMP pathway, avanafil may potentiate the hypotensive effects of organic nitrates, nitrites, and GC stimulators. Patients receiving nitrates in any form are not to receive avanafil. This includes any patient who receives intermittent nitrate therapies. In a life-threatening situation, nitrate therapy should only be considered if at least 12 hours has elapsed since the last dose of avanafil; medical supervision is warranted.
Avanafil tablets are not recommended in patients with severe hepatic disease (Child-Pugh class C) or end stage renal disease requiring dialysis (severe renal impairment or renal failure). There are no controlled clinical studies on the safety and efficacy of avanafil in these patients. Patients with mild to moderate hepatic impairment or mild to moderate renal impairment do not require adjustments in the avanafil dosage. Do not use avanafil if a patient is taking a potent hepatic CYP3A4 inhibitor. The concomitant use of certain moderate hepatic cytochrome P450 3A4 inhibitors may result in a requirement to adjust the avanafil dosage.
Advise patients to stop use of all phosphodiesterase 5 (PDE5) inhibitors, including avanafil, and seek medical attention for evaluation in the event of a sudden visual disturbance in 1 or both eyes. Postmarketing reports with PDE5 inhibitors have included cases of visual disturbances including retinal vein occlusion, visual field defects, reduced visual acuity, and loss of vision (temporary or permanent). Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. This can cause permanent loss of vision; discontinue avanafil in the event of sudden loss of vision in one or both eyes. Patients with a history of NAION are at increased risk for recurrence. Only use a PDE5 inhibitor in these individuals if the anticipated benefit outweighs the risk. Patients with low cup to disc ratio ('crowded disc') are also at increased risk; however, this condition is uncommon, and there is insufficient evidence to support screening of prospective users of a PDE5 inhibitor. Avanafil was not studied in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. Additionally, a minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Avanafil use is not recommended in these patients until further information is available.
Patients should be reminded that avanafil offers no protection against sexually transmitted disease. Counseling of patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, should be considered.
In clinical evaluation of avanafil, approximately 23% of study subjects were 65 years of age and older. Although no differences were observed in the efficacy or safety of avanafil, greater sensitivity to the medication should be considered in some geriatric patients.
Patients with a sudden decrease or loss of hearing (hearing impairment) should stop taking avanafil and seek prompt medical attention. Hearing loss, which may be accompanied by tinnitus and dizziness, has been reported in temporal association with the intake of PDE5 inhibitors; however, it is unknown if the hearing loss is directly related to PDE5 inhibitors or to other factors.
There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. In particular, avanafil use is not recommended in the following patient groups: patients who have suffered a myocardial infarction, stroke, or life-threatening cardiac arrhythmias in the last 6 months; patients with resting hypotension (BP < 90/50) or resting hypertension (BP > 170/110); patients with cardiac disease, New York Heart Association Class 2 or greater heart failure or coronary artery disease (CAD) which causes unstable angina including those with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis). Based on recommendations by the American College of Cardiology for similar medications for ED, it is recommended that avanafil be used with caution in the following: patients with active coronary ischemia who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of avanafil. Avanafil is contraindicated in patients currently on nitrate/nitrite therapy. In addition, the systemic vasodilatory properties of avanafil may augment the hypotensive effects of other anti-hypertensive medications. In clinical evaluation, avanafil (200 mg) reduced the sitting blood pressure of healthy subjects by 8 mmHg systolic and 3.3 mmHg diastolic, with the maximum decrease observed at 1 hour after dosing. Patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.
Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Use avanafil, and other agents for the treatment of erectile dysfunction, with caution in patients with penile structural abnormality (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 disease, leukemia, multiple myeloma, polycythemia, or history of priapism).
Anafanil should be administered to patients with coagulopathy or significant active peptic ulcer disease only after careful benefit vs. risk assessment. In vitro studies with human platelets indicate that anafanil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide [NO] donor). Anafanil has not been studied or administered to patients with bleeding disorders or significant active peptic ulceration.
Avanafil is not indicated for use in females. There are no adequate and well-controlled trials of avanafil in humans during pregnancy. Based on animal data, avanafil is predicted to have a low risk for major developmental abnormalities in humans.
Avanafil is not indicated for use in females and is therefore not recommended during breast-feeding. It is not known if avanafil is excreted in human breast milk.
There is no known indication for the use of avanafil in neonates, infants, or children. Avanafil should not be prescribed to these populations.
For the treatment of erectile dysfunction (ED):
Oral dosage:
Adults: 100 mg PO as needed as early as 15 minutes before anticipated sexual activity. May decrease the dose to 50 mg or increase the dose to 200 mg PO as needed as early as 15 minutes before sexual activity. Max: 1 dose/day and 200 mg/dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Maximum Dosage Limits:
-Adults
200 mg/day PO.
-Geriatric
200 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild to moderate hepatic impairment (Child Pugh Class A or B): No dosage adjustments necessary.
Severe hepatic impairment (Child Pugh Class C): No data available; avoid use.
Patients with Renal Impairment Dosing
CrCl 30 to 89 mL/minute: No dosage adjustment is necessary.
CrCl less than 30 mL/minute: No data available; avoid use in patients with severe renal impairment or renal failure.
Intermittent hemodialysis
No data available; avoid use.
*non-FDA-approved indication
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Acetaminophen; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Acetaminophen; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Adagrasib: (Major) Do not use avanafil in patients receiving adagrasib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of other strong CYP3A inhibitors increased the avanafil AUC by 13-fold.
Alfuzosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alfuzosin therapy before initiating therapy with avanafil at the lowest dose. Conversely, patients already receiving an optimized dose of avanafil should be started on the lowest dose of alfuzosin; increases in the alpha-blocker dose should be done in a stepwise fashion. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of avanafil and alfuzosin.
Alpha-blockers: (Moderate) Concomitant use of avanafil and an alpha-blocker may increase the risk for symptomatic hypotension. To minimize the risk for harm if concomitant use is necessary, optimize the dose of one medication before starting the other, initiate therapy at the lowest recommended dose, and monitor blood pressure. Both medications are vasodilators and may have an additive blood pressure lowering effect when used together.
Amlodipine: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Amlodipine; Atorvastatin: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Amlodipine; Benazepril: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Amlodipine; Celecoxib: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Amlodipine; Olmesartan: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Amlodipine; Valsartan: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Amobarbital: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Concomitant use of avanafil and clarithromycin is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; clarithromycin would be expected to have similar effects. (Minor) Avanafil is a weak inhibitor of CYP2C19 isoenzymes. A single avanafil (200 mg) dose increased the AUC and Cmax of a single omeprazole (40 mg) dose, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively.
Apalutamide: (Major) Coadministration of avanafil with apalutamide is not recommended by the manufacturer of avanafil due to the potential for decreased efficacy. Avanafil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Aprepitant, Fosaprepitant: (Moderate) Use caution if avanafil and a multi-day regimen of oral aprepitant are used concurrently and monitor for an increase in avanafil-related adverse effects for several days after administration. During coadministration of a multi-day aprepitant regimen, the maximum recommended adult dose of avanafil is 50 mg, not to exceed once every 24 hours. Avanafil is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of avanafil. Moderate CYP3A4 inhibitors may increase plasma concentrations of avanafil. For example, erythromycin increased avanafil Cmax and AUC by 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours. The AUC of another CYP3A4 substrate, midazolam (single dose), increased by 2.3-fold on day 1 and by 3.3-fold on day 5 when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. The effect of weak CYP3A4 inhibitors on avanafil plasma concentrations has not been studied.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Aspirin, ASA; Omeprazole: (Minor) Avanafil is a weak inhibitor of CYP2C19 isoenzymes. A single avanafil (200 mg) dose increased the AUC and Cmax of a single omeprazole (40 mg) dose, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively.
Atazanavir: (Major) Concomitant use of avanafil and atazanavir is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; atazanavir is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; atazanavir would be expected to have similar effects.
Atazanavir; Cobicistat: (Major) Concomitant use of avanafil and atazanavir is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; atazanavir is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; atazanavir would be expected to have similar effects. (Major) Do not use avanafil in patients receiving cobicistat due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Barbiturates: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Belzutifan: (Major) Coadministration of avanafil with belzutifan is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and belzutifan is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Berotralstat: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving berotralstat. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Bosentan: (Minor) Avanafil is primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as bosentan, will decrease plasma levels of avanafil, however, no interaction studies have been performed. Concomitant use is not recommended.
Brigatinib: (Major) Coadministration of avanafil with brigatinib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Brompheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Brompheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Butalbital; Acetaminophen: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Butalbital; Acetaminophen; Caffeine: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Butalbital; Acetaminophen; Caffeine; Codeine: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Butalbital; Aspirin; Caffeine; Codeine: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Carbamazepine: (Major) Coadministration of avanafil with carbamazepine is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and carbamazepine is a strong CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Cenobamate: (Major) Coadministration of avanafil with cenobamate is not recommended due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Ceritinib: (Major) Do not use avanafil in patients receiving ceritinib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Chloramphenicol: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including chloramphenicol, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Chlorpheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Ciprofloxacin: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving ciprofloxacin. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate and ciprofloxacin is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Clarithromycin: (Major) Concomitant use of avanafil and clarithromycin is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; clarithromycin would be expected to have similar effects.
Cobicistat: (Major) Do not use avanafil in patients receiving cobicistat due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Codeine; Phenylephrine; Promethazine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Conivaptan: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving conivaptan. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Administration of another moderate CYP3A inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Crizotinib: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving crizotinib. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Dabrafenib: (Major) Avoid the concomitant use of dabrafenib and avanafil; decreased avanafil concentrations and loss of efficacy may occur. Use of an alternative agent is recommended. Dabrafenib is a moderate CYP3A4 inducer and avanafil is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
Darunavir: (Major) Coadministration of avanifil with darunavir is not recommended. Concurrent use may increase avanafil concentrations. Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors, including darunavir, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Darunavir; Cobicistat: (Major) Coadministration of avanifil with darunavir is not recommended. Concurrent use may increase avanafil concentrations. Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors, including darunavir, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day. (Major) Do not use avanafil in patients receiving cobicistat due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of avanifil with darunavir is not recommended. Concurrent use may increase avanafil concentrations. Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors, including darunavir, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day. (Major) Do not use avanafil in patients receiving cobicistat due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Delavirdine: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking strong CYP3A4 inhibitors including delavirdine, should not take avanafil.
Desipramine: (Minor) Avanafil is a weak inhibitor of CYP2D6 isoenzymes. A single avanafil (200 mg) dose increased the AUC and Cmax of a single desipramine (50 mg) dose, a CYP2D6 substrate, by 5.7% and 5.2%, respectively.
Dexamethasone: (Major) Coadministration of avanafil with dexamethasone is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and dexamethasone is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Diltiazem: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving diltiazem. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Doxazosin: (Moderate) Concomitant use of avanafil and an alpha-blocker may increase the risk for symptomatic hypotension. To minimize the risk for harm if concomitant use is necessary, optimize the dose of one medication before starting the other, initiate therapy at the lowest recommended dose, and monitor blood pressure. Both medications are vasodilators and may have an additive blood pressure lowering effect when used together.
Dronedarone: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including dronedarone, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Dutasteride; Tamsulosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on tamsulosin therapy before initiating therapy with the lowest dose of avanafil. Conversely, patients already receiving an optimized dose of avanafil should be started on the lowest dose of tamsulosin; increases in the alpha-blocker dose should be done in a stepwise fashion. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of avanafil and tamsulosin.
Duvelisib: (Major) Do not exceed an avanfil dose of 50 mg once every 24 hours during coadministration with duvelisib as avanafil serum conentrations may be increased. Avanafil is a substrate of and primarily metabolized by CYP3A4; duvelisib is a moderate inhibitor of CYP3A4. In drug interaction studies, another moderate CYP3A inhibitor increased avanafil Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours.
Efavirenz: (Moderate) Avanafil is a substrate of and primarily metabolized by CYP3A4. Efavirenz is an inducer of CYP3A4; coadministration may result in decreased avanafil concentrations. The concomitant use of avanafil and CYP inducers is not recommended.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Avanafil is a substrate of and primarily metabolized by CYP3A4. Efavirenz is an inducer of CYP3A4; coadministration may result in decreased avanafil concentrations. The concomitant use of avanafil and CYP inducers is not recommended.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Avanafil is a substrate of and primarily metabolized by CYP3A4. Efavirenz is an inducer of CYP3A4; coadministration may result in decreased avanafil concentrations. The concomitant use of avanafil and CYP inducers is not recommended.
Elagolix: (Major) Coadministration of avanafil with elagolix is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Elagolix; Estradiol; Norethindrone acetate: (Major) Coadministration of avanafil with elagolix is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Elbasvir; Grazoprevir: (Major) Administering avanafil with grazoprevir may result in elevated avanafil plasma concentrations. Avanafil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Do not use avanafil in patients receiving cobicistat due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not use avanafil in patients receiving cobicistat due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Enasidenib: (Major) Coadministration of avanafil with enasidenib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and enasidenib is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Encorafenib: (Major) Coadministration of avanafil with encorafenib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and encorafenib is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Enzalutamide: (Major) Coadministration of avanafil with enzalutamide is not recommended by the manufacturer of avanafil due to the potential for decreased efficacy. Avanafil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations of avanafil may decrease.
Erythromycin: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving erythromycin. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor. Coadministration with erythromycin increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Ethanol: (Major) 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. Both alcohol and PDE5 inhibitors including avanafil act as vasodilators. Concomitant use may attenuate the blood-pressure-lowering effects of each individual compound.
Etravirine: (Moderate) The concomitant use of avanafil and etravirine is not recommended. Coadministration may result in decreased avanafil concentrations. Avanafil is a substrate of and primarily metabolized by CYP3A4. Etravirine is an inducer of CYP3A4.
Fedratinib: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving fedratinib. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Fluconazole: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving fluconazole. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Fluvoxamine: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including fluvoxamine, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Fosamprenavir: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving fosamprenavir. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A substrate; fosamprenavir is a moderate CYP3A inhibitor. Administration of another moderate CYP3A inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Fosphenytoin: (Major) Coadministration of avanafil with fosphenytoin is not recommended due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and fosphenytoin is a strong CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Glycerol Phenylbutyrate: (Major) Coadministration of avanafil with glycerol phenylbutyrate is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Grapefruit juice: (Moderate) Avanafil serum concentrations may increase with concurrent consumption of grapefruit juice and grapefruit-containing foods; it is possible that avanafil-induced side effects could also be increased in some individuals, although this specific interaction have not been studied. Avanafil is a primary substurate of CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Grapefruit juice has been reported to decrease the metabolism of drugs metabolized via this enzyme. Grapefruit juice contains a furano-coumarin compound, 6,7dihydroxybergamottin that inhibits CYP3A4 in enterocytes in the GI tract.
Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Hydralazine; Isosorbide Dinitrate, ISDN: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Idelalisib: (Major) Avoid the concomitant use of idelalisib and avanafil; significantly increased avanafil exposure may occur resulting in avanafil-related adverse events. Idelalisib is a strong CYP3A4 inhibitor and avanafil is a sensitive CYP3A substrate. Coadministration with other strong CYP3A4 inhibitors increased exposure to avanafil by 13-fold.
Imatinib: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including imatinib, STI-571, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Indinavir: (Major) Concomitant use of avanafil and indinavir is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; indinavir is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; indinavir would be expected to have similar effects.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with avanafil may result in increased serum concentrations of avanafil. Avanafil is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as rifampin, may decrease avanafil plasma levels. Concomitant use is not recommended.
Isoniazid, INH; Rifampin: (Minor) Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as rifampin, may decrease avanafil plasma levels. Concomitant use is not recommended.
Isosorbide Dinitrate, ISDN: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Isosorbide Mononitrate: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Itraconazole: (Contraindicated) Avanafil is contraindicated for use during and for 2 weeks after itraconazole therapy. Use of these drugs together increases avanafil serum concentrations and may result in serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; itraconazole is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; itraconazole would be expected to have similar effects.
Ivosidenib: (Major) Coadministration of avanafil with ivosidenib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and ivosidenib is a CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Ketoconazole: (Major) Do not use avanafil in patients receiving ketoconazole due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the avanafil AUC by 13-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Concomitant use of avanafil and clarithromycin is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; clarithromycin would be expected to have similar effects.
Lefamulin: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving oral lefamulin. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Lenacapavir: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving lenacapavir. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A substrate; lenacapavir is a moderate CYP3A inhibitor. Administration of another moderate CYP3A inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Letermovir: (Major) Do not exceed an avanafil dose of 50 mg every 24 hours when administered concurrently with letermovir due to increased avanafil exposure. Concurrent use should be avoided if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. Avanafil is a sensitive substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The AUC of avanafil was increased by approximately 3-fold in the presence of a moderate CYP3A4 inhibitor and by 13-fold with a strong inhibitor.
Levamlodipine: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Levoketoconazole: (Major) Do not use avanafil in patients receiving ketoconazole due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the avanafil AUC by 13-fold.
Lonafarnib: (Major) Do not use avanafil in patients receiving lonafarnib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Lopinavir; Ritonavir: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking strong CYP3A4 inhibitors such as ritonavir, should not take avanafil. For example, ketoconazole increased avanafil AUC and Cmax equal to 13-fold and 3-fold, respectively and prolonged the half-life of avanafil to approximately 9 hours. Likewise, coadministration of ritonavir with avanafil resulted in an approximate 13-fold increase in AUC and 2.4-fold increase in Cmax of avanafil. Therefore, concomitant use with strong CYP3A4 inhibitors is not recommended.
Lorcaserin: (Moderate) Lorcaserin is a serotonin 2C receptor agonist, and priapism is a potential effect of 5-HT2C receptor agonism. Because there is little experience with the combination of lorcaserin and medications indicated for erectile dysfunction (e.g., phosphodiesterase inhibitors), combined use should be approached with caution.
Lorlatinib: (Major) Coadministration of avanafil with lorlatinib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and lorlatinib is a CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of avanafil by decreasing its systemic exposure; concomitant use is not recommended. Avanafil is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of avanafil by decreasing its systemic exposure; concomitant use is not recommended. Avanafil is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
Mavacamten: (Major) Coadministration of avanafil with mavacamten is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and mavacamten is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Meropenem: (Major) Coadministration of avanafil with meropenem is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and meropenem is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Meropenem; Vaborbactam: (Major) Coadministration of avanafil with meropenem is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and meropenem is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Methohexital: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Mifepristone: (Major) Do not use avanafil in patients receiving mifepristone due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Mitapivat: (Major) Coadministration of avanafil with mitapivat is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and mitapivat is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Mitotane: (Major) The concomitant use of mitotane with avanafil is not recommended; if coadministration cannot be avoided, monitor for decreased efficacy of avanafil. Mitotane is a strong CYP3A4 inducer and avanafil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of avanafil. The potential effect of CYP inducers on avanafil has not been evaluated.
Mobocertinib: (Major) Coadministration of avanafil with mobocertinib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and mobocertinib is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Nefazodone: (Major) Concomitant use of avanafil and nefazodone is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; nefazodone is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; nefazodone would be expected to have similar effects.
Nelfinavir: (Major) Concomitant use of avanafil and nelfinavir is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; nelfinavir is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; nelfinavir would be expected to have similar effects.
Nevirapine: (Major) Coadministration of avanafil with nevirapine is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and nevirapine is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
NIFEdipine: (Moderate) Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. For example, in patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 3 to 4 mmHg (age group 65 to 69 years) and 5 to 6 mmHg (age group 70 to 80 years) compared to placebo.
Nirmatrelvir; Ritonavir: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking strong CYP3A4 inhibitors such as ritonavir, should not take avanafil. For example, ketoconazole increased avanafil AUC and Cmax equal to 13-fold and 3-fold, respectively and prolonged the half-life of avanafil to approximately 9 hours. Likewise, coadministration of ritonavir with avanafil resulted in an approximate 13-fold increase in AUC and 2.4-fold increase in Cmax of avanafil. Therefore, concomitant use with strong CYP3A4 inhibitors is not recommended. (Major) Consider temporary discontinuation of avanafil during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase avanafil exposure resulting in increased toxicity. Avanafil is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
Nirogacestat: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving nirogacestat. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Administration of another moderate CYP3A inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Nitrates: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Nitroglycerin: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Nitroprusside: (Contraindicated) Concomitant use of nitroprusside and avanafil is contraindicated due to the risk of additive hypotension. If the patient has taken avanafil, at least 12 hours must elapse before nitroprusside administration is considered; monitor hemodynamics closely. In addition, avanafil may potentiate the nitric oxide-mediated platelet anti-aggregatory effect of nitroprusside.
Odevixibat: (Major) Coadministration of avanafil with odevixibat is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and odevixibat is a weak CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Olutasidenib: (Major) Coadministration of avanafil with olutasidenib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and olutasidenib is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Omaveloxolone: (Major) Coadministration of avanafil with omaveloxolone is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and omaveloxolone is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Omeprazole: (Minor) Avanafil is a weak inhibitor of CYP2C19 isoenzymes. A single avanafil (200 mg) dose increased the AUC and Cmax of a single omeprazole (40 mg) dose, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively.
Omeprazole; Amoxicillin; Rifabutin: (Minor) Avanafil is a weak inhibitor of CYP2C19 isoenzymes. A single avanafil (200 mg) dose increased the AUC and Cmax of a single omeprazole (40 mg) dose, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively. (Minor) Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as rifabutin, may decrease avanafil plasma levels. Concomitant use is not recommended.
Omeprazole; Sodium Bicarbonate: (Minor) Avanafil is a weak inhibitor of CYP2C19 isoenzymes. A single avanafil (200 mg) dose increased the AUC and Cmax of a single omeprazole (40 mg) dose, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively.
Pentobarbital: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Perindopril; Amlodipine: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Pexidartinib: (Major) Coadministration of avanafil with pexidartinib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and pexidartinib is a CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Phenobarbital: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Phenoxybenzamine: (Moderate) Concomitant use of avanafil and an alpha-blocker may increase the risk for symptomatic hypotension. To minimize the risk for harm if concomitant use is necessary, optimize the dose of one medication before starting the other, initiate therapy at the lowest recommended dose, and monitor blood pressure. Both medications are vasodilators and may have an additive blood pressure lowering effect when used together.
Phentolamine: (Moderate) Concomitant use of avanafil and an alpha-blocker may increase the risk for symptomatic hypotension. To minimize the risk for harm if concomitant use is necessary, optimize the dose of one medication before starting the other, initiate therapy at the lowest recommended dose, and monitor blood pressure. Both medications are vasodilators and may have an additive blood pressure lowering effect when used together.
Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Phenytoin: (Major) Coadministration of avanafil with phenytoin is not recommended due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Posaconazole: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including posaconazole, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Prazosin: (Moderate) Concomitant use of avanafil and an alpha-blocker may increase the risk for symptomatic hypotension. To minimize the risk for harm if concomitant use is necessary, optimize the dose of one medication before starting the other, initiate therapy at the lowest recommended dose, and monitor blood pressure. Both medications are vasodilators and may have an additive blood pressure lowering effect when used together.
Primidone: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Promethazine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together.
Quinine: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including quinine, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Repotrectinib: (Major) Coadministration of avanafil with repotrectinib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and repotrectinib is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Ribociclib: (Major) Do not use avanafil in patients receiving ribociclib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Ribociclib; Letrozole: (Major) Do not use avanafil in patients receiving ribociclib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Rifabutin: (Minor) Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as rifabutin, may decrease avanafil plasma levels. Concomitant use is not recommended.
Rifampin: (Minor) Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as rifampin, may decrease avanafil plasma levels. Concomitant use is not recommended.
Rifapentine: (Major) Coadministration of avanafil with rifapentine is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Riociguat: (Contraindicated) Use of riociguat and avanafil is contraindicated due to the risk of hypotension. Discontinue riociguat at least 24 hours prior to avanafil administration. Monitor for signs and symptoms of hypotension during transition of therapy. PDE5 inhibitors, including avanafil, may potentiate the hypotensive effects of riociguat.
Ritlecitinib: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving ritlecitinib. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A substrate; ritlecitinib is a moderate CYP3A inhibitor. Administration of another moderate CYP3A inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Ritonavir: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking strong CYP3A4 inhibitors such as ritonavir, should not take avanafil. For example, ketoconazole increased avanafil AUC and Cmax equal to 13-fold and 3-fold, respectively and prolonged the half-life of avanafil to approximately 9 hours. Likewise, coadministration of ritonavir with avanafil resulted in an approximate 13-fold increase in AUC and 2.4-fold increase in Cmax of avanafil. Therefore, concomitant use with strong CYP3A4 inhibitors is not recommended.
Rosiglitazone: (Minor) Avanafil is a weak inhibitor of CYP2C8 isoenzymes. A single avanafil (200 mg) dose increased AUC by 2% and decreased Cmax by 14% of a single rosiglitazone (8 mg) dose, a CYP2C8 substrate.
Sapropterin: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
Saquinavir: (Major) Concomitant use of avanafil and saquinavir is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; saquinavir is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; saquinavir would be expected to have similar effects.
Secobarbital: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Silodosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on silodosin therapy before initiating therapy with the lowest dose of avanafil. Conversely, patients already receiving an optimized dose of avanafil should be started on the lowest dose of silodosin; increases in the alpha-blocker dose should be done in a stepwise fashion. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of avanafil and silodosin.
Sodium Phenylbutyrate; Taurursodiol: (Major) Coadministration of avanafil with taurursodiol is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and taurursodiol is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Sotorasib: (Major) Coadministration of avanafil with sotorasib is not recommended due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
St. John's Wort, Hypericum perforatum: (Major) Coadministration of avanafil with St. John's Wort is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and St. John's Wort is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Stiripentol: (Moderate) Consider a dose adjustment of avanafil when coadministered with stiripentol. Coadministration may alter plasma concentrations of avanafil resulting in an increased risk of adverse reactions and/or decreased efficacy. Avanafil is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Tamsulosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on tamsulosin therapy before initiating therapy with the lowest dose of avanafil. Conversely, patients already receiving an optimized dose of avanafil should be started on the lowest dose of tamsulosin; increases in the alpha-blocker dose should be done in a stepwise fashion. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of avanafil and tamsulosin.
Telmisartan; Amlodipine: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Telotristat Ethyl: (Major) Coadministration of avanafil with telotristat is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and telotristat is a weak CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Terazosin: (Moderate) Concomitant use of avanafil and an alpha-blocker may increase the risk for symptomatic hypotension. To minimize the risk for harm if concomitant use is necessary, optimize the dose of one medication before starting the other, initiate therapy at the lowest recommended dose, and monitor blood pressure. Both medications are vasodilators and may have an additive blood pressure lowering effect when used together.
Ticagrelor: (Contraindicated) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including ticagrelor, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Tipranavir: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking strong CYP3A4 inhibitors including tipranavir, should not take avanafil.
Tovorafenib: (Major) Coadministration of avanafil with tovorafenib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and tovorafenib is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Trandolapril; Verapamil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving verapamil. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Tucatinib: (Major) Do not use avanafil in patients receiving tucatinib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Verapamil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving verapamil. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Vericiguat: (Contraindicated) Use of vericiguat and avanafil is contraindicated due to the risk of hypotension. Monitor for signs and symptoms of hypotension during transition of therapy. PDE5 inhibitors, including avanafil, may potentiate the hypotensive effects of vericiguat.
Vigabatrin: (Major) Vigabatrin should not be used with phosphodiesterase inhibitors, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Concomitant use of avanafil and clarithromycin is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; clarithromycin would be expected to have similar effects.
Voriconazole: (Major) Do not use avanafil in patients receiving voriconazole due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Voxelotor: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving voxelotor. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A substrate; voxelotor is a moderate CYP3A inhibitor. Administration of another moderate CYP3A inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Zafirlukast: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including zafirlukast, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Zanubrutinib: (Major) Coadministration of avanafil with zanubrutinib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and zanubrutinib is a CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Avanafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 (PDE5) is responsible for degradation of cGMP in the corpus cavernosum. Avanafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Avanafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. In vitro studies show that avanafil is selective for PDE5, with a greater effect on PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. 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.
Avanafil is administered orally. The drug is approximately 99% bound to plasma proteins. It is predominately metabolized by hepatic cytochrome P450 (CYP) enzymes. CYP3A4 is the major metabolizing enzyme and CYP2C is a minor one. In vitro, an active metabolite (M4), has been found to have 18% of the inhibitory potency for PDE5 of that of the parent drug and accounts for approximately 4% of the pharmacologic activity of avanafil. Avanafil is excreted as metabolites; approximately 62% and 21% of the dose appears in the feces and urine, respectively. The half-life is approximately 5 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2D6
For patients taking concomitant strong CYP3A4 inhibitors, avanafil use is contraindicated. When used with concomitant moderate CYP3A4 inhibitors, an avanafil dose reduction is necessary. Avanafil has weak inhibitory effects toward CYP2C8, 2C9, 2C19, 2D6, and 3A4 isoforms.
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, avanafil exhibits a median Tmax of 30 to 45 minutes in the fasted state. A high fat meal reduces avanafil drug exposure, delaying Tmax to 1.12 to 1.25 hours, reducing Cmax by 24% to 39% (depending on dose), and decreasing AUC by approximately 3.8%. These changes are not considered clinically significant. Avanafil may be administered without regard to food or meals.
-Special Populations
Hepatic Impairment
The pharmacokinetics of avanafil have been studied in patients with mild and moderate hepatic impairment. Avanafil exposure was similar after a single avanafil (200 mg) dose in normal subjects compared to patients with mild hepatic impairment (Child-Pugh Class A). Avanafil Cmax was approximately 51% lower and AUC was 11% higher in patients with moderate hepatic impairment (Child Pugh Class B) compared to subjects with normal hepatic function; however, dose adjustments are not considered necessary. The pharmacokinetics of avanafil in patients with severe hepatic disease have not been studied, therefore, avanafil should not be used in such patients.
Renal Impairment
The pharmacokinetics of avanafil have been studied in patients with mild and moderate renal impairment. Avanafil exposure was similar after a single avanafil (200 mg) dose in patients with normal subjects compared to patients with mild to moderate renal impairment (CrCl 30 to 89 mL/minute). The pharmacokinetics of avanafil in patients with severe renal disease or on renal dialysis have not been studied; therefore, avanafil should not be used in such patients.
Geriatric
The pharmacokinetics of a single avanafil (200 mg) dose in older adult subjects (65 to 80 years) was compared to younger adult subjects (18 to 43 years). Drug exposure was not significantly affected by age in these patients. The AUC increased by 6.8% and Cmax decreased by 2.1% in the older adult group, compared to younger adults.