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  • CLASSES

    Erectile Dysfunction Products

    DEA CLASS

    Rx

    DESCRIPTION

    A phosphodiesterase type 5 (PDE5) inhibitor
    Used for erectile dysfunction and taken prior to sexual activity
    As with other PDE5 inhibitors, contraindicated for use with nitrates because the combination can cause a sudden drop in blood pressure

    COMMON BRAND NAMES

    Stendra

    HOW SUPPLIED

    Stendra Oral Tab: 50mg, 100mg, 200mg

    DOSAGE & INDICATIONS

    For the treatment of erectile dysfunction (ED).
    Oral dosage
    Adults

    100 mg PO once daily, approximately 15 minutes before sexual activity. The dose may be increased up to 200 mg PO, approximately 15 minutes before sexual activity or decreased to 50 mg PO, approximately 30 minutes before sexual activity, based on clinical response. Maximum dosing frequency is once daily. 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. A course of 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. Patients refractory to PDE5 inhibitors 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 his partner), and the risks and benefits of other therapies. Second-line treatment options include intracavernous injection and intra-urethral therapy. Follow-up visits for ED patients, regardless of therapy, are necessary to determine whether therapy continues to be effective and whether cardiovascular health has significantly changed.

    Adults receiving potent CYP3A4 inhibitors

    Do not use avanafil.

    Adults receiving moderate CYP3A4 inhibitors (e.g., erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) concomitantly

    Do not exceed 50 mg PO once daily, approximately 30 minutes before sexual activity.

    Adults receiving alpha-blocker therapy concomitantly

    Initiate treatment at lowest dose, 50 mg PO once daily, approximately 30 minutes before sexual activity. Monitor for dose tolerance, due to potential additive effect on blood pressure. Patients should be stable on alpha-blocker therapy prior to initiating ED treatment.

    MAXIMUM DOSAGE

    Adults

    200 mg/day PO; when given with moderate CYP3A4 inhibitors no more than 50 mg/day PO.

    Geriatric

    200 mg/day PO; when given with moderate CYP3A4 inhibitors no more than 50 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. 

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild to moderate hepatic impairment (Child Pugh Class A or B): No dose adjustments necessary.
    Severe hepatic impairment (Child Pugh Class C): No data available; avoid use.

    Renal Impairment

    CrCl 30—89 mL/min: No dose adjustment is necessary for mild to moderate renal impairment.
    CrCl < 30 mL/min: No data available; avoid use in patients with severe renal impairment or renal failure.
     
    Intermittent hemodialysis
    No data available; avoid use.

    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.

    STORAGE

    Stendra:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: 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.

    Nitrate/nitrite therapy

    Avanafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, avanafil may potentiate the hypotensive effects of organic nitrates and nitrites. 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.

    Dialysis, hepatic disease, renal disease, renal failure, renal impairment

    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.

    Non-arteritic anterior ischemic optic neuropathy, retinitis pigmentosa, visual disturbance

    Use avanafil cautiously in patients with pre-existing visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors. 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. Avanafil use should be discontinued in the event of sudden loss of vision in one or both eyes. Avanafil use is not recommended in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. 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.

    Human immunodeficiency virus (HIV) infection

    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.

    Geriatric

    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.

    Hearing impairment, tinnitus

    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.

    Angina, aortic stenosis, cardiac arrhythmias, cardiac disease, coronary artery disease, heart failure, hypertension, hypotension, idiopathic hypertrophic subaortic stenosis, myocardial infarction, stroke

    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.

    Leukemia, multiple myeloma, penile structural abnormality, Peyronie's disease, polycythemia, priapism, sickle cell disease

    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).

    Coagulopathy, peptic ulcer disease

    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.

    Pregnancy

    Avanafil is not indicated for use in females. Avanafil is classified as FDA pregnancy risk category C. There are no adequate and well-controlled trials of avanafil in humans during pregnancy.

    Breast-feeding

    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.

    Children, infants, neonates

    There is no known indication for the use of avanafil in neonates, infants, or children. Avanafil should not be prescribed to these populations.

    ADVERSE REACTIONS

    Severe

    thrombosis / Delayed / 0-1.0
    hearing loss / Delayed / 0-1.0
    non-arteritic anterior ischemic optic neuropathy / Delayed / Incidence not known
    visual impairment / Early / Incidence not known

    Moderate

    hypertension / Early / 1.0-2.0
    constipation / Delayed / 1.0-2.0
    hematuria / Delayed / 0-1.0
    nephrolithiasis / Delayed / 0-1.0
    depression / Delayed / 0-1.0
    angina / Early / 0-1.0
    palpitations / Early / 0-1.0
    hypotension / Rapid / 0-1.0
    orthostatic hypotension / Delayed / 0-1.0
    gastritis / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    dyspnea / Early / 0-1.0
    wheezing / Rapid / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    hypoglycemia / Early / 0-1.0
    peripheral edema / Delayed / 0-1.0
    priapism / Early / Incidence not known
    blurred vision / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known

    Mild

    headache / Early / 5.1-12.1
    flushing / Rapid / 3.2-10.1
    pharyngitis / Delayed / 0.9-5.1
    nasal congestion / Early / 1.0-3.4
    back pain / Delayed / 1.1-3.2
    dizziness / Early / 1.0-2.0
    rash (unspecified) / Early / 1.0-2.0
    dyspepsia / Early / 1.0-2.0
    diarrhea / Early / 1.0-2.0
    nausea / Early / 1.0-2.0
    sinusitis / Delayed / 1.0-2.0
    influenza / Delayed / 1.0-2.0
    arthralgia / Delayed / 1.0-2.0
    increased urinary frequency / Early / 0-1.0
    infection / Delayed / 0-1.0
    urinary urgency / Early / 0-1.0
    drowsiness / Early / 0-1.0
    vertigo / Early / 0-1.0
    insomnia / Early / 0-1.0
    syncope / Early / 0-1.0
    pruritus / Rapid / 0-1.0
    tinnitus / Delayed / 0-1.0
    vomiting / Early / 0-1.0
    gastroesophageal reflux / Delayed / 0-1.0
    abdominal pain / Early / 0-1.0
    cough / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    myalgia / Early / 0-1.0
    muscle cramps / Delayed / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    fatigue / Early / 0-1.0

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: 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.
    Acetaminophen; Butalbital; Caffeine: 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.
    Acetaminophen; Butalbital; Caffeine; Codeine: 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.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Dextromethorphan; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Guaifenesin; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Aliskiren; Amlodipine: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Alpha-blockers: Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Avanafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the 50 mg dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers
    Amiodarone: 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 amiodarone, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Amlodipine: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Amlodipine; Atorvastatin: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Amlodipine; Benazepril: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Amlodipine; Olmesartan: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Amlodipine; Telmisartan: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Amlodipine; Valsartan: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Amobarbital: 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; Lansoprazole: 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 clarithromycin, 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.
    Amoxicillin; Clarithromycin; Omeprazole: 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 clarithromycin, 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. 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.
    Amprenavir: Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Particular caution should be used when prescribing avanafil to patients receiving concomitant moderate CYP3A4 inhibitors including erythromycin, amprenavir, aprepitant, fosaprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil. Moderate CYP3A4 inhibitors may increase plasma concentrations of avanafil. For example, erythromycin 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. Therefore, during coadministration, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours. The effect of weak CYP3A4 inhibitors on avanafil plasma concentrations has not been studied.
    Amyl Nitrite: 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.
    Aprepitant, Fosaprepitant: Use caution if avanafil and aprepitant, fosaprepitant are used concurrently and monitor for an increase in avanafil-related adverse effects for several days after administration of a multi-day aprepitant regimen. 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: 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; Butalbital; Caffeine; Codeine: 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: 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: 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 atazanavir 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.
    Atazanavir; Cobicistat: 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 atazanavir 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. Avoid coadministration of avanafil with cobicistat, as safety and efficacy data are not available. Concurrent use may increase avanafil concentrations.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: 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.
    Barbiturates: 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.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: 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.
    Boceprevir: 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 boceprevir, should not take avanafil.
    Bosentan: 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.
    Bromocriptine: 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 bromocriptine, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Brompheniramine; Carbetapentane; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Butabarbital: 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: Avanafil is primarily metabolized by CYP3A4, and although no studies have been preformed, concomitant administration of CYP3A4 inducers, such as carbamazepine, may decrease avanafil plasma levels. Concomitant use is not recommended.
    Carbetapentane; Chlorpheniramine; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Diphenhydramine; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Guaifenesin; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine; Pyrilamine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbinoxamine; Hydrocodone; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbinoxamine; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlophedianol; Guaifenesin; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chloramphenicol: 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: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Hydrocodone; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Cimetidine: Phosphodiesterase inhibitors are metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Cimetidine is a known inhibitor of hepatic CYP enzymes. Cimetidine (800 mg) caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil 50 mg to healthy volunteers. Population data from patients in clinical trials also indicate a reduction in sildenafil clearance when it was coadministered with cimetidine. If possible, cimetidine use should be avoided in patients who take phosphodiesterase inhibitors
    Clarithromycin: 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 clarithromycin, 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.
    Cobicistat: Avoid coadministration of avanafil with cobicistat, as safety and efficacy data are not available. Concurrent use may increase avanafil concentrations.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Avoid coadministration of avanafil with cobicistat, as safety and efficacy data are not available. Concurrent use may increase avanafil concentrations.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Avoid coadministration of avanafil with cobicistat, as safety and efficacy data are not available. Concurrent use may increase avanafil concentrations.
    Codeine; Phenylephrine; Promethazine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Crizotinib: 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 crizotinib, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Darunavir: Avoid coadministration is avanafil with darunavir, as safety and efficacy data are not available. 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: Avoid coadministration is avanafil with darunavir, as safety and efficacy data are not available. 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. Avoid coadministration of avanafil with cobicistat, as safety and efficacy data are not available. Concurrent use may increase avanafil concentrations.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: 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.
    Dasatinib: 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 dasatinib, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Delavirdine: 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: 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: Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as dexamethasone, may decrease avanafil plasma levels. Concomitant use is not recommended.
    Dextromethorphan; Diphenhydramine; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Dextromethorphan; Guaifenesin; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Diltiazem: Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Particular caution should be used when prescribing avanafil to patients receiving concomitant moderate CYP3A4 inhibitors such as diltiazem. For example, erythromycin 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. Therefore, during coadministration, the maximum recommended adult dose of avanafil is 50 mg, not to exceed once every 24 hours.
    Diphenhydramine; Hydrocodone; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Diphenhydramine; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Doxazosin: Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Avanafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the 50 mg dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers
    Dronedarone: 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: Since the symptoms of orthostasis (e.g., postural hypotension, dizziness and vertigo) are reported more frequently in tamsulosin-treated vs. placebo patients, there is a theoretical risk of enhanced hypotensive effects in individual patients when tamsulosin co-administered with vasodilatory agents such as phosphodiesterase inhibitors. Concurrent use of PDE5 inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. When sildenafil (25 mg) was simultaneously administered with doxazosin (4 mg) to patients with BPH, mean additional reductions in supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic were observed. When higher doses of sildenafil were administered with doxazosin (4 mg), symptomatic postural hypotension within 1 to 4 hours was reported in some patients. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers. The manufacturers for tadalafil and vardenafil state that patients should be stabilized on alpha blocker therapy prior to starting either tadalafil or vardenafil, or if already receiving optimum dose of tadalafil or vardenafil, alpha blocker therapy should be started at the lowest possible dose.
    Efavirenz: 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: 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.
    Elbasvir; Grazoprevir: 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.
    Erythromycin: Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Particular caution should be used when prescribing avanafil to patients receiving concomitant moderate CYP3A4 inhibitors including erythromycin. Moderate CYP3A4 inhibitors may increase plasma concentrations of avanafil. For example, erythromycin 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. Therefore, during coadministration, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours. The effect of weak CYP3A4 inhibitors on avanafil plasma concentrations has not been studied.
    Erythromycin; Sulfisoxazole: Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Particular caution should be used when prescribing avanafil to patients receiving concomitant moderate CYP3A4 inhibitors including erythromycin. Moderate CYP3A4 inhibitors may increase plasma concentrations of avanafil. For example, erythromycin 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. Therefore, during coadministration, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours. The effect of weak CYP3A4 inhibitors on avanafil plasma concentrations has not been studied.
    Ethanol: Both alcohol and PDE5 inhibitors including avanafil act as vasodilators. Concomitant use may attenuate the blood-pressure-lowering effects of each individual compound. Therefore, clinicians should inform patients that substantial consumption of ethanol (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.
    Etravirine: 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.
    Fluconazole: Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Particular caution should be used when prescribing avanafil to patients receiving concomitant moderate CYP3A4 inhibitors including fluconazole. For example, erythromycin 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. Therefore, during coadministration, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours.
    Fluvoxamine: 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: Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Particular caution should be used when prescribing avanafil to patients receiving concomitant moderate CYP3A4 inhibitors including fosamprenavir. Moderate CYP3A4 inhibitors may increase plasma concentrations of avanafil. For example, erythromycin 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. Therefore, during coadministration, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours. The effect of weak CYP3A4 inhibitors on avanafil plasma concentrations has not been studied.
    Fosphenytoin: Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as fosphenytoin, may decrease avanafil plasma levels. Concomitant use is not recommended.
    Glimepiride; Rosiglitazone: 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.
    Grapefruit juice: 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: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Hydralazine; Isosorbide Dinitrate, ISDN: 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.
    Hydrocodone; Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Imatinib, STI-571: 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: 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 indinavir, 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.
    Isavuconazonium: 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: 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 isoniazid, INH, should not take avanafil.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: 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 isoniazid, INH, should not take avanafil. 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: 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 isoniazid, INH, should not take avanafil. 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: 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: 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: 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 itraconazole, 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.
    Ketoconazole: 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 ketoconazole, 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.
    Lanreotide: 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 lanreotide, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Lapatinib: 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 lapatinib, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Lesinurad: Lesinurad may decrease the systemic exposure and therapeutic efficacy of avanafil; monitor for potential reduction in efficacy. Avanafil is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lopinavir; Ritonavir: 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: 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.
    Lumacaftor; Ivacaftor: 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.
    Mephobarbital: 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.
    Metformin; Rosiglitazone: 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.
    Methohexital: 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, RU-486: Coadministration of mifepristone and avanafil may lead to increased serum concentrations of avanafil. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. Avanafil is a primary substrate of CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Mifepristone, RU-486 inhibits CYP3A4 in vitro.
    Mitotane: 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.
    Nefazodone: 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 nefazodone, 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.
    Nelfinavir: 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 nelfinavir, 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.
    Nevirapine: Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as nevirapine, may decrease avanafil plasma levels. Concomitant use is not recommended.
    Nicardipine: 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 nicardipine, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Nifedipine: 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. Nifedipine is a CYP3A4 substrate. Vardenafil did not affect the AUC or Cmax of slow-release nifedipine, which is CYP3A4 substrate, and nifedipine did not alter plasma levels of vardenafil. In patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mm Hg compared to placebo.
    Nitrates: 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: 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: The hypotensive effects of nitroprusside may be augmented by phosphodiesterase inhibitors. Monitor blood pressure when co-administering phosphodiesterase inhibitors and blood pressure lowering medications, like nitroprusside. Phosphodiesterase inhibitors have vasodilatory properties, and nitroprusside is a potent vasodilator. In addition, phosphodiesterase type-5 (PDE5) is found in platelets, and PDE5 inhibitors may potentiate the nitric oxide-mediated platelet anti-aggregatory activity of nitroprusside.
    Octreotide: 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 octreotide, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Ombitasvir; Paritaprevir; Ritonavir: 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.
    Omeprazole: 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; Sodium Bicarbonate: 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: 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: Avanafil is a substrate of and primarily metabolized by CYP3A4. Particular caution should be used when prescribing avanafil to patients receiving concomitant CYP3A4 substrates, such as amlodipine. Coadministration of avanafil with amlodipine increased the Cmax and AUC of avanafil by approximately 22% and 70%, respectively. The half-life of avanafil was prolonged to approximately 10 hrs. The Cmax and AUC of amlodipine decreased by approximately 9% and 4%, respectively. In addition, in a clinical pharmacology trial, additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single avanafil (200 mg) dose with amlodipine compared with placebo. Patients should be monitored carefully and drug dosages should be adjusted based on clinical response.
    Phenobarbital: 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: Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Avanafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the 50 mg dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers
    Phentolamine: Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Avanafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the 50 mg dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers
    Phenylephrine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Phenylephrine; Promethazine: The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Phenytoin: Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as phenytoin, may decrease avanafil plasma levels. Concomitant use is not recommended.
    Posaconazole: 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: Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Avanafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the 50 mg dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers
    Primidone: 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.
    Quinine: 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.
    Rifabutin: 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: 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: Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as rifapentine, may decrease avanafil plasma levels. Concomitant use is not recommended.
    Riociguat: Coadministration of riociguat and phosphodiesterase inhibitors, inlcuding specific phosphodiesterase-5 inhibitors (PDE5 inhibitors, including sildenafil, tadalafil, vardenafil) is contraindicated due to the risk of hypotension. The addition of riociguat to a stable sildenafil regimen (20 mg three times a day) resulted in additive hemodynamic effects in an exploratory interaction study in 7 patients with pulmonary arterial hypertension (PAH). Among patients with PAH on stable sildenafil treatment and riociguat there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension.
    Ritonavir: 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: 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: 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: 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 saquinavir, 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.
    Secobarbital: 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.
    Tamsulosin: Since the symptoms of orthostasis (e.g., postural hypotension, dizziness and vertigo) are reported more frequently in tamsulosin-treated vs. placebo patients, there is a theoretical risk of enhanced hypotensive effects in individual patients when tamsulosin co-administered with vasodilatory agents such as phosphodiesterase inhibitors. Concurrent use of PDE5 inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. When sildenafil (25 mg) was simultaneously administered with doxazosin (4 mg) to patients with BPH, mean additional reductions in supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic were observed. When higher doses of sildenafil were administered with doxazosin (4 mg), symptomatic postural hypotension within 1 to 4 hours was reported in some patients. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers. The manufacturers for tadalafil and vardenafil state that patients should be stabilized on alpha blocker therapy prior to starting either tadalafil or vardenafil, or if already receiving optimum dose of tadalafil or vardenafil, alpha blocker therapy should be started at the lowest possible dose.
    Telaprevir: 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 telaprevir, should not take avanafil.
    Telithromycin: 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 telithromycin, 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.
    Terazosin: Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Avanafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the 50 mg dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers
    Thiopental: 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.
    Ticagrelor: 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: 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.
    Trandolapril; Verapamil: Avanafil is a primary substrate of CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Particular caution should be used when prescribing avanafil to patients receiving concomitant moderate CYP3A4 inhibitors including verapamil. For example, erythromycin 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. Therefore, during coadministration, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours.
    Verapamil: Avanafil is a primary substrate of CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Particular caution should be used when prescribing avanafil to patients receiving concomitant moderate CYP3A4 inhibitors including verapamil. For example, erythromycin 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. Therefore, during coadministration, the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours.
    Vigabatrin: 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.
    Voriconazole: 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 voriconazole, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Zafirlukast: 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.

    PREGNANCY AND LACTATION

    Pregnancy

    Avanafil is not indicated for use in females. Avanafil is classified as FDA pregnancy risk category C. There are no adequate and well-controlled trials of avanafil in humans during pregnancy.

    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.

    MECHANISM OF ACTION

    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 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 compared to other known phosphodiesterases (greater than 100-fold for PDE6; greater than 1,000-fold for PDE4, PDE8 and PDE10; greater than 5,000-fold for PDE2 and PDE7; greater than 10,000-fold for PDE1, PDE3, PDE9, and PDE11). Avanafil has a 100-fold greater affinity for PDE5 than PDE6, which is found in the retina and is responsible for 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. The inhibition of PDE5 in these tissues by avanafil may be the basis for the enhanced platelet anti-aggregatory activity of NO observed in vitro and peripheral vasodilatation in vivo.

    PHARMACOKINETICS

    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: CYP2C2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4
    Avanafil has weak inhibitory effects toward CYP2C8, 2C9, 2C19, 2D6, and 3A4 isoforms.
     

    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—1.25 hours, reducing Cmax by 24%—39% (depending on dose), and decreasing AUC by approximately 3.8%. These changes are not considered clinically significant, thus, avanafil may be administered without regard to food.