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Avanafil

Pronunciation

(a VAN a fil)

Index Terms

  • Stendra

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Stendra: 50 mg, 100 mg, 200 mg

Brand Names: U.S.

  • Stendra

Pharmacologic Category

  • Phosphodiesterase-5 Enzyme Inhibitor

Pharmacology

Does not directly cause penile erections, but affects the response to sexual stimulation. The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation and inflow of blood to the corpus cavernosum. Avanafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE-5), which is responsible for degradation of cGMP in the corpus cavernosum; when sexual stimulation causes local release of NO, inhibition of PDE-5 by avanafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum; at recommended doses, it has no effect in the absence of sexual stimulation.

Absorption

Rapid

Metabolism

Hepatic via CYP3A4 (major), CYP2C (minor); forms metabolites (active and inactive)

Excretion

Feces (~62%); urine (~21%)

Time to Peak

Plasma: 30 to 45 minutes (fasting); 1.12 to1.25 hours (high-fat meal)

Half-Life Elimination

Terminal: ~5 hours

Protein Binding

~99%

Special Populations: Renal Function Impairment

In mild renal impairment, AUC0-inf decreased by 2.9%and Cmax increased by 2.8%; in moderate renal impairment, AUC0-inf increased by 9.1% and Cmax decreased by 2.8%.

Special Populations: Hepatic Function Impairment

In mild hepatic impairment, AUC0-inf increased by 3.8% and Cmax decreased by 2.7%; in moderate hepatic impairment, AUC0-inf increased by 11.2% and Cmax decreased by 51%.

Special Populations: Elderly

AUC0-inf increased by 6.8% and Cmax decreased by 2.1%.

Use: Labeled Indications

Erectile dysfunction: Treatment of erectile dysfunction

Contraindications

Hypersensitivity to avanafil or any component of the formulation; coadministration with any form of organic nitrates (either regularly and/or intermittently) or guanylate cyclase stimulators (eg, riociguat)

Dosing: Adult

Erectile dysfunction: Oral: Initial: 100 mg taken ~15 minutes prior to sexual activity; taken as one single dose and not more than once daily; dose may be increased to 200 mg ~15 minutes prior to sexual activity or decreased to 50 mg ~30 minutes prior to sexual activity using the lowest dose that provides benefit; maximum 200 mg daily

Dosing adjustment with concomitant medications:

Alpha-blocker (dose should be stable at time of avanafil initiation): Initial avanafil dose: 50 mg taken as one single dose and not more than once daily.

Moderate CYP34A inhibitors (including amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil): Maximum avanafil dose: 50 mg taken as one single dose and not more than once daily.

Strong CYP3A4 inhibitors (including atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, saquinavir, ritonavir, telithromycin): Avoid concomitant use of avanafil.

Dosing: Geriatric

Elderly ≥65 years: Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Has not been studied; use is not recommended by the manufacturer.

ESRD requiring hemodialysis: Has not been studied; use is not recommended by the manufacturer.

Dosing: Hepatic Impairment

Mild-to-moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe hepatic impairment (Child-Pugh class C): Has not been studied; use is not recommended by the manufacturer.

Administration

May be administered with or without food, ~15 to 30 minutes prior to sexual activity.

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted to 30°C (86°F). Protect from light.

Drug Interactions

Alcohol (Ethyl): May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Monitor therapy

Alpha1-Blockers: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Alpha1-Blockers. Management: Ensure patient is stable on one agent prior to initiating the other, and always initiate combination using the lowest possible dose of the drug being added. When tadalafil is used for treatment of BPH, concurrent alpha 1-blockers are not recommended. Consider therapy modification

Alprostadil: Phosphodiesterase 5 Inhibitors may enhance the adverse/toxic effect of Alprostadil. Avoid combination

Amyl Nitrite: Phosphodiesterase 5 Inhibitors may enhance the vasodilatory effect of Amyl Nitrite. Avoid combination

Blood Pressure Lowering Agents: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bosentan: May decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Phosphodiesterase 5 Inhibitors may increase the serum concentration of Bosentan. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Avanafil. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the orthostatic hypotensive effect of Phosphodiesterase 5 Inhibitors. Avoid combination

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Etravirine: May decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Management: No empiric dosage adjustments are recommended with concomitant therapy; however, dose of the phosphodiesterase inhibitor may need to be altered based on clinical response. Monitor therapy

Fluconazole: May increase the serum concentration of Avanafil. Management: Limit avanafil to a maximum dose of 50 mg per 24-hour period in any patient who is also receiving a moderate inhibitor of CYP3A4 such as fluconazole. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Itraconazole: May increase the serum concentration of Avanafil. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Avanafil. Avoid combination

Lorcaserin: May enhance the adverse/toxic effect of Phosphodiesterase 5 Inhibitors. Specifically, the risk of developing priapism may be increased. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Avoid combination

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the adverse/toxic effect of other Phosphodiesterase 5 Inhibitors. Avoid combination

Posaconazole: May increase the serum concentration of Avanafil. Avoid combination

Riociguat: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Riociguat. Avoid combination

Sapropterin: May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of Phosphodiesterase 5 Inhibitors. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Vasodilators (Organic Nitrates): Phosphodiesterase 5 Inhibitors may enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Avoid combination

Voriconazole: May increase the serum concentration of Avanafil. Avoid combination

Adverse Reactions

>10%: Central nervous system: Headache (1% to 12%)

2% to 10%:

Cardiovascular: Flushing (3% to 10%), ECG abnormality (1% to 3%)

Central nervous system: Dizziness (1% to 2%)

Gastrointestinal: Viral gastroenteritis (≤2%)

Neuromuscular & skeletal: Back pain (1% to 3%)

Respiratory: Nasopharyngitis (1% to 5%), nasal congestion (1% to 3%), upper respiratory tract infection (1% to 3%)

<2% (Limited to important or life-threatening): Angina pectoris, anterior ischemic optic neuropathy (nonarteritic), balanitis, deep vein thrombosis, depression, gastritis, gastroesophageal reflux disease, hearing loss, hematuria, hyperglycemia, hypertension, hypoglycemia, hypotension, increased serum ALT, myalgia, nausea, nephrolithiasis, palpitations, peripheral edema, pollakiuria, priapism, skin rash, urinary tract infection, vision color changes, vision loss (temporary or permanent), wheezing

Warnings/Precautions

Concerns related to adverse effects:

• Color discrimination: May cause dose-related impairment of color discrimination. Use caution in patients with retinitis pigmentosa; a minority have genetic disorders of retinal phosphodiesterases (no safety information available).

• Hearing loss: Sudden decrease or loss of hearing has been reported rarely; hearing changes may be accompanied by tinnitus and dizziness. A direct relationship between therapy and hearing loss has not been determined.

• Hypotension: Decreases in blood pressure may occur due to vasodilator effects; use with caution in patients with left ventricular outflow obstruction (aortic stenosis or hypertrophic obstructive cardiomyopathy); may be more sensitive to hypotensive actions. Concurrent use with alpha-adrenergic antagonist therapy may cause symptomatic hypotension; patients should be hemodynamically stable prior to initiating therapy at the lowest possible dose. Patients should avoid or limit concurrent substantial ethanol consumption as this may increase the risk of symptomatic hypotension.

• Priapism: Painful erection >6 hours in duration has been reported (rarely). Instruct patients to seek immediate medical attention if erection persists >4 hours. Use with caution in patients who have conditions which may predispose them to priapism (sickle cell anemia, multiple myeloma, leukemia).

• Vision loss: Vision loss may occur rarely and be a sign of nonarteritic anterior ischemic optic neuropathy (NAION). Instruct patients to seek medical assistance for sudden loss of vision in one or both eyes. Patients who have already experienced NAION are at an increased risk of recurrence. Other risk factors for NAION include low cup-to-disc ratio (“crowded disc”), coronary artery disease, diabetes, hypertension, hyperlipidemia, smoking, and >50 years of age. Use with caution in these patients only when the benefits outweigh the risks. Safety and efficacy were not studied in patients with known degenerative retinal disorders (eg, retinitis pigmentosa); use is not recommended.

Disease-related concerns:

• Anatomical penis deformation: Use with caution in patients with anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie's disease).

• Bleeding disorders: Use with caution in patients with bleeding disorders; safety and efficacy have not been established.

• Cardiovascular disease: Use is not recommended in patients with hypotension (<90/50 mm Hg); uncontrolled hypertension (>170/100 mm Hg); unstable angina or angina during intercourse; life-threatening arrhythmias, stroke, MI, or coronary revascularization within the last 6 months; cardiac failure or coronary artery disease causing unstable angina. Safety and efficacy have not been studied in these patients. Use caution in patients with left ventricular outflow obstruction (eg, aortic stenosis, hypertrophic cardiomyopathy with outflow tract obstruction). There is a degree of cardiac risk associated with sexual activity; therefore, physicians may wish to consider the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction.

• Hepatic impairment: Safety and efficacy have not been studied in patients with severe hepatic impairment (Child-Pugh class C); therefore, use in these patients is not recommended.

• Peptic ulcer disease: Use with caution in patients with active peptic ulcer disease; safety and efficacy have not been established.

• Renal impairment: Safety and efficacy have not been studied in patients with severe renal impairment or end-stage renal disease requiring dialysis, therefore, use in these patients is not recommended.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Nitrates: Use of avanafil is contraindicated in patients currently taking nitrate preparations. According to the manufacturer, when nitrate administration is deemed medically necessary in a life-threatening situation, may administer nitrates only if 12 hours has elapsed after avanafil use. Of note, the elimination half-life of avanafil is similar to that of sildenafil and vardenafil which both require 24 hours to elapse prior to administration of nitrates (ACCF/AHA [Anderson, 2013]; ACCF/AHA [O'Gara, 2013]).

Other warnings/precautions:

• Appropriate use: Potential underlying causes of erectile dysfunction should be evaluated prior to treatment.

Monitoring Parameters

Monitor for response, adverse reactions, blood pressure, and heart rate.

Pregnancy Risk Factor

C

Pregnancy Considerations

Based on data from animal reproduction studies, avanafil is predicted to have a low risk for major developmental abnormalities in humans. This product is not indicated for use in women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flushing, pharyngitis, back pain, rhinitis, or rhinorrhea. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), angina, tachycardia, abnormal heartbeat, severe dizziness, passing out, severe headache, severe nausea, severe vomiting, vision changes, eye pain, severe eye irritation, blindness, hearing impairment, tinnitus, or priapism (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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