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Stendra

Generic Name: Avanafil
Class: Phosphodiesterase Type 5 Inhibitors
Chemical Name: 4 - [(3 - chloro - 4 - methoxyphenyl)methylamino] - 2 - [(2S) - 2 - (hydroxymethyl)pyrrolidin - 1 - yl] - N - (pyrimidin - 2 - ylmethyl)pyrimidine - 5 - carboxamide
Molecular Formula: C23H26ClN7O3
CAS Number: 330784-47-9

Introduction

Avanafil is a phosphodiesterase type 5 (PDE5) inhibitor.

Uses for Stendra

Avanafil has the following uses:

Avanafil is a phosphodiesterase type 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction (ED).1

Stendra Dosage and Administration

General

Avanafil is available in the following dosage form(s) and strength(s):

Tablets: 50 mg, 100 mg, 200 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • The starting dose is 100 mg taken as early as approximately 15 minutes before sexual activity, on an as needed basis.1

  • Take avanafil no more than once a day.1

  • Based on efficacy and/or tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg taken approximately 30 minutes before sexual activity. Use the lowest dose that provides benefit.1

  • Avanafil may be taken with or without food.1

  • Do not use avanafil with strong CYP3A4 inhibitors.1

  • If taking a moderate CYP3A4 inhibitor, the dose should be no more than 50 mg in a 24-hour period.1

  • In patients on stable alpha-blocker therapy, the recommended starting dose of avanafil is 50 mg.1

Cautions for Stendra

Contraindications

  • Administration of avanafil to patients using any form of organic nitrate is contraindicated.1

  • Hypersensitivity to any component of the avanafil tablet.1

  • Administration with guanylate cyclase (GC) stimulators, such as riociguat.1

Warnings/Precautions

Cardiovascular Risks

There is a potential for cardiac risk during sexual activity in patients with pre-existing cardiovascular disease. Therefore, treatments for ED, including avanafil, should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.1

Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of vasodilators, including avanafil.1

The following groups of patients were not included in clinical safety and efficacy trials for avanafil, and therefore until further information is available, avanafil is not recommended for the following groups: 1

  • Patients who have suffered a myocardial infarction, stroke, life-threatening arrhythmia, or coronary revascularization within the last 6 months.1

  • Patients with resting hypotension (blood pressure less than 90/50 mmHg) or hypertension (blood pressure greater than 170/100 mmHg).1

  • Patients with unstable angina, angina with sexual intercourse, or New York Heart Association Class 2 or greater congestive heart failure.1

As with other PDE5 inhibitors avanafil has systemic vasodilatory properties and may augment the blood pressure-lowering effect of other anti-hypertensive medications. Avanafil 200 mg resulted in transient decreases in sitting blood pressure in healthy volunteers of 8.0 mmHg systolic and 3.3 mmHg diastolic, with the maximum decrease observed at 1 hour after dosing. While this normally would be expected to be of little consequence in most patients, prior to prescribing avanafil, physicians should carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.1

Concomitant Use of CYP3A4 Inhibitors

Avanafil metabolism is principally mediated by the CYP450 isoform 3A4 (CYP3A4). Inhibitors of CYP3A4 may reduce avanafil clearance and increase plasma concentrations of avanafil.1

For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin), do not use avanafil.1

For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir [no longer commercially available in the US], aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of avanafil is 50 mg, not to exceed once every 24 hours.1

Prolonged Erection

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported with other PDE5 inhibitors. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If not treated immediately, penile tissue damage and permanent loss of potency could result.1

Avanafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).1

Effects on Eye

Physicians should advise patients to stop use of all PDE5 inhibitors, including avanafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors.1

Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥ 50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.1

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including avanafil, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including avanafil, for this uncommon condition. 1

Sudden Hearing Loss

Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus or dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Patients experiencing these symptoms should be advised to stop taking avanafil and seek prompt medical attention.1

Alpha-blockers and Other Antihypertensives

Physicians should discuss with patients the potential for avanafil to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications.1

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase type 5 inhibitors, including avanafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).1

Consideration should be given to the following:1

  • Patients should be stable on alpha-blocker therapy prior to initiating treatment with a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.1

  • In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose (avanafil 50 mg).1

  • In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.1

Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.1

Alcohol

Patients should be made aware that both alcohol and PDE5 inhibitors including avanafil act as vasodilators. When vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., greater than 3 units) in combination with avanafil may increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.1

Combination with Other PDE5 Inhibitors or Erectile Dysfunction Therapies

The safety and efficacy of combinations of avanafil with other treatments for ED has not been studied. Therefore, the use of such combinations is not recommended.1

Effects on Bleeding

The safety of avanafil is unknown in patients with bleeding disorders and patients with active peptic ulceration. In vitro studies with human platelets indicate that avanafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide [NO] donor).1

Counseling Patients about Sexually Transmitted Diseases

The use of avanafil offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV), should be considered.1

Specific Populations

Pregnancy

Pregnancy Category C.1

Avanafil is not indicated for use in women. There are no adequate and well-controlled studies of avanafil in pregnant women.1

Based on animal data, avanafil is predicted to have a low risk for major developmental abnormalities in humans.1

In pregnant rats administered 100, 300, or 1000 mg/kg/day from gestation days 6 to 17, no evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed at exposures up to approximately 8 times the exposure at the Maximum Recommended Human Dose (MRHD) of 200 mg based on AUCs for total avanafil (protein bound plus free avanafil). At the maternally toxic dose (1000 mg/kg/day), a dose producing exposures approximately 30 times the MRHD on an AUC basis, decreased fetal body weight occurred with no signs of teratogenicity. In pregnant rabbits administered 30, 60, 120, or 240 mg/kg/day from gestation days 6 to 18, no teratogenicity was observed at exposures up to approximately 6 times the human exposure at the MRHD based on AUC. At the high dose associated with maternally-reduced body weights, increased postimplantation loss was observed consistent with increased late resorptions.1

In a pre- and post-natal development study in rats given 100, 300, or 600 mg/kg/day on gestation days 6 through lactation day 20, offspring growth and maturation were reduced when maternal rats were given avanafil doses greater than or equal to 300 mg/kg/day resulting in exposures greater than or equal to 17 times the human exposure. There was no effect on reproductive performance of the maternal rats or offspring, or on the behavior of the offspring at up to the highest dose tested. The no observed adverse effect level (NOAEL) for developmental toxicity (100 mg/kg/day) was approximately 2-fold greater than the systemic exposure in humans at the MRHD.1

Pediatric Use

Avanafil is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years has not been established.1

Geriatric Use

Of the total number of subjects in clinical studies of avanafil, approximately 23% were 65 and over. No overall differences in efficacy and safety were observed between subjects over 65 years of age compared to younger subjects; therefore no dose adjustment is warranted based on age alone. However, a greater sensitivity to medication in some older individuals should be considered.1

Renal Impairment

In a clinical pharmacology trial using single 200 mg doses of avanafil, avanafil exposure (AUC or Cmax) in normal subjects was comparable to patients with mild (creatinine clearance greater than or equal to 60 to less than 90 mL/min) or moderate (creatinine clearance greater than or equal to 30 to less than 60 mL/min) renal impairment. No dose adjustment is necessary for patients with mild to moderate renal impairment (creatinine clearance greater than or equal to 30 to less than 90 mL/min). The pharmacokinetics of avanafil in patients with severe renal disease or on renal dialysis has not been studied; do not use avanafil in such patients. 1

Hepatic Impairment

In a clinical pharmacology trial, avanafil AUC and Cmax in patients with mild hepatic impairment (Child-Pugh Class A) was comparable to that in healthy subjects when a dose of 200 mg was administered. Avanafil Cmax was approximately 51% lower and AUC was 11% higher in patients with moderate hepatic impairment (Child Pugh Class B) compared to subjects with normal hepatic function. No dose adjustment is necessary for patients with mild to moderate hepatic impairment (Child Pugh Class A or B). The pharmacokinetics of avanafil in patients with severe hepatic disease have not been studied; do not use avanafil in such patients.1

Common Adverse Effects

Most common adverse reactions (greater than or equal to 2%) include headache, flushing, nasal congestion, nasopharyngitis, and back pain.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Avanafil can potentiate the hypotensive effect of nitrates, alpha-blockers, antihypertensives, and alcohol.1

  • CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, erythromycin) increase avanafil exposure.1

Actions

Mechanism of Action

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 (GC), which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Avanafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting PDE5, which is responsible for degradation of cGMP in the corpus cavernosum. Because sexual stimulation is required to initiate the local release of NO, the inhibition of PDE5 has no effect in the absence of sexual stimulation.1

Studies in vitro have shown that avanafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (greater than 100-fold for PDE6; greater than 1,000-fold for PDE4, PDE8, and PDE10; greater than 5,000-fold for PDE2 and PDE7; greater than 10,000-fold for PDE1, PDE3, PDE9, and PDE11). Avanafil is greater than 100-fold more potent for PDE5 than PDE6, which is found in the retina and is responsible for phototransduction. In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of 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.1

Advice to Patients

See FDA-approved patient labeling.1

Nitrates

Physicians should discuss with patients the contraindication of avanafil with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of avanafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.1

Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of avanafil. In such a patient, who has taken avanafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Patients who experience anginal chest pain after taking avanafil should seek immediate medical attention.1

Cardiovascular Considerations

Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and should seek immediate medical attention.1

Concomitant Use with Drugs Which Lower Blood Pressure

Physicians should advise patients of the potential for avanafil to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications.1

Potential for Drug Interactions

Patients should be advised to contact the prescribing physician if new medications that may interact with avanafil are prescribed by another healthcare provider.1

Priapism

There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Physicians should advise patients who have an erection lasting greater than 4 hours, whether painful or not, to seek emergency medical attention.1

Sudden Loss of Vision

Physicians should advise patients to stop use of all PDE5 inhibitors, including avanafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision that has been reported rarely in temporal association with the use of PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a "crowded" optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including avanafil, for these uncommon conditions.1

Sudden Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including avanafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.1

Alcohol

Patients should be made aware that both alcohol and PDE5 inhibitors including avanafil act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., greater than 3 units) in combination with avanafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.1

Sexually Transmitted Disease

The use of avanafil offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.1

Recommended Administration

Physicians should discuss with patients the appropriate use of avanafil and its anticipated benefits. It should be explained that sexual stimulation is required for an erection to occur after taking avanafil. Patients should be counseled regarding the dosing of avanafil. Inform patients that the recommended starting dose of avanafil is 100 mg, taken as early as approximately 15 minutes before initiating sexual activity. Based on efficacy and tolerability, the dose may be increased to 200 mg taken as early as approximately 15 minutes before sexual activity, or decreased to 50 mg taken approximately 30 minutes before sexual activity. The lowest dose that provides benefit should be used. Patients should be advised to contact their healthcare provider for dose modification.1

Guanylate Cyclase Stimulators

Physicians should discuss with patients the contraindication of avanafil with use of guanylate cyclase (GC) stimulators such as riociguat.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Avanafil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

50 mg

Stendra

VIVUS Inc.

100 mg

Stendra

VIVUS Inc.

200 mg

Stendra

VIVUS Inc.

AHFS Drug Information. © Copyright 2016, Selected Revisions September 8, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. VIVUS, Inc. Stendra (avanafil) ORAL prescribing information. 2015 Sept.

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