Pharmacologic Category: Anti-erectile dysfunction agent, phosphodiesterase type 5 (PDE5) inhibitor
What is this medicine? AVANAFIL (ah VA Na fil) is used to treat erection problems in men. Avanafil belongs to the phosphodiesterase type 5 (PDE5) inhibitors drug class, a class of drugs commonly indicated for treatment of erectile dysfunction (ED).1 PDE5 inhibitors do not inhibit prostaglandins as do some agents for treating impotence (e.g., alprostadil). The safety and efficacy of avanafil was studied in three clinical trials; compared to placebo, improved erections were recorded in patients with organic and/or psychogenic ED when avanafil was administered prior to visual sexual stimulation. Avanafil is taken prior to sexual activity without regard to food. Patients with preexisting cardiovascular disease should discuss the potential cardiac risks associated with sexual activity with their healthcare professional. As with other PDE5 inhibitors, avanafil has systemic vasodilatory proprieties. 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. Avanafil should not be used by men who also take nitrates because the combination can cause a sudden drop in blood pressure that can be dangerous. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy.2
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.3
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.3
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.3
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.
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.3
The pharmacokinetics of avanafil have been studied in patients with mild and moderate hepatic impairment. Avanafil exposure was similar after a single avanafil (200 mg) dose in normal subjects compared to patients with mild hepatic impairment (Child-Pugh Class A). Avanafil Cmax was approximately 51% lower and AUC was 11% higher in patients with moderate hepatic impairment (Child Pugh Class B) compared to subjects with normal hepatic function; however, dose adjustments are not considered necessary. The pharmacokinetics of avanafil in patients with severe hepatic disease have not been studied, therefore, avanafil should not be used in such patients.3
The pharmacokinetics of avanafil have been studied in patients with mild and moderate renal impairment. Avanafil exposure was similar after a single avanafil (200 mg) dose in patients with normal subjects compared to patients with mild to moderate renal impairment (CrCl 30—89 mL/min). The pharmacokinetics of avanafil in patients with severe renal disease or on renal dialysis have not been studied; therefore, avanafil should not be used in such patients.3
The pharmacokinetics of a single avanafil (200 mg) dose in elderly subjects (65—80 years) was compared to younger adult subjects (18—43 years). Drug exposure was not significantly affected by age in these patients: AUC increased by 6.8% and Cmax decreased by 2.1% in the elderly group, compared to the younger group.3
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.3 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.4 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.5
Adults receiving potent CYP3A4 inhibitors: Do not use avanafil.3
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.3
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.3
Maximum Dosage Limits
200 mg/day PO; when given with moderate CYP3A4 inhibitors no more than 50 mg/day PO.
200 mg/day PO; when given with moderate CYP3A4 inhibitors no more than 50 mg/day PO.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
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.
Contraindications/Precautions: 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.3
Avanafil troches 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.3
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.3
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.3
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.3
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).36
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.3
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.3
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.3
There is no known indication for the use of avanafil in neonates, infants, or children. Avanafil should not be prescribed to these populations.3
How should I use this medicine? Take this medicine by mouth with a glass of water. Follow the directions on the prescription label. The dose is taken 15 to 30 minutes before sexual activity, depending on the dose you are being prescribed. You should not take the dose more than once per day. Do not take your medicine more often than directed.
Talk to your pediatrician regarding the use of this medicine in children. This medicine is not used in children for this condition.
Overdosage: If you think you've taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.
What if I miss a dose? This does not apply. Do not take double or extra doses.
What may interact with this medicine? Do not take this medicine with any of the following medications:
- methscopolamine nitrate
- nitrates like amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin
- other medicines for erectile dysfunction like sildenafil, tadalafil, vardenafil
This medicine may also interact with the following medications:
- certain drugs for high blood pressure
- certain drugs for the treatment of HIV infection or AIDS
- certain drugs used for fungal or yeast infections, like fluconazole, itraconazole, ketoconazole, and voriconazole
- grapefruit juice
- macrolide antibiotics like clarithromycin, erythromycin, troleandomycin
- medicines for prostate problems
- rifabutin, rifampin or rifapentine
- St. John's wort
This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.
What side effects may I notice from receiving this medicine? Side effects that you should report to your doctor or health care professional as soon as possible:
- allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
- breathing problems
- changes in hearing
- changes in vision
- chest pain
- fast, irregular heartbeat
- prolonged or painful erection
Adverse Reactions: There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) associated with PDE5 inhibitors, such as avanafil. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Additional urogenital related adverse events reported in < 1% of patients receiving avanafil in clinical trials include: balanitis, increased erection, hematuria, nephrolithiasis, urinary urgency or increased urinary frequency, and urinary tract infection; a causal relationship to avanafil use could not be determined.3
Avanafil safety was evaluated in 3 placebo-controlled trials. Study patients received avanafil as needed for 3 months at varying doses, 50 mg (n=217), 100 mg (n=349), and 200 mg (n=352). Adverse reactions reported in >= 2% of patients, independent of dose and relative to placebo included: headache 5.1—10.5% vs. 1.7%. Headache was also reported among 5.6% of patients receiving avanafil (n=711) in an open-label extension trial. In an additional placebo-controlled study of men who underwent bilateral nerve-sparing radical prostatectomy, patients received avanafil at varying doses, 100 mg (n=99), and 200 mg (n=99); headache was reported in 8.1—12.1% vs. 1% of patients, independent of dose and relative to placebo. It appears headache may be a dose dependent adverse event; the incidence of headache increased with dose in clinical evaluation. Dizziness was also reported in prostatectomy patients at an incidence of 1—2% vs. 0% relative to placebo and was independent of dose. Additional central nervous system related adverse events reported in less than 1% of patients receiving avanafil in clinical trials include: depression, insomnia, drowsiness (somnolence), and vertigo; a causal relationship to avanafil use could not be determined.3
As with other PDE5 inhibitors, avanafil exhibits systemic vasodilatory proprieties and may result in subsequent hypotension. In clinical evaluation, avanafil (200 mg) reduced the sitting blood pressure of healthy subjects by 8 mmHg systolic and 3.3 mmHg diastolic, with the maximum decrease in blood pressure observed at 1 hour after dosing. In most patients, this reduction in blood pressure is transient and is of little clinical consequence. However, patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. Additional lowering of blood pressure by 3 to 5 mmHg can be expected when avanafil is combined with antihypertensive therapies. Hypertension was reported in 1—2% of patients in clinical evaluation of avanafil. Additional cardiovascular related adverse events reported in < 1% of patients receiving avanafil in clinical trials included: angina, unstable angina, deep vein thrombosis, and palpitations; a causal relationship to avanafil use could not be determined.3 Syncope, orthostatic hypotension (decrease in standing blood pressure) and other forms of symptomatic hypotension (e.g., dizziness, lightheadedness) appear more likely occur in patients concomitantly using alpha-blockers or in those patients who consume substantial alcohol during dosing.
Single oral doses of phosphodiesterase type 5 (PDE5) inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. Across all trials with any avanafil dose, 1 patient reported a change in color vision. Post-marketing reports with other PDE5 inhibitors have included cases of visual disturbances including retinal vein occlusion, visual field defects, reduced visual acuity, and loss of vision (temporary or permanent). Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors.78910 It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision (< 2%) and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio ('crowded disc'), age over 50 years, diabetes, high blood pressure, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy.7 It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Patients should be instructed to discontinue avanafil use and seek immediate medical attention if visual impairment including sudden loss of vision occurs in one or both eyes. Such an event may be a sign of NAION. Clinicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of avanafil.3
Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing. Twenty-nine reports of sudden changes in hearing including hearing loss or decrease in hearing, usually in 1 ear only, have been reported to the FDA during post-marketing surveillance in patients taking PDE5 inhibitors such as sildenafil, tadalafil, or vardenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Many times, the hearing changes are accompanied by vestibular effects including tinnitus and vertigo. Follow-up has been limited in many of the reports; however, in approximately one-third of the patients, the hearing loss was temporary. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Patients should be instructed to contact their physician if they experience changes in hearing while taking avanafil.3
Gastrointestinal (GI) adverse events reported in 1—2% of patients in clinical evaluation of avanafil included: dyspepsia, nausea, constipation, and diarrhea. Other GI adverse events reported in less than 1% of patients receiving avanafil in clinical trials include: gastritis, gastroesophageal reflux disease, elevated hepatic enzymes (increased ALT), oropharyngeal pain, abdominal pain (stomach discomfort), and vomiting; a causal relationship to avanafil use could not be determined.3
Miscellaneous adverse events reported in less than 1% of patients receiving avanafil in clinical trials include: peripheral edema, fatigue, hypoglycemia, and hyperglycemia. A causal relationship to avanafil use could not be determined.3
Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
- back pain
- muscle aches
- stuffy or runny nose
What should I watch for while using this medicine? If you notice any changes in your vision while taking this drug, call your doctor or health care professional as soon as possible. Stop using this medicine and call your health care provider right away if you have a loss of sight in one or both eyes. Contact your doctor or health care professional right away if you have an erection that lasts longer than 4 hours or if it becomes painful. This may be a sign of a serious problem and must be treated right away to prevent permanent damage. If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medicine, you should refrain from further activity and call your doctor or health care professional as soon as possible. Do not drink alcohol to excess (examples, 5 glasses of wine or 5 shots of whiskey) when taking this medicine. When taken in excess, alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate or lowering your blood pressure. Using this medicine does not protect you or your partner against HIV infection (the virus that causes AIDS) or other sexually transmitted diseases.
Where should I keep my medicine? Keep out of the reach of children. Store at room temperature between 20 and 30 degrees C (68 and 86 degrees F). Protect from light. Throw away any unused medicine after the expiration date.
General statements: Do not share or take any one else's medicine. Talk with your healthcare provider before starting any new medicine, including over-the-counter, natural products, or vitamins. The capsule formulation was compounded specifically for you. This patient information summarizes the most important information about your medication; if you would like more information, talk with your doctor.
- 1. Stendra (avanafil) package insert. Mountain View, CA: VIVUS, Inc.; 2014 Sep.
- 2. Montague DK, Jarow JP, Broderick GA, et al. Chapter 1: The management of erectile dysfunction: an AUA update. J Urol 2005;174:230-9.
- 3. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. y. z. A. B. Stendra (avanafil) package insert. Mountain View, CA: VIVUS, Inc.; 2014 Sep.
- 4. Shamloul R, Ghanem H. Erectile dysfunction. Lancet 2013;381:153-65.
- 5. Montague DK, Jarow JP, Broderick GA, et al. Chapter 1: The management of erectile dysfunction: an AUA update. J Urol 2005;174:230-9.
- 6. Burnett AL, Bivalacqua TJ. Priapism: current principles and practice. Urol Clin N Am 2007;34:631-642.
- 7. a. b. Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmol 2005;25:9-13.
- 8. Escaravage GK Jr, Wright JD Jr, Givre SJ. Tadalafil associated with anterior ischemic optic neuropathy. Arch Ophthalmol 2005;123(3):399-400.
- 9. Bollinger K, Lee MS. Recurrent visual field defect and ischemic optic neuropathy associated with tadalafil rechallenge. Arch Ophthalmol 2005;123(3):400-1.
- 10. Peter NM, Singh MV, Fox PD. Tadalafil-associated anterior ischaemic optic neuropathy. Eye 2005;19(6):715-7.