Avanafil (Dosing, Interaction, Side Effect, Administration, Etc..)

CLASS:
Erectile Dysfunction Agent
Phosphodiesterase Type 5 Inhibitor

DOSING:
Adult Dose:
Erectile dysfunction:
initial, 100 mg ORALLY as needed, taken as early as 15 minutes prior to sexual activity; Maximum once daily; use lowest dose to provide benefit; may decrease to 50 mg taken 30 minutes prior to sexual activity or increase to Maximum 200 mg

Pediatric Dose:
General Dosage Information:
Not indicated in pediatric patients under 18 years of age; safety and efficacy not established

INDICATIONS:
FDA-LABELED INDICATIONS:
Erectile dysfunction

MECHANISM OF ACTION:
Nitric oxide increases levels of cGMP, which relaxes smooth muscles in corpus cavernosum to allow inflow of blood to achieve and maintain penial erection. Avanafil, a selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE-5), enhances the effect of nitric oxide by inhibiting PDE-5, which degrades cGMP in the corpus cavernosum. Sexual stimulation is required to initiate the local release of nitric oxide.

Avanafil

has no direct relaxant effect on corpus cavernosum.

ADVERSE EFFECT:
Common:
Dermatologic:
Flushing (3.2% to 10.1%)

Musculoskeletal:
Backache (1.1% to 3.2%)

Neurologic:
Headache (1.4% to 12.1%)

Respiratory:
Nasal congestion (0.7% to 4.1%)
Nasopharyngitis (0.9% to 5.1%)

Serious:
Ophthalmic:
Non-arteritic ischemic optic neuropathy
Anterior (Rare)

Otic:
Sudden hearing loss

Reproductive:
Priapism
Prolonged erection of penis

CONTRAINDICATION:
Concomitant use of nitrates (any form) either regularly or intermittently; if nitrate required for a life-threatening situation, allow 12 hours or more to elapse after last

dose of avanafil

before administering nitrate only under close medical supervision with appropriate hemodynamic monitoring
Hypersensitivity to avanafil or any component of the product
Concomitant use with a guanylate cyclase stimulator (e.g., riociguat)

INTERACTION:
Nitrates:

Administration of avanafil

to patients who are using any form of organic nitrate, is contraindicated. In a clinical pharmacology trial, avanafil was shown to potentiate the hypotensive effect of nitrates. In 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 only be administered under close medical supervision with appropriate hemodynamic monitoring

Alpha-Blockers:
Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 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)

Antihypertensives:
PDE5 inhibitors, including avanafil, are mild systemic vasodilators. A clinical pharmacology trial was conducted to assess the

effect of avanafil

on the potentiation of the blood pressure-lowering effects of selected antihypertensive medications (amlodipine and enalapril). Additional reductions in blood pressure of 3 to 5 mmHg occurred following co-administration of a single 200 mg dose avanafil with these agents compared with placebo

Alcohol:
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. 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.

Potential for Other Drugs to Affect AVANAFIL:
avanafil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure.

Strong CYP3A4 Inhibitors:
Ketoconazole (400 mg daily), a selective and strong inhibitor of CYP3A4, increased avanafil 50 mg single-dose systemic exposure (AUC) and maximum concentration (Cmax) equal to 13-fold and 3-fold, respectively and prolonged the

half-life of avanafil

to approximately 9 hours. Other potent inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir and telithromycin) would be expected to have similar effects. Do not

use avanafil

in patients taking strong CYP3A4 inhibitors

HIV Protease inhibitor — Ritonavir (600 mg twice daily), a strong CYP3A4 inhibitor, which also inhibits CYP2C9, increased avanafil 50 mg single-dose Cmax and AUC equal to approximately 2-fold and 13-fold, and prolonged the half-life of avanafil to approximately 9 hours in healthy volunteers.

Do not use avanafil

in patients taking ritonavir.

Moderate CYP 3A4 Inhibitors:
Erythromycin (500 mg twice daily) increased avanafil 200 mg single-dose Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours in healthy volunteers. Moderate CYP3A4 inhibitors (e.g., erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. Consequently, the maximum recommended

dose of avanafil

is 50 mg, not to exceed once every 24 hours for patients taking concomitant moderate CYP3A4 inhibitors. Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice are likely to increase avanafil exposure.

Weak CYP3A4 Inhibitors:
No in vivo drug-drug interaction studies with weak CYP3A4 inhibitors were conducted.

CYP3A4 Substrate:
When administered with

avanafil 200 mg

, amlodipine (5 mg daily) 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

Cytochrome P450:
Inducers The potential effect of CYP inducers on the

pharmacokinetics of avanafil

was not evaluated. The concomitant

use of avanafil

and CYP inducers is not recommended.

Potential for AVANAFIL to Affect Other Drugs:
In vitro studies:
Avanafil had no effect on CYP1A1/2, 2A6, 2B6 and 2E1 (IC50 greater than 100 micromolar) and weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4). Major circulating

metabolites of avanafil

(M4 and M16) had no effect on CYPs 1A, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Avanafil and its metabolites (M4 and M16) are unlikely to cause clinically significant inhibition of CYPs 1A, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4.

In vivo studies:
Warfarin —A single 200 mg dose of avanafil did not alter the changes in PT or INR induced by warfarin, and did not affect collagen-induced platelet aggregation or the AUC or Cmax of R- or S-warfarin, a 2C9 substrate.

Desipramine — A single avanafil 200 mg dose increased AUC and Cmax of a single 50 mg dose of desipramine, a CYP2D6 substrate, by 5.7% and 5.2%, respectively.

Omeprazole — A single avanafil 200 mg dose increased AUC and Cmax of a single 40 mg dose of omeprazole, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively.

Rosiglitazone — A single avanafil 200 mg dose increased AUC by 2.0% and decreased Cmax by 14% of a single 8 mg dose of rosiglitazone, a CYP2C8 substrate.

Amlodipine — A single avanafil 200 mg dose did not affect the pharmacokinetics of amlodipine (5 mg daily), a CYP3A4 substrate

Alcohol — A single

oral dose of avanafil

200 mg did not affect alcohol (0.5 g ethanol/kg) plasma concentrations

Major:
Atazanavir (theoretical)
Boceprevir (theoretical)
Clarithromycin (theoretical)
Cobicistat (theoretical)
Conivaptan (theoretical)
Darunavir (theoretical)
Efavirenz (theoretical)
Etravirine (theoretical)
Fosnetupitant (theoretical)
Indinavir (theoretical)
Ivosidenib (theoretical)
Ketoconazole (probable)
Lopinavir (probable)
Nefazodone (theoretical)
Nelfinavir (theoretical)
Netupitant (theoretical)
Nevirapine (theoretical)
Posaconazole (theoretical)
Ritonavir (probable)
Saquinavir (theoretical)
Telaprevir (theoretical)
Telithromycin (theoretical)
Voriconazole (theoretical)

Moderate:
Doxazosin (established)
Erythromycin (probable)
Tamsulosin (established)

PHARMACOKINETICS:
Absorption:
Time for Maximum Plasma Concentration (Tmax):
30 to 45 minutes
Oral, Korean patients: 20 to 30 minutes

Effects of food:
Delay in Tmax of 1.12 to 1.25 hours
AUC and Cmax not clinically insignificant

Distribution:
Plasma Protein binding: 99% bound

Metabolism:
Hepatic:
Extensive via CYP3A4
Minor extent by CYP2C isoforms

Metabolite, M4: active, 4% of the pharmacologic activity
Excretion:
Fecal: 62%
Renal: 21%

Elimination:
5 hours

PRECAUTION:
Cardiovascular:
Sexual activity or

vasodilatory effects of avanafil

could aggravate conditions of preexisting cardiovascular disease
Congestive heart failure (NYHA Class 2 or greater); use not recommended
Coronary revascularization, myocardial infarction, stroke, life-threatening arrhythmia, or coronary revascularization within last 6 months; use not recommended
Angina occurring during sexual intercourse or unstable angina; use not recommended
Increased sensitivity to vasodilators may occur with severely impaired autonomic control of blood pressure or left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis)
Hypotension (resting blood pressure less than 90/50 mmHg) or hypertension (resting blood pressure greater than 170/100 mmHg); use not recommended

Concomitant Use:
Use with CYP450 inducers not recommended
Use with other phosphodiesterase type 5 (PDE5) inhibitors or erectile dysfunction therapies not recommended
Use with strong CYP3A4 inhibitors not recommended
Use with efavirenz, etravirine, nevirapine, or rilpivirine not recommended

Hematologic:
May increase risk of bleeding in patients with bleeding disorders or active peptic ulceration

Ophthalmic:
History of non-arteritic anterior ischemic optic neuropathy (NAION); increased risk for recurrence
Non-arteritic anterior ischemic optic neuropathy (NAION) leading to permanent vision loss may occur; discontinuation recommended in the event of any sudden vision loss

Otic:
Sudden hearing decrease or loss may occur; discontinuation recommended
Reproductive: Priapism or prolonged erections lasting greater than 4 hours may occur and could result in permanent penile tissue damage if not treated immediately

Reproductive:
Use caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie disease)
Use with caution in patients with conditions which may predispose them to priapism, such as sickle cell anemia, multiple myeloma, or leukemia

PREGNANCY CATEGORY:
C (FDA)

BREAST FEEDING:
Infant risk cannot be ruled out.

MONITORING:
Erectile dysfunction: vaginal penetration and successful intercourse is evidence of efficacy.
No specific monitoring has been determined.

HOW TO TAKE OR ADMINISTRATION:
Oral:
Take with or without food

DOSAGE FORM:
Oral Tablet:
50 MG
100 MG
200 MG

TREATMENTS:
MILD TO MODERATE TOXICITY:
Treatment is symptomatic and supportive. Monitor vital signs.

HYPOTENSION:
Monitor blood pressure; administer isotonic fluids at 10 to 20 mL/kg.

CHEST PAIN:
Nitrates are contraindicated in patients with a recent avanafil ingestion due to the possibility of a severe hypotensive reaction. Nitrates should be avoided for 24 hours (longer if on P450 inhibitors or if hepatic or renal dysfunction are present), given the risk of hypotension and exacerbation of ischemia.

SEVERE TOXICITY:
Treatment is symptomatic and supportive.

HYPOTENSION:
Monitor blood pressure, administer isotonic fluids at 10 to 20 mL/kg. Administer norepinephrine or dopamine if hypotension persists. PRIAPISM is an emergency requiring immediate consult with a urologist.

TOXICOLOGY:
Specific toxic dose has not been established. In clinical trials, patients tolerated single doses of 800 mg and multiple doses up to 300 mg.

PATIENT COUNSELING OR CLINICAL TEACHING:
Instruct patient to report an erection lasting longer than 4 hours or priapism.
Warn patient to report sudden vision loss, hearing loss, tinnitus, or dizziness.
Side effects may include headache, nasal congestion, nasopharyngitis, flushing, or back pain.
Advise patient to report symptoms of symptomatic hypotension.
Instruct patient to take dose 15 minutes before sexual activity, but no more than once a day.
Counsel patient to limit alcohol use (e.g., 3 units or less) due to potential for enhanced vasodilation
Advise patient to avoid grapefruit juice.




Disclaimer:
For the Registered Medical Practitioner Only. We are not recommended for self medication. self medication is may harmful for health. We are only Provide information about medicine.