STENDRA® (avanafil) tablets

STENDRA® (avanafil) tablets

STENDRA® (avanafil) tablets

STENDRA (avanafil) is a selective inhibitor of cGMP-specific PDE5.

Avanafil is designated chemically as (S)-4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N­(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide.

Avanafil occurs as white crystalline powder, molecular formula C23H26ClN7O3 and molecular weight of 483.95 and is slightly soluble in ethanol, practically insoluble in water, soluble in 0.1 mol/L hydrochloric acid. STENDRA, for oral administration, is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strengths. In addition to the active ingredient, avanafil, each tablet contains the following inactive ingredients: mannitol, fumaric acid, hydroxypropylcellulose, low substituted hydroxypropylcellulose, calcium carbonate, magnesium stearate, and ferric oxide yellow.

INDICATIONS AND USAGE

STENDRA is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction in adult males.

Mechanism of Action

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 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 nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation.

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 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.

DOSAGE AND ADMINISTRATION

Erectile Dysfunction: The recommended starting dose is 100 mg. STENDRA should be taken orally as needed as early as approximately 15 minutes before sexual activity.

Based on individual 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.

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The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment.

Use with Food: STENDRA may be taken with or without food.

Concomitant Medications

Nitrates: Concomitant use of nitrates in any form is contraindicated.

Alpha-Blockers: If STENDRA is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating treatment with STENDRA, and STENDRA should be initiated at the 50 mg dose.

CYP3A4 Inhibitors

  • For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin), do not use STENDRA.
  • For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of STENDRA is 50 mg, not to exceed once every 24 hours.

CONTRAINDICATIONS

Nitrates: Administration of STENDRA with any form of organic nitrates, either regularly and/or intermittently, is contraindicated. Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, STENDRA has been shown to potentiate the hypotensive effects of nitrates.

In a patient who has taken STENDRA, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of STENDRA before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.

Hypersensitivity Reactions: STENDRA is contraindicated in patients with a known hypersensitivity to any component of the tablet. Hypersensitivity reactions have been reported, including pruritis and eyelid swelling.

Concomitant Guanylate Cyclase (GC) Stimulators: Do not use STENDRA in patients who are using a GC stimulator, such as riociguat or vericiguat. PDE5 inhibitors, including STENDRA may potentiate the hypotensive effects of GC stimulators.

WARNINGS AND PRECAUTIONS

Evaluation of erectile dysfunction (ED) should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.

Before prescribing STENDRA, it is important to note the following:

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

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 STENDRA.

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

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

For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of STENDRA is 50 mg, not to exceed once every 24 hours.

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.

STENDRA 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).

Effects on Eye: Physicians should advise patients to stop use of all PDE5 inhibitors, including STENDRA 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. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥ 50.

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 STENDRA and seek prompt medical attention.

Alpha-Blockers and Other Antihypertensives: Physicians should discuss with patients the potential for STENDRA to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications.

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase type 5 inhibitors, including STENDRA, 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).

Alcohol: Patients should be made aware that both alcohol and PDE5 inhibitors including STENDRA 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 STENDRA may increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.

Combination with Other PDE5 Inhibitors or Erectile Dysfunction Therapies: The safety and efficacy of combinations of STENDRA with other treatments for ED has not been studied. Therefore, the use of such combinations is not recommended.

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

Counseling Patients about Sexually Transmitted Diseases: The use of STENDRA 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.

DRUG INTERACTIONS

Nitrates: Administration of STENDRA to patients who are using any form of organic nitrate, is contraindicated. In a clinical pharmacology trial, STENDRA was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken STENDRA, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 12 hours should elapse after the last dose of STENDRA 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 STENDRA, 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 STENDRA, are mild systemic vasodilators. A clinical pharmacology trial was conducted to assess the effect of STENDRA 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 of STENDRA with these agents compared with placebo.

Alcohol: Both alcohol and PDE5 inhibitors, including STENDRA, 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 STENDRA can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.

USE IN SPECIFIC POPULATIONS

Pediatric Use: STENDRA is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years has not been established.

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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.

Renal Impairment: In a clinical pharmacology trial using single 200 mg doses of STENDRA, 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 STENDRA in such patients.

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 has not been studied; do not use STENDRA in such patients.

OVERDOSAGE

Single doses up to 800 mg have been given to healthy subjects, and multiple doses up to 300 mg have been given to patients. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance because avanafil is highly bound to plasma proteins and is not significantly eliminated in the urine.

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