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Stendra

Generic Name: Avanafil
Class: Phosphodiesterase Type 5 Inhibitors
VA Class: 00
Chemical Name: 4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1- pyrrolidinyl]-N-(2 pyrimidinylmethyl)-5-pyrimidinecarboxamide
Molecular Formula: C23H26ClN7O3
CAS Number: 330784-47-9

Introduction

Vasodilating agent; a selective phosphodiesterase (PDE) type 5 inhibitor.1

Uses for Stendra

Erectile Dysfunction (ED)

To facilitate attainment of a sexually functional erection in men with ED (impotence).1 2 3 4 5 7 10

Some experts recommend a selective PDE type 5 inhibitor as first-line therapy for ED unless contraindicated.6 8 12 13 15 Evidence currently insufficient to establish superiority of one selective PDE type 5 inhibitor over another.8

Effective for ED only in the presence of adequate sexual stimulation.1

Stendra Dosage and Administration

Administration

Oral Administration

Administer orally, no more than once daily, without regard to meals.1

Administer approximately 15–30 minutes before anticipated sexual activity.1

Dosage

Individualize dose carefully according to patient tolerance and erectile response.1

Adults

ED
Oral

Initially, 100 mg as a single dose, given approximately 15 minutes before anticipated sexual activity.1

Depending on effectiveness and tolerance, may increase dose to 200 mg or decrease to 50 mg, given approximately 30 minutes before anticipated sexual activity.1 Use lowest effective dose.1

Do not take more than one dose per day.1

Prescribing Limits

Adults

ED
Oral

Maximum 200 mg as a single dose; do not exceed one dose per day.1

Special Populations

Hepatic Impairment

Dose adjustments not required in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 Use not recommended in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Dose adjustments not required in patients with mild to moderate (Clcr of 30 to <90 mL/minute) renal impairment.1 Use not recommended in patients with severe renal impairment or those requiring renal dialysis.1

Geriatric Patients

Dose adjustment not required.1

Cautions for Stendra

Contraindications

  • Concomitant use of any form of organic nitrate (e.g., nitrates, nitrites, nitric oxide donors) either regularly or intermittently.1 (See Specific Drugs and Foods under Interactions.)

  • Known hypersensitivity to avanafil or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including pruritus and eyelid swelling, reported.1 (See Contraindications under Cautions.)

Patient Assessment

Thorough medical history and physical examination recommended to determine potential underlying causes and identify appropriate treatment options for ED.1 7 8 9 14

Review of patient’s current drug regimen recommended to detect possible drug-induced ED.7 202

Cardiovascular Effects

Sexual activity associated with a degree of cardiac risk; risk greater in men with preexisting cardiovascular disease.1 5 8 Assess cardiovascular status of patient before initiating avanafil therapy.1 Therapy for ED not recommended for men in whom sexual activity is inadvisable because of their underlying cardiovascular status.1 5

Safety and efficacy for treatment of ED not established and use not recommended in patients with a recent (within 6 months) MI, stroke, life-threatening arrhythmia, or coronary revascularization;1 resting hypotension (BP <90/50 mm Hg) or hypertension (BP >170/110 mm Hg);1 heart failure (NYHA class ≥II);1 or those with unstable angina or angina occurring during sexual intercourse.1

Possible hypotension, particularly in patients with left-ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and in patients with severely impaired autonomic control of BP.1 Additive BP-lowering effects may occur when used concomitantly with other vasodilating agents (e.g., α-adrenergic blocking agents or other antihypertensive drugs, alcohol).1 5 16 (See Specific Drugs and Foods under Interactions.)

Potentiation of hypotensive effect with any form of organic nitrate; concomitant use is contraindicated.1 5 (See Specific Drugs and Foods under Interactions.)

Consider whether patients with underlying cardiovascular disease could be adversely affected by avanafil’s vasodilatory activity, especially in combination with sexual activity.1

Concomitant Use with CYP3A4 Inhibitors

Consider potential for increased avanafil concentrations when used concomitantly with inhibitors of CYP3A4; in some cases, dose adjustments may be necessary, while in other cases, concomitant use not recommended.1 47 200 (See Specific Drugs and Foods under Interactions.)

Priapism

Possible prolonged erections (>4 hours) and priapism (painful erection >6 hours).1 5

May result in penile tissue damage and permanent loss of potency if priapism not treated immediately.1 (See Advice to Patients.) Use avanafil with caution in patients with conditions predisposing to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia) and in patients with anatomic deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie’s disease).1

Ocular Effects

Nonarteritic anterior ischemic optic neuropathy (NAION) reported rarely during postmarketing experience in temporal association with use of all PDE type 5 inhibitors.1 24 25 26 Potential increased risk of NAION in the other eye in patients who have already experienced NAION in one eye.1 24 25 26 If sudden vision loss or decreased vision occurs, discontinue avanafil and contact clinician immediately.1

Visual disturbances (e.g., blurred vision, blue/green vision) also reported rarely with avanafil.1 3

Otic Effects

Sudden decrease or loss of hearing reported with PDE type 5 inhibitors.1 24 25 26 Vestibular manifestations (e.g., dizziness, tinnitus) also observed.44

Although not clear whether such effects are directly related to PDE type 5 inhibitors or to other factors (e.g., patient’s underlying medical condition, concomitant use of other ototoxic drugs), a strong temporal relationship has been observed.1 44

Concomitant Use with α-Adrenergic Blocking Agents

Use with caution in patients receiving α-adrenergic blocking agents; possible potentiation of hypotensive effects due to additive vasodilatory action.1 In some cases, dose adjustments are necessary, while in other cases, concomitant use not recommended.1 (See Specific Drugs and Foods under Interactions.) Safety of concomitant therapy also may be affected by intravascular volume depletion and use of additional antihypertensive agents.1

Concomitant Use with Alcohol

Combined use of alcohol and PDE type 5 inhibitors may have additive BP-lowering effects.1 Inform patients that consumption of substantial amounts of alcohol (e.g., >3 glasses of wine or shots of whiskey) with avanafil may increase potential for orthostatic hypotension.1 5 (See Specific Drugs and Foods under Interactions.)

Concomitant Use with Other PDE Type 5 Inhibitors or ED Therapies

Safety and efficacy of combined use with other PDE type 5 inhibitors or other treatments for ED not established; such concomitant use not recommended.1

Hematologic Effects

Avanafil inhibits PDE type 5.1 Safety not established in patients with bleeding disorders or active peptic ulcers.1

Specific Populations

Pregnancy

Category C.1 Manufacturer states not indicated for use in women.1

Lactation

Manufacturer states not indicated for use in women.1

Pediatric Use

Safety and efficacy not established, and not indicated in pediatric patients.1

Geriatric Use

Safety and efficacy similar to that in younger patients.1 Possibility of greater sensitivity to the drug exists in some geriatric individuals.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Insufficient experience in patients with severe hepatic impairment (Child-Pugh C); use not recommended.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Insufficient experience in patients with severe renal impairment or in patients requiring renal dialysis; use not recommended.1 \

Common Adverse Effects

Headache,1 2 3 flushing,1 2 3 nasal congestion,1 2 3 nasopharyngitis,1 2 3 back pain.1 2 3

Interactions for Stendra

Metabolized principally by CYP3A4; CYP2C appears to play a minor role.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased avanafil exposure) and increased risk of PDE type 5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual changes, priapism).1 47 48 200 Do not use concomitantly with potent CYP3A4 inhibitors; reduce avanafil dose when used concomitantly with moderate CYP3A4 inhibitors.1 (See Specific Drugs and Foods under Interactions.)

Inducers of CYP: Potential pharmacokinetic interaction (decreased avanafil exposure) and possible decreased efficacy of avanafil.17 Drug interaction studies with CYP inducers not performed to date;1 concomitant use with CYP inducers not recommended.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

α-Adrenergic blocking agents

Possible symptomatic hypotension 1

In those who are stable on an α-adrenergic blocker, initiate avanafil at dose of 50 mg; in those currently receiving avanafil, initiate α-adrenergic blocker at the lowest dose1

Alcohol

Possible additive hypotensive effects1

Do not use alcohol excessively (e.g., ≥3 glasses of wine or shots of whiskey)5

Amlodipine

Possible additive hypotensive effects1

Antifungal agents, azole (i.e., fluconazole, itraconazole, ketoconazole)

Possible increased AUC and peak plasma concentrations of avanafil1

Itraconazole, ketoconazole: Do not use concomitantly1

Fluconazole: Reduced avanafil dosage (≤50 mg once every 24 hours) recommended1

Antiretroviral agents, HIV protease inhibitors (e.g., atazanavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir)

Possible increased AUC and peak plasma concentrations of avanafil1 47 48 200

Atazanavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir: Do not use concomitantly1

Fosamprenavir: Reduced avanafil dosage (≤50 mg once every 24 hours) recommended1

Aprepitant

Possible increased AUC and peak plasma concentrations of avanafil1

Reduced avanafil dosage (≤50 mg once every 24 hours) recommended 1

Diltiazem

Possible increased AUC and peak plasma concentrations of avanafil1

Reduced avanafil dosage (≤50 mg once every 24 hours) recommended1

Enalapril

Possible additive hypotensive effects1

Grapefruit juice

Possible increased AUC of avanafil1

Macrolides (clarithromycin, erythromycin, telithromycin)

Possible increased AUC and peak plasma concentrations of avanafil1

Clarithromycin, telithromycin: Do not use concomitantly1

Erythromycin: Reduced avanafil dosage (≤50 mg once every 24 hours) recommended1

Nefazodone

Possible increased AUC and peak plasma concentrations of avanafil1

Do not use concomitantly1

Nitrates, nitrites, nitric oxide donors (e.g., nitroglycerin, isosorbide dinitrate, amyl nitrite)

Potentiation of hypotensive effect1

Concomitant use contraindicated1

If nitrate administration necessary for a life-threatening condition, allow ≥12 hours to elapse between avanafil administration and nitrate use;1 administer under close supervision with caution and appropriate hemodynamic monitoring1

Verapamil

Possible increased AUC and peak plasma concentrations of avanafil1

Reduced avanafil dosage (≤50 mg once every 24 hours) recommended1

Warfarin

Clinically important effects on avanafil pharmacokinetics not observed;1 no substantial effect on PT or INR1

Stendra Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations usually attained within 30–45 minutes.1

Onset

Following a single oral dose, effects apparent within 15 minutes.1 10

Duration

Erectile response: Likely up to 2 hours based on available data.1 16

Food

Food does not appear to appreciably affect absorption.1

Special Populations

In patients with mild hepatic impairment, avanafil exposure is comparable to values in healthy individuals.1 In patients with moderate hepatic impairment, peak plasma concentrations decreased by 51% and AUC increased by 11% compared with values in healthy individuals.1 Pharmacokinetic data lacking in patients with severe hepatic impairment.1

In patients with mild to moderate renal impairment, avanafil exposure is comparable to values in healthy individuals.1 Pharmacokinetic data lacking in patients with severe renal impairment or patients on renal dialysis.1

Distribution

Extent

Appears to be widely distributed in the body.18

Distributed to a limited extent in semen.1

Plasma Protein Binding

Approximately 99%.1 18

Elimination

Metabolism

Metabolized in the liver, principally by CYP3A4, to largely inactive metabolites.1

Elimination Route

Excreted as metabolites in the feces (approximately 62%) and urine (approximately 21%).1

Half-life

Approximately 5 hours.1

Stability

Storage

Oral

Tablets

20–25°C (may be temporarily exposed to ≤30°C).1 5 Protect from light.1 5

Actions

  • Selective inhibitor of PDE, with high selectivity for PDE type 5, the principal isoenzyme involved in the metabolism of cGMP to GMP in the corpora cavernosa of the penis.1 2 3 7 In vitro, avanafil does not substantially inhibit other PDE isoenzymes.1 2 3 7

  • Enhances the effect of nitric oxide by inhibiting PDE type 5-mediated hydrolysis of cGMP, resulting in vascular relaxation.1

  • Potentiates accumulation of cGMP only when cGMP production in the penis is increased by sexual arousal; no effect on erectile function in the absence of sexual stimulation.1

  • Although pharmacologically related to other PDE type 5 inhibitors, avanafil generally has a faster onset compared with sildenafil, vardenafil, or tadalafil.2 3 7

Advice to Patients

  • Importance of providing a copy of the manufacturer’s written patient information.1 5

  • Provide instructions regarding proper administration for optimal use, including necessity of sexual stimulation for the achievement of an erection.1 5 Importance of taking the drug exactly as prescribed and not exceeding recommended dose or frequency of use.5

  • Importance of informing clinicians about any risk factors for cardiovascular disease (e.g., current or previous MI, arrhythmia, angina, heart failure) prior to initiating any treatment for ED.1 5 Importance of not using avanafil if underlying cardiovascular disease precludes sexual activity.1

  • Potential for sudden vision loss or decreased vision (i.e., NAION).1 5 If NAION already has occurred in one eye, possible increased risk of NAION developing in the other eye.1 Importance of discontinuing avanafil and other PDE type 5 inhibitors and seeking immediate medical attention if sudden vision loss or decreased vision occurs in one or both eyes.1 5

  • Risk of sudden hearing impairment; advise patients to discontinue avanafil and other PDE type 5 inhibitors and seek immediate medical attention if sudden hearing loss or decreased hearing occurs.1 5

  • Importance of avoiding concurrent use of organic nitrates or nitrites (e.g., nitroglycerin, isosorbide dinitrate) or nitric oxide donors (e.g., sodium nitroprusside) in any form, including the recreational use of inhaled nitrites (“poppers”), because of the potential for hypotension and associated dizziness, syncope, or even MI or stroke.1 5

  • Potential for interactions with concurrent drugs (e.g., nitrates, α-adrenergic blocking agents, antihypertensive agents, potent inhibitors of CYP3A4) or alcohol.1 5 47 48 (See Specific Drugs under Interactions.)

  • Risk of symptomatic hypotension (e.g., dizziness, fainting) with concurrent use of α-adrenergic blocking agents (or other antihypertensive drugs).1

  • Importance of refraining from further sexual activity and seeking immediate medical attention if symptoms such as angina pectoris, dizziness, or nausea occur during sexual activity.1 5 (See Cardiovascular Effects under Cautions.)

  • Importance of seeking immediate medical attention if an erection persists >4 hours or is painful.1 5

  • Advise patient of potential for transmission of sexually transmitted diseases (e.g., HIV) and the need to use protective measures to guard against transmission of such diseases.1 5

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, and alcohol consumption, as well as any concomitant illnesses.1 5 Importance of limiting intake of alcohol-containing beverages or products.1 5

  • Importance of informing patients of other important precautionary information.1 5 (See Cautions.)

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

Tablets

50 mg

Stendra

Vivus

100 mg

Stendra

Vivus

200 mg

Stendra

Vivus

AHFS DI Essentials. © Copyright 2017, Selected Revisions January 30, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Vivus. Stendra (avanafil) tablets prescribing information. Mountain View, CA; 2015 Jan.

2. Goldstein I, McCullough AR, Jones LA et al. A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction. J Sex Med. 2012; 9:1122-33. [PubMed 22248153]

3. Goldstein I, Jones LA, Belkoff LH et al. Avanafil for the treatment of erectile dysfunction: a multicenter, randomized, double-blind study in men with diabetes mellitus. Mayo Clin Proc. 2012; 87:843-52. [PubMed 22857780]

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application Number 202276Orig1s000: Summary Review. From FDA Website. Accessed 2014 Apr 4.

5. Vivus, Inc. Stendra (avanafil) tablets patient information. Mountain View, CA; 2015 Jan.

6. Qaseem, A, Snow V, Denberg T et al. Hormonal testing and pharmacologic testing of erectile dysfunction: A clinical practice guidelines from the the American College of Physicians. Ann Intern Med. 2009; 151:639-49. [PubMed 19884625]

7. Burke RM, Evans, JD. Avanavil for treatment of erectile dysfunction: review of its potential. Vasc Health Risk Manag. 2012; 8:517-23. [PubMed 22973106]

8. Erectile Dysfunction Guideline Update Panel, American Urological Association Education and Research. Management of erectile dysfunction: An update. 2005. Available from website. Accessed 2014 May 23

9. Nehra A, Jackson G, Miner, M et al. The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc. 2012; 87:766-78. [PubMed 22862865]

10. Hellstrom WH, Kaminetsky J, Belkoff LH et al. Efficacy of avanafil fifteen minutes after dosing in men with erectile dysfunction: A randomized, double-blind, placebo-controlled study. J Urol. 2015;

12. The Process of Care Consensus Panel. Position paper: the process of care model for evaluation and treatment of erectile dysfunction. Int J Impotence Res. 1999; 11:59-70.

13. Palmer BF. Sexual dysfunction in uremia. J Am Soc Nephrol. 1999; 10:1381-8. [PubMed 10361878]

14. Guay AT, Nankin AR et al. AACE clinical practice guidelines for the evaluation and treatment of male sexual dysfunction. From American Association of Clinical Endocrinologists web site.

15. Hatzimouratidis K, Eardley I, Giuliano D, et al. Guidelines on male sexual dysfunction: Erectile dysfunction and premature ejaculation: European Association of Urology, 2013 Mar. Available from website. Accessed 2014 Dec.

16. US Food and Drug Administration. Center for Drug Evaluation and Research. Application Number 202276Orig1s000: Medical Review(s). From FDA Website. Accessed 2014 Apr 4.

17. Schwartz BG, Kloner RA. Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation. 2010; 122:88-95. [PubMed 20606131]

18. US Food and Drug Administration. Center for Drug Evaluation and Research. Application Number 202276Orig1s000: Pharmacology Review(s). From FDA Website. Accessed 2014 Apr 4.

24. Pfizer Inc. Viagra (sildenafil citrate) tablets prescribing information. New York, NY; 2014 Mar.

25. Lilly. Cialis (tadalafil) tablets prescribing information. Indianapolis, IN; 2014 Apr.

26. GlaxoSmithKline. Levitra (vardenafil hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2015 Sep.

35. Goldstein I, Lue TF, Padma-Nathan H et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998; 338:1397-404.

44. Food and Drug Administration, Center for Drug Evaluation and Research. Questions and answers about Viagra, Levitra, Cialis, and Revatio: Possible sudden hearing loss. From FDA Website.

47. AbbVie. Kaletra (lopinavir/ritonavir) oral tablets and solution prescribing information. North Chicago, IL; 2013 Nov.

48. AbbVie. Norvir (ritonavir) tablets and solution, for oral use, prescribing information. North Chicago, Il; 2015 Nov.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (November 13, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Schering-Plough, Kenilworth, NJ: Personal communication on vardenafil monograph.

202. Jackson G, Betteridge J, Dean J et al. A systematic approach to erectile dysfunction in the cardiovascular patient: a Consensus Statement—update 2002. Int J Clin Pract. 2002, 56(9):663-71.

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