Vardenafil Hydrochloride

Pronunciation

Class: Phosphodiesterase Type 5 Inhibitors
VA Class: GU900
Chemical Name: 1 - [[3 - (3,4 - Dihydro - 5 - methyl - 4 - oxo - 7 - propylimidazo[5,1 - f] - as - triazin - 2 - yl) - 4 - ethoxyphenyl]sulfonyl] - 4 - ethylpiperazine
Molecular Formula: C23H32N6O4S
CAS Number: 224785-90-4
Brands: Levitra

Warning(s)

Special Alerts:

[Posted 10/18/2007] FDA informed healthcare professionals of reports of sudden decreases or loss of hearing following the use of PDE5 inhibitors sildenafil (Viagra), tadalafil (Levitra), vardenafil (Cialis) for the treatment of erectile dysfunction, and sildenafil (Revatio) for the treatment of pulmonary arterial hypertension. In some cases, the sudden hearing loss was accompanied by tinnitus and dizziness. Medical follow-up on these reports was often limited which makes it difficult to determine if the loss of hearing was related to the use of one of the drugs, an underlying medical condition or other risk factors for hearing loss, a combination of these factors or other factors. The PRECAUTIONS and ADVERSE REACTIONS sections of the approved product labeling for sildenafil (Viagra), tadalafil, and vardenafil were revised. FDA is working with the manufacturer to revise the labeling for sildenafil (Revatio). For more information visit the FDA website at: , and .

Introduction

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

Uses for Vardenafil Hydrochloride

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Slideshow: The Rise to Fame: Viagra, PDE5 Inhibitors, and ED

Erectile Dysfunction

To facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence).1

Vardenafil Hydrochloride Dosage and Administration

General

  • Dosage must be individualized carefully according to the patient’s tolerance and erectile response.1

  • Sexual stimulation is required for response to therapy.1

Administration

Oral Administration

Administer orally, no more than once daily, without regard to meals.1 3

Administer approximately 1 hour before anticipated sexual activity.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as vardenafil hydrochloride; dosage expressed in terms of vardenafil.1

Adults

Erectile Dysfunction
Oral

Initially, 10 mg.1 Depending on effectiveness and tolerance, increase dosage to a maximum of 20 mg or decrease to 5 mg. Administer no more frequently than once daily.1

Prescribing Limits

Adults

Erectile Dysfunction
Oral

Maximum 20 mg daily.1

Special Populations

Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh class B), decrease initial dosage to 5 mg; maximum dosage is 10 mg once daily.1 Not studied in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Dosage adjustments not required in patients with patients with mild (Clcr of 50–80 mL/minute) to severe (Clcr <30 mL/minute) renal impairment.1 Not studied in patients requiring renal dialysis.1

Geriatric Patients

Reduce initial dose to 5 mg given no more frequently than once daily in men ≥65 years of age.1 26

Cautions for Vardenafil Hydrochloride

Contraindications

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

  • Concomitant use of nitrates, nitrites, or nitric oxide donors, either regularly or intermittently, or α-adrenergic blocking agents.1 28

  • Should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.1 5

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Cardiovascular Effects

Serious, potentially fatal cardiovascular events reported rarely.1 5 6

Use not recommended in patients with a recent (within 6 months) MI, stroke, or life-threatening arrhythmia; resting hypotension (<90 mm Hg resting SBP) or hypertension (170/110 mm Hg SBP/DBP); or severe heart failure or unstable angina.1 4 7 8 26

Possible hypotension; consider whether patients with underlying cardiovascular disease could be affected adversely by vardenafil’s vasodilatory activity.1 Risk of an undesired hypotensive or vasodilatory response is of particular concern in patients with left-ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis).1 6

Potentiation of hypotensive effect with organic nitrates may result in life-threatening hypotension and/or hemodynamic compromise.1 Possible significant hypotension when given concurrently with α-adrenergic blocking agents.1 Manufacturers state that concomitant use of nitrates or α-adrenergic blocking agents with vardenafil is contraindicated.1 (See Specific Drugs under Interactions.)

Possible prolonged QT interval.1 Use not recommended in patients with known prolongation of the QT interval and those receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents.1

Concomitant Use with Potent CYP3A4 Inhibitors

Safety not established with long-term use of vardenafil concomitantly with potent CYP3A4 inhibitors (e.g., ritonavir, indinavir, ketoconazole, itraconazole).1 Increased plasma vardenafil concentrations with concomitant use; dosage reduction of vardenafil recommended.1 (See Specific Drugs under Interactions.)

Priapism

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

May result in penile tissue damage and permanent loss of potency if priapism is not treated immediately.1 Use with caution in patients with conditions that may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia).1

Ocular Effects

Possible visual disturbances (e.g., abnormal, dim, or blurred vision; changes in color vision [e.g., chromatopsia]).1 4

Not studied in patients with hereditary degenerative retinal disorders, including those with retinitis pigmentosa.1 Use not recommended until further information is available.1

Sensitivity Reactions

Anaphylactic reaction, including laryngeal edema, reported.1

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Patient Assessment

Thorough medical history and physical examination recommended to diagnose erectile dysfunction, determine potential underlying causes, and identify appropriate treatment.1 5

Review of the patient’s current drug regimens recommended to detect possible drug-induced erectile dysfunction.5

Hematologic Effects

No prolongation of bleeding time with vardenafil dosages ≤20 mg.1

However, not studied in patients with bleeding disorders or active peptic ulcers;1 4 8 therefore, careful risk/benefit assessment is necessary before use in such patients.1 4 8

GU Effects

Use with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie’s disease).1

Specific Populations

Pregnancy

Category B.1 Not indicated for use in women.1

Lactation

Not indicated for use in women.1

Pediatric Use

Not indicated for use in neonates or children.1

Geriatric Use

Safety and efficacy in males ≥65 years of age similar to that in younger males.1 Increased plasma vardenafil concentrations in men ≥65 years of age compared to that in younger males; therefore consider lower initial dosage.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Decreased clearance in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.) Not studied in patients with severe hepatic impairment (Child-Pugh class C), and use of the drug in such patients is not recommended.1 26

Renal Impairment

Clearance decreased in patients with moderate (Clcr 30–50 mL/minute) to severe (Clcr <30 mL/minute) renal impairment.1 (See Renal Impairment under Dosage and Administration.) Not studied in patients with end-stage renal disease requiring dialysis.1

Common Adverse Effects

Headache,1 2 7 8 flushing, 1 2 7 8 rhinitis,1 2 8 dyspepsia.1 2 7

Interactions for Vardenafil Hydrochloride

Metabolized principally by CYP3A4; CYP2C and CYP3A5 appear to play a minor role.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma vardenafil concentrations).1

Specific Drugs

Drug

Interaction

Comments

α-Adrenergic blocking agents

Possible symptomatic hypotension 1

Concurrent use is contraindicated1

Alcohol

No potentiation of hypotensive effect reported1

Antacids (aluminum hydroxide and magnesium hydroxide)

Pharmacokinetic interaction unlikely1

Antiarrhythmic agents (amiodarone, procainamide, quinidine, sotalol)

Possible prolongation of the QTc interval1

Avoid concomitant use1

Antihypertensive agents

Possible additive hypotensive effects

Antiretroviral agents, HIV protease inhibitors

Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)1 29 31 33

Decreased indinavir and ritonavir concentrations1 29 31 33

Ritonavir or lopinavir: Do not exceed a single vardenafil dose of 2.5 mg in 72 hours;1 29 no change in ritonavir dosage needed29

Ritonavir in combination with indinavir, atazanavir, saquinavir, fosamprenavir, or nelfinavir: Do not exceed a vardenafil dosage of 2.5 mg in 72 hours29 33

Nelfinavir, indinavir, amprenavir, saquinavir, fosamprenavir, or atazanavir: Use initial vardenafil dosage of 2.5 mg and do not exceed a single dose of 2.5 mg in 24 hours1 29 30 31 33

Monitor closely 29 31 32 33 34

Antiretroviral agents, nonnucleoside reverse transcriptase inhibitors

Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)29

Delavirdine: Use initial vardenafil dosage of 2.5 mg; do not exceed 2.5 mg once in 24 hours29

Aspirin

No increase in bleeding time reported1

Cimetidine

Pharmacokinetic interaction unlikely1

Digoxin

Pharmacokinetic interaction unlikely1

Erythromycin

Increased AUC and peak plasma concentrations of vardenafil1

Reduce initial vardenafil dosage to 5 mg in patients receiving erythromycin1

Glyburide

Pharmacokinetic interaction unlikely1

Inhaled nitrites (e.g., amyl or butyl nitrite)

Potentiation of hypotensive effect28

Concomitant use is contraindicated28 (see Cautions)

Itraconazole

Possible increased vardenafil concentrations1

Reduce initial vardenafil dosage to 2.5 mg in patients receiving itraconazole 400 mg daily1

Reduce initial vardenafil dosage to 5 mg in patients receiving itraconazole 200 mg daily1

Ketoconazole

Increased vardenafil concentrations 1

Reduce initial vardenafil dosage to 2.5 mg in patients in patients receiving ketoconazole 400 mg daily1

Reduce initial vardenafil dosage to 5 mg in patients receiving ketoconazole 200 mg daily1

Nifedipine

Possible additive hypotensive effect1

Nitrates and nitric acid donors

Potentiation of vasodilatory effects; potentially life-threatening hypotension and/or hemodynamic compromise can result1

Concomitant use is contraindicated1 28

Ranitidine

Pharmacokinetic interaction unlikely

Warfarin

Pharmacokinetic and pharmacodynamic interaction unlikely1

Vardenafil Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak concentrations usually attained within 0.5–2 hours.1

Absolute bioavailability is approximately 15%.1

Food

Administration with a high-fat meal reduces the peak plasma concentrations by 18–50%.1 3

Distribution

Extent

Extensively distributed into tissues.1

Plasma Protein Binding

Approximately 95% for the drug and major metabolite.1

Elimination

Metabolism

Metabolized in the liver to active metabolite(s) principally via CYP3A4, with minor contributions from CYP3A5 and CYP2C.1

Elimination Route

Excreted as metabolites principally in the feces (91–95%) and to a lesser extent in urine (2–6%).1

Half-life

Terminal half-life 4–5 hours for drug and major metabolite.1

Special Populations

Clearance reduced in men ≥65 years of age, resulting in an increase in AUC and peak plasma concentrations compared with younger males.1

Clearance reduced in patients with moderate (Clcr of 30–50 mL/minute) or severe (Clcr <30 ml/minute) renal impairment, resulting in an increase in AUC compared with patients with normal renal function.1

Clearance reduced in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, resulting in an increase in AUC and peak plasma concentrations compared with healthy adults.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Selective inhibitor of phosphodiesterases (PDEs) with the greatest selectivity for PDE type 5, the principal isoenzyme involved in the metabolism of cGMP to GMP in the corpora cavernosa of the penis.1

  • Enhances the effect of nitric oxide by inhibiting PDE type 5-mediated hydrolysis of cGMP.1 2

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

  • Modest peripheral vasodilation accompanied by a small increase in heart rate at usual dosages.1 6 27

  • Although less affinity than sildenafil for PDE type 6 receptor in the retina, some transient visual abnormalities observed.1 27

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of informing clinician of risk factors for cardiovascular disease prior to initiating any treatment for erectile dysfunction.1 5

  • Importance of informing clinician of stroke history.1

  • Importance of informing clinician of low or high BP.1

  • Importance of informing clinician of the presence of retinitis pigmentosa.2

  • Importance of informing patients of the potential for life-threatening hypotension and/or hemodynamic compromise with concurrent use of organic nitrates and 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 26

  • Importance of avoiding concurrent use of α-adrenergic blocking agents because of the potential for hypotension, dizziness, or fainting.1

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

  • Importance of advising patient that vardenafil does not protect against sexually transmitted diseases (e.g., HIV) and about measures to protect against such transmission.1

  • Importance of contacting a clinician for assessment of therapeutic benefit, the need for possible dosage adjustment, and potential adverse effects.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

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

Preparations

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

Vardenafil Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2.5 mg (of vardenafil)

Levitra

Schering-Plough

5 mg (of vardenafil)

Levitra

Schering-Plough

10 mg (of vardenafil)

Levitra

Schering-Plough

20 mg (of vardenafil)

Levitra

Schering-Plough

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Levitra 10MG Tablets (GLAXO SMITH KLINE): 10/$202.99 or 30/$582.97

Levitra 2.5MG Tablets (SCHERING): 10/$164.00 or 20/$328.00

Levitra 20MG Tablets (GLAXO SMITH KLINE): 10/$202.99 or 30/$582.97

Levitra 5MG Tablets (GLAXO SMITH KLINE): 10/$212.99 or 30/$608.97

Staxyn 10MG Dispersible Tablets (GLAXO SMITH KLINE): 4/$62.99 or 12/$165.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Schering-Plough. Levitra (vardenafil hydrochloride) tablets prescribing information. West Haven, CT; 2004 Oct.

2. Coleman CI, Carabino JM, Vergara CM. Vardenafil: an oral selective phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction. Formulary. 2003; 38:131-148.

3. Rajagopalan P, Mazzu A, Xia C et al. Effect of high-fat breakfast and moderate-fat evening meal on the pharmacokinetics of vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction. J Clin Pharmacol. 2003; 43(3):260-7. [IDIS 495567] [PubMed 12638394]

4. Brock G, Nehra A, Lipshultz LI et al. Safety and efficacy of vardenafil for the treatment of men with erectile dysfunction after radical retropubic prostatectomy. J Urol. 2003; 170(4 Pt 1):1278-83. [IDIS 504241] [PubMed 14501741]

5. 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. [IDIS 491098] [PubMed 12469980]

6. Cheitkin MD, Hutter AM, Brindis RG for the American College or Cardiology and American Heart Association. Technology and Practice Executive Committee [duplicate publication of Cheitkin MD, Hutter AM, Brindis RG for the American College or Cardiology and American Heart Association. ACC/AHA expert consensus document: use of sildenafil (viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol. 1999; 33:273-82.

7. Hellstrom WJ, Gittelman M, Karlin G et al. Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial. Urology. 2003; 61(4 Suppl 1):8-14. [PubMed 12657355]

8. Goldstein I, Young JM, Fischer J et al. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care. 2003; 26(3):777-83. [IDIS 517794] [PubMed 12610037]

9. National Institutes of Health Office of Medical Applications of Research. Consensus Conference: impotence. JAMA. 1993; 270:83-90. [IDIS 316686] [PubMed 8510302]

10. Pfizer Inc, New York, NY: Personal communication on sildenafil.

11. Reviewers’ comments on sildenafil (personal observations).

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. Whitehead ED, Klyde BJ, Zussman S et al. Treatment alternatives for impotence. Postgrad Med. 1990; 88:139-52. [IDIS 269901] [PubMed 2199954]

16. Gerber GS, Levine LA. Pharmacological erection program using prostaglandin E1. J Urol. 1991; 146:786-9. [IDIS 287641] [PubMed 1875494]

17. Porst H. Editorial comments on the process of care model for evaluation and treatment of erectile dysfunction. Int J Impotence Res. 1999; 11: 72-3.

18. Sarramon JP. Editorial comments on the process of care model for evaluation and treatment of erectile dysfunction. Int J Impotence Res. 1999; 11:73.

19. Vermeuler A. Editorial comments on the process of care model for evaluation and treatment of erectile dysfunction. Int J Impotence Res. 1999; 11:74.

20. Sohn MHH. Editorial comments on the process of care model for evaluation and treatment of erectile dysfunction. Int J Impotence Res. 1999; 11:72.

21. Sefetl AD. Phosphodiesterase type 5 inhibitor differentiation based on selectivity, pharmacokinetic, and efficacy profiles. Clin Cardiol. 2004; 27(Suppl. 1):I-14-9.

22. Padma-Nathan H. A new era in the treatment of erectile dysfunction. Am J Cardiol. 1999; 84:18-23N. [PubMed 10404845]

23. Wespes E, Amar E, Hatzichtistou D et al. Guidelines on reactile dysfunction. Arnhem: European Association of Urology, 2004 Mar. Available at . Accessed 2004 Aug.

24. Pfizer Inc. Viagra (sildenafil citrate) prescribing information. New York, NY; 2002 Sep.

25. Lilly ICOS. Cialis (tadalafil) tablets prescribing information. Indianapolis, IN; 2003 Nov.

26. Schering-Plough, Kenilowrth, NJ. Personal communication.

27. Crowe SM, Streetman DS. Vardenafil treatment for erectile dysfunction. Ann Pharmacother. 2004; 38:77-85. [IDIS 514325] [PubMed 14742800]

28. Schering-Plough. Levitra (vardenafil hydrochloride) tablets patient information. From Levitra website: (). Accessed 2005 May16.

29. Panel on Clinical Practices for Treatment of HIV infection of the Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (Apr 7, 2005). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website ().

30. Merck & Company Inc. Crixivan (indinavir sulfate) capsules prescribing information. West Point, PA; 2004 May.

31. Bristol-Myers Squibb. Reyataz (atazanavir sulfate) prescribing information. Princeton, NJ; 2004 Jul.

32. Roche Pharmaceuticals. Fortovase (saquinavir) soft gelatin capsules prescribing information. Nutley, NJ; 2003 Dec.

33. GlaxoSmithKline. Lexiva (fosamprenavir calcium) tablets prescribing information. Research Triangle Park, NC; 2004 May.

34. Roche Laboratories. Invirase (saquinavir mesylate) capsules prescribing information. Nutley, NJ; 2004 Dec.

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