indication

Used for the treatment of erectile dysfunction

pharmacology

Vardenafil is used to treat male erectile dysfunction (impotence) and pulmonary arterial hypertension (PAH). Part of the physiological process of erection involves the release of nitric oxide (NO) in the corpus cavernosum. This then activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in the corpus cavernosum, resulting in increased inflow of blood and an erection. Vardenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum. This means that, with vardenafil on board, normal sexual stimulation leads to increased levels of cGMP in the corpus cavernosum which leads to better erections. Without sexual stimulation and no activation of the NO/cGMP system, vardenafil should not cause an erection.

mechanism of action

Vardenafil inhibits the cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by vardenafil enhances erectile function by increasing the amount of cGMP.

toxicity

Symptoms of overdose include vision changes and back and muscle pain.

biotransformation

Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil.

absorption

Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%.

half life

4-5 hours

route of elimination

After oral administration, vardenafil is excreted as metabolites predominantly in the feces (approximately 91-95% of administered oral dose) and to a lesser extent in the urine (approximately 2-6% of administered oral dose).

drug interactions

Alfuzosin: Additive hypotensive effects of the PDE5 inhibitor, Vardenafil, and alpha1-blocker, Alfuzosin, may occur. Monitor for hypotension during concomitant therapy.

Amiodarone: Increased risk of cardiotoxicity and arrhythmias

Amprenavir: Amprenavir, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Atazanavir: Atazanavir, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Clarithromycin: Clarithromycin, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Conivaptan: Conivaptan, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Darunavir: Darunavir, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Delavirdine: Delavirdine, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Doxazosin: Additive hypotensive effects of the PDE5 inhibitor, Vardenafil, and alpha1-blocker, Doxazosin, may occur. Monitor for hypotension during concomitant therapy.

Erythromycin: Erythromycin, a moderate CYP3A4 inhibitor, may reduce the metabolism and clearance of vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of vardenafil if erythromycin is initiated, discontinued or dose changed.

Fosamprenavir: Fosamprenavir, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Imatinib: Imatinib, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Indinavir: Indinavir, a potent CYP3A4 inhibitor, may decrease the metabolism and clearance of Vardenafil. Concomitant therapy is contraindicated.

Isoniazid: Isoniazid, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Isosorbide Dinitrate: The vasodilatory effects of Isosorbide dinitrate may be increased by Vardenafil. Severe hypotension may occur. Concomitant therapy is contraindicated.

Isosorbide Mononitrate: The vasodilatory effects of Isosorbide mononitrate may be increased by Vardenafil. Severe hypotension may occur. Concomitant therapy is contraindicated.

Itraconazole: Itraconazole, a potent CYP3A4 inhibitor, may decrease the metabolism and clearance of Vardenafil. Concomitant therapy is contraindicated.

Ketoconazole: Ketoconazole, a potent CYP3A4 inhibitor, may decrease the metabolism and clearance of Vardenafil. Concomitant therapy is contraindicated.

Lopinavir: Lopinavir, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Miconazole: Miconazole, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Nefazodone: Nefazodone, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Nelfinavir: Nelfinavir, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Nicardipine: Nicardipine, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Nitroglycerin: The vasodilatory effects of Nitroglycerin may be increased by Vardenafil. Severe hypotension may occur. Concomitant therapy is contraindicated.

Phenoxybenzamine: Additive hypotensive effects of the PDE5 inhibitor, Vardenafil, and alpha1-blocker, Phenoxybenzamine, may occur. Monitor for hypotension during concomitant therapy.

Phentolamine: Additive hypotensive effects of the PDE5 inhibitor, Vardenafil, and alpha1-blocker, Phentolamine, may occur. Monitor for hypotension during concomitant therapy.

Posaconazole: Posaconazole, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Prazosin: Additive hypotensive effects of the PDE5 inhibitor, Vardenafil, and alpha1-blocker, Prazosin, may occur. Monitor for hypotension during concomitant therapy.

Procainamide: Increased risk of cardiotoxicity and arrhythmias

Quinidine: Quinidine, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Ritonavir: Ritonavir, a potent CYP3A4 inhibitor, may decrease the metabolism and clearance of Vardenafil. Concomitant therapy is contraindicated.

Saquinavir: Saquinavir, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Tamsulosin: Additive hypotensive effects of the PDE5 inhibitor, Vardenafil, and alpha1-blocker, Tamsulosin, may occur. Monitor for hypotension during concomitant therapy.

Telithromycin: Telithromycin, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Terazosin: Additive hypotensive effects of the PDE5 inhibitor, Vardenafil, and alpha1-blocker, Terazosin, may occur. Monitor for hypotension during concomitant therapy.

Tipranavir: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Vardenafil. Concomitant therapy is contraindicated.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of vardenafil by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of vardenafil if voriconazole is initiated, discontinued or dose changed.