Brands, Medical Use, Clinical Data
- Anti-Impotence Agents
- Vasoconstrictor Agents
- Phosphodiesterase Inhibitors
- Tablet (5, 10, and 20 mg)
Brands / Synonyms
Levitra; VARDENAFIL, LEVITRA; VDN
Used for the treatment of erectile dysfunction
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.
Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%.
Symptoms of overdose include vision changes and back and muscle pain.
Biotrnasformation / Drug Metabolism
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.
Nitrates: Administration of LEVITRA with nitrates (either regularly and/or intermittently) and nitric oxide
donors is contraindicated. Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine
monophosphate pathway, PDE5 inhibitors may potentiate the hypotensive effects of nitrates. A suitable time interval
following LEVITRA dosing for the safe administration of nitrates or nitric oxide donors has not been determined.
Hypersensitivity: LEVITRA is contraindicated for patients with a known hypersensitivity to any component of
Effect of other drugs on Vardenafil
In vitro studies: Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance.
In vivo studies: Cytochrome P450 Inhibitors
Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (Cmax) of vardenafil when co-administered with 20 mg Vardenafil in healthy volunteers.
Erythromycin (500 mg t.i.d) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax when co-administered with Vardenafil 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of Vardenafil in a 24-hour period when used in combination with erythromycin. Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in Cmax when co-administered with Vardenafil (5 mg) in healthy volunteers. A 5-mg Vardenafil dose should not be exceeded when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in Cmax and AUC, a single 2.5 mg dose of Vardenafil should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily.
HIV Protease Inhibitors: Indinavir (800 mg t.i.d.) co-administered with Vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg Vardenafil dose in a 24-hour period when used in combination with indinavir.
Ritonavir (600 mg b.i.d.) co-administered with Vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg Vardenafil dose in a 72-hour period when used in combination with ritonavir.
Other Drug Interactions: No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, Maalox, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.
Effects of Vardenafil on other drugs
In vitro studies: Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki > 100uM). Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing. The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1.4 uM toward CYP3A4, which is about 20 times higher than the M1 Cmax values after an 80 mg Vardenafil dose.
In vivo studies: Nitrates: The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1, 4 and 8 hours were potentiated by a 20 mg dose of Vardenafil in healthy middle-aged subjects. These effects were not observed when Vardenafil 20 mg was taken 24 hours before the NTG. Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of Vardenafil and nitrates is contraindicated.
Nifedipine: Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative bioavailability (AUC) or maximum concentration (Cmax) of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of Vardenafil when taken in combination. In these patients whose hypertension was controlled with nifedipine, Vardenafil 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mm Hg compared to placebo.
Alpha-blockers: When Vardenafil 10 or 20 mg was given to healthy volunteers either simultaneously or 6 hours after a 10 mg dose of terazosin, significant hypotension developed in a substantial number of subjects. With simultaneous dosing of Vardenafil 10 mg and terazosin 10 mg, 6 of 8 subjects experienced a standing systolic blood pressure of less than 85 mm Hg. With simultaneous dosing of Vardenafil 20 mg and terazosin 10 mg, 2 of 9 subjects experienced a standing systolic blood pressure of less than 85 mm Hg. When Vardenafil dosing was separated from terazosin 10 mg by 6 hours, 7 of 28 subjects who received 20 mg of Vardenafil experienced a decrease in standing systolic blood pressure below 85 mm Hg. In a similar study with tamsulosin in healthy volunteers, 1 of 24 subjects dosed with Vardenafil 20 mg and tamsulosin 0.4 mg separated by 6 hours experienced a standing systolic blood pressure below 85 mm Hg. Two of 16 subjects dosed simultaneously with Vardenafil 10 mg and tamsulosin 0.4 mg experienced a standing systolic blood pressure below 85 mm Hg. The administration of lower doses of Vardenafil with alpha-blockers has not been completely evaluated to determine if they can be safely administered together. Based on these data, Vardenafil should not be used in patients on alpha-blocker therapy.
Ritonavir and indinavir: Upon concomitant administration of 5 mg of Vardenafil with 600 mg BID ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of Vardenafil with 800 mg TID indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively.
Alcohol: Alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person) and vardenafil plasma levels were not altered when dosed simultaneously. Vardenafil (20 mg) did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight).
Aspirin: Vardenafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).
Other interactions: Vardenafil had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).