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LEVITRA (VARDENAFIL): DRUG INTERACTIONS

Effect of other drugs on Levitra

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 Levitra 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 Levitra 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of Vardenafil (Levitra) tablets 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 4fold increase in Cmax when co-administered with Levitra (5 mg) in healthy volunteers. A 5 mg Levitra (Vardenafil Hydrochloride) 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 Levitra 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 Levitra 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 Levitra (Vardenafil Hydrochloride) tablets dose in a 24-hour period when used in combination with indinavir.

Ritonavir (600 mg b.i.d.) co-administered with Levitra 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 Levitra dose in a 72-hour period when used in combination with ritonavir.

Other CYP3A4 inhibitors

Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase vardenafil exposure.

Other Drug Interactions

No pharmacokinetic interactions were observed between vardenafil and the following drugs: warfarin, glyburide, digoxin, Maalox, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.

Effects of Vardenafil HCl (Levitra) on other drugs

In vitro studies

Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 µM). 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 µM toward CYP3A4, which is about 20 times higher than the M1 Cmax values after an 80 mg Levitra 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 Levitra in healthy middle-aged subjects. These effects were not observed when Levitra 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 HCl (Levitra) tablets 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 Levitra (Vardenafil) when taken in combination. In these patients whose hypertension was controlled with nifedipine, Levitra 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo.

Alpha-blockers

Blood pressure effects in patients on stable alpha-blocker treatment

Two clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment for at least four weeks.

Study 1: This study was designed to evaluate the effect of 5 mg vardenafil compared to placebo when administered to BPH patients on chronic alpha-blocker therapy in two separate cohorts: tamsulosin 0.4 mg daily (cohort 1, n=21) and terazosin 5 or 10 mg daily (cohort 2, n=21). The design was a randomized, double blind, cross-over study with four treatments: vardenafil 5 mg or placebo administered simultaneously with the alpha-blocker and vardenafil 5 mg or placebo administered 6 hours after the alpha-blocker. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. One patient after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of < 85 mmHg; two and one patient (vardenafil and placebo, respectively) had a decrease in standing SBP of >30 mmHg. When tamsulosin and Levitra (Vardenafil) tablets 5 mg were separated by 6 hours, two patients had a standing SBP < 85 mmHg and one patient had a decrease in SBP of > 30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope.

Study 2: This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=23) on stable therapy with tamsulosin 0.4 mg or 0.8 mg daily for at least four weeks. The design was a randomized, double blind, two-period cross-over study. Vardenafil Hydrochloride (Levitra) or placebo was given simultaneously with tamsulosin. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. One patient experienced a decrease from baseline in standing SBP of >30 mmHg following vardenafil 10 mg. There were no other instances of outlier blood pressure values (standing SBP < 85 mmHg or decrease from baseline in standing SBP of > 30 mmHg). Three patients reported dizziness following vardenafil 20 mg. There were no cases of syncope.

Concomitant treatment with Vardenafil Hydrochloride (Levitra) tablets and alpha-blockers should be initiated only if the patient is stable on his alpha-blocker therapy. In those patients who are stable on alpha-blocker therapy, Levitra should be initiated at the lowest recommended starting dose.

Blood pressure effects in normotensive men after forced titration with alpha-blockers

Two randomized, double blind, placebo-controlled clinical pharmacology studies with healthy normotensive volunteers (age range, 45-74 years) were performed after forced titration of the alpha-blocker terazosin to 10 mg daily over 14 days (n=29), and after initiation of tamsulosin 0.4 mg daily for five days (n=24). There were no severe adverse events related to hypotension in either study. Symptoms of hypotension were a cause for withdrawal in 2 subjects receiving terazosin and in 4 subjects receiving tamsulosin. Instances of outlier blood pressure values (defined as standing SBP < 85 mmHg and/or a decrease from baseline of standing SBP > 30 mmHg) were observed in 9/24 subjects receiving tamsulosin and 19/29 receiving terazosin. The incidence of subjects with standing SBP < 85 mmHg given vardenafil and terazosin to achieve simultaneous Tmax led to early termination of that arm of the study. In most (7/8) of these subjects, instances of standing SBP < 85 mmHg were not associated with symptoms. Among subjects treated with terazosin, outlier values were observed more frequently when vardenafil and terazosin were given to achieve simultaneous Tmax than when dosing was administered to separate Tmax by 6 hours. There were 3 cases of dizziness observed with concomitant administration of terazosin and Levitra (Vardenafil HCl). Seven subjects experienced dizziness mainly occurring with simultaneous Tmax administration of tamsulosin. There were no cases of syncope.

Ritonavir and indinavir

Upon concomitant administration of 5 mg of Levitra with 600 mg BID ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of Levitra (Vardenafil HCl) tablets 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. Levitra 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 (Acetylsalicylic Acid)

Levitra 10 mg and 20 mg did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).

Other interactions

Vardenafil (Levitra) had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).

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