Levitra (Vardenafil Hydrochloride) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

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 (see WARNINGS and DOSAGE AND ADMINISTRATION).

In vivo studies: Cytochrome P450 Inhibitors

Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (C_max) 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 C_max when co-administered with LEVITRA 5 mg in healthy volunteers (see DOSAGE AND ADMINISTRATION). It is recommended not to exceed a single 5 mg dose of LEVITRA 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 C_max when co-administered with LEVITRA (5 mg) in healthy volunteers. A 5-mg LEVITRA 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 C_max 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 (see WARNINGS and DOSAGE AND ADMINISTRATION).

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 C_max and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg LEVITRA dose in a 24-hour period when used in combination with indinavir (see WARNINGS and DOSAGE AND ADMINISTRATION).

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 C_max. 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 (see WARNINGS and DOSAGE AND ADMINISTRATION).

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: glyburide, warfarin, digoxin, Maalox, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.

Effects of 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 C_max 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 LEVITRA and nitrates is contraindicated (see CLINICAL PHARMACOLOGY, Pharmacodynamics, Effects on Blood Pressure and Heart Rate when LEVITRA is Combined with Nitrates; CONTRAINDICATIONS).

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 (C_max) of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of LEVITRA 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. For BP results see Table 2. 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 vardenafil 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.

Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)

Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

Blood pressure effects (standing SBP) in normotensive men on stable dose tamsulosin 0.4 mg following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours are shown in Figure 3. Blood pressure effects (standing SBP) in normotensive men on stable dose terazosin (5 or 10 mg) following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours, are shown in Figure 4.

Figure 3: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 1)

Figure 4: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose terazosin (5 or 10 mg) in normotensive BPH patients (Study 1)

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 or placebo was given simultaneously with tamsulosin. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. For BP results see Table 3. 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.

Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)

	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

Blood pressure effects (standing SBP) in normotensive men on stable dose tamsulosin 0.4 mg following simultaneous administration of vardenafil 20 mg or placebo, or following administration of vardenafil 20 mg or placebo separated by 6 hours are shown in Figure 5.

Figure 5: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous administration of vardenafil 10 mg (Stage 1), vardenafil 20 mg (Stage 2), or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 2)

Concomitant treatment with vardenafil 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 (see DOSAGE and ADMINISTRATION).

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 T_max 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 T_max than when dosing was administered to separate T_max by 6 hours. There were 3 cases of dizziness observed with concomitant administration of terazosin and vardenafil. Seven subjects experienced dizziness mainly occurring with simultaneous T_max administration of tamsulosin. There were no cases of syncope.

Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy

		Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours		Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker		Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted	Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted
Terazosin 10 mg daily	Standing SBP	-7 (-10, -3)	-11 (-14, -7)	-23 (-31, 16) 1	-14 (-33, 11)
	Supine SBP	-5 (-8, -2)	-7 (-11, -4)	-7 (-25, 19)	-7 (-31, 22)
Tamsulosin 0.4 mg daily	Standing SBP	-4 (-8, -1)	-8 (-11, -4)	-8 (-14, -2)	-8 (-14, -1)
	Supine SBP	-4 (-8, 0)	-7 (-11, -3)	-5 (-9, -2)	-3 (-7, 0)

Figure 6: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 10 mg, vardenafil 20 mg or placebo with terazosin (10 mg) in healthy volunteers

Figure 7: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 10 mg, vardenafil 20 mg or placebo with tamsulosin (0.4 mg) in healthy volunteers

Ritonavir and indinavir: Upon concomitant administration of 5 mg of LEVITRA with 600 mg BID ritonavir, the C_max and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of LEVITRA with 800 mg TID indinavir, the C_max 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: LEVITRA (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).

Other interactions: LEVITRA had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).

OVERDOSAGE

The maximum dose of LEVITRA for which human data are available is a single 120 mg dose administered to eight healthy male volunteers. The majority of these subjects experienced reversible back pain/myalgia and/or “abnormal vision.”

In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance because vardenafil is highly bound to plasma proteins and is not significantly eliminated in the urine.

CONTRAINDICATIONS

Nitrates: Administration of LEVITRA with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated (see CLINICAL PHARMACOLOGY, Pharmacodynamics, Effects on Blood Pressure and Heart Rate when LEVITRA is Combined with Nitrates). 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 the tablet.