Vardenafil

Vardenafil hydrochloride tablets can potentiate the hypotensive effects of nitrates, alpha- blockers, and antihypertensives. ( 7.1 )

7.1 Potential for Pharmacodynamic Interactions with Vardenafil Hydrochloride Tablets Nitrates: Concomitant use of vardenafil hydrochloride tablets and nitrates and nitric oxide donors is contraindicated. 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 after vardenafil were potentiated by a 20 mg dose of vardenafil hydrochloride tablets in healthy middle-aged subjects. These effects were not observed when vardenafil hydrochloride tablets 20 mg were taken 24 hours before the nitroglycerin (NTG).

Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of vardenafil hydrochloride tablets and nitrates is contraindicated [see Contraindications (4.1) and Clinical Pharmacology (12.2) . Alpha-Blockers: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including vardenafil hydrochloride tablets and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated.

Clinical pharmacology studies have been conducted with co-administration of vardenafil with alfuzosin, terazosin or tamsulosin. [See Dosage and Administration (2.4) , Warnings and Precautions (5.6) , and Clinical Pharmacology (12.2) .] Antihypertensives: Vardenafil hydrochloride tablets may add to the blood pressure lowering effects of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute.

The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1. Alcohol: Vardenafil hydrochloride tablets (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, approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma levels were not altered when dosed simultaneously.

7.2 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 [see Dosage and Administration (2.4) and Warnings and Precautions (5.2) ] . In vivo studies Strong CYP3A4 inhibitors Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in maximum concentration (C max ) when co-administered with vardenafil hydrochloride tablets (5 mg) in healthy volunteers.

A 5-mg vardenafil hydrochloride tablet dose should not be exceeded in a 24-hour period 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 vardenafil hydrochloride tablets should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily. [See Dosage and Administration (2.4) and Warnings and Precautions (5) .] Indinavir (800 mg t.i.d.) co-administered with vardenafil hydrochloride tablets 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 vardenafil hydrochloride tablets dose in a 24-hour period when used in combination with indinavir. [See Dosage and Administration (2.4) and Warnings and Precautions (5.2) .] Ritonavir (600 mg b.i.d.) co-administered with vardenafil hydrochloride tablets 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 HIV protease inhibitor and a highly strong 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 hydrochloride tablets dose in a 72-hour period when used in combination with ritonavir. [See Dosage and Administration (2.4) and Warnings and Precautions (5.2) .] . Cobicistat with vardenafil hydrochloride tablets can result in increased plasma concentrations, therefore it is recommended that a single 2.5 mg dose of vardenafil hydrochloride tablets should not be exceeded in a 72-hour period. [See Dosage and Administration (2.4) and Warnings and Precautions (5) .] .

Moderate CYP3A4 inhibitors 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 vardenafil hydrochloride tablets 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of vardenafil hydrochloride tablets in a 24-hour period when used in combination with erythromycin. [See Dosage and Administration (2.4) and Warnings and Precautions (5) .] 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, an antacid based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters. 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 vardenafil hydrochloride tablets in healthy volunteers.

7.3 Effects of Vardenafil on Other Drugs In vitro studies Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 micromolar). 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 micromolar toward CYP3A4, which is about 20 times higher than the M1 C max values after an 80 mg vardenafil dose. In vitro data suggest that vardenafil has the potential to inhibit P-glycoprotein (P-gp) at therapeutic doses.

While concomitant use of vardenafil hydrochloride tablets did not significantly increase plasma concentrations of digoxin, a P-gp substrate, the effect on plasma concentrations of P-gp substrates that are more sensitive than digoxin (e.g. dabigatran) is not known. In vivo studies Nifedipine: Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the AUC or C max of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of vardenafil hydrochloride tablets when taken in combination.

In these patients whose hypertension was controlled with nifedipine, vardenafil hydrochloride tablets 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo. Ritonavir and Indinavir: Upon concomitant administration of 5 mg of vardenafil hydrochloride tablets with 600 mg BID ritonavir, the C max and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of vardenafil hydrochloride tablets with 800 mg TID indinavir, the C max and AUC of indinavir were reduced by 40% and 30%, respectively.

Aspirin: Vardenafil hydrochloride tablets (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets). Other interactions: Vardenafil hydrochloride tablets had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).

8.1 Pregnancy Risk Summary Vardenafil hydrochloride tablets are not indicated for use in females. There are no data with the use of vardenafil hydrochloride tablets in pregnant women to inform any drug-associated risks. In animal reproduction studies conducted in pregnant rats and rabbits, no adverse developmental outcomes were observed with oral administration of vardenafil during organogenesis at exposures for unbound vardenafil and its major metabolite at approximately 100 and 29 times, respectively, the maximum recommended human dose (MRHD) of 20 mg based on AUC (see Data) .

Data Animal Data No evidence of specific potential for teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits that received vardenafil at up to 18 mg/kg/day during organogenesis. This dose is approximately 100 fold (rat) and 29 fold (rabbit) greater than the AUC values for unbound vardenafil and its major metabolite in humans given the MRHD of 20 mg. In the rat pre-and postnatal development study, the NOAEL (no observed adverse effect level) for maternal toxicity was 8 mg/kg/day.

Retarded physical development of pups in the absence of maternal effects was observed following maternal exposure to 1 and 8 mg/kg possibly due to vasodilatation and/or secretion of the drug into milk. The number of living pups born to rats exposed pre- and postnatally was reduced at 60 mg/kg/day. Based on the results of the pre- and postnatal study, the developmental NOAEL is less than 1 mg/kg/day. Based on plasma exposures in the rat developmental toxicity study, 1 mg/kg/day in the pregnant rat is estimated to produce total AUC values for unbound vardenafil and its major metabolite comparable to the human AUC at the MRHD of 20 mg.