Levitra Tablets (Luh-VEE-Trah) (vardenafil HCl)

Drug Interactions

Effect of other drugs on Levitra
Effects of Levitra on other drugs
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy, Nursing Mothers and Pediatric
Geriatric Use

Effect of other drugs on Levitra

In vitro studies: Studies in human liver microsomes showed that vardenafil is metabolised primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP 2C9. 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.) has 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.) produces a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax 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 Cmax 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 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 (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 Cmax and 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 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 24-hour period when used in combination with ritonavir (see WARNINGS and DOSAGE AND ADMINISTRATION).

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>100µM). Weak inhibitory effects toward the other isoforms (CYP2C8, 2C9, 2C19, 2Dg, 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 1.4µM 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 Hypotensive effects of nitrates for patients with isochemic 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 AAUC) or maximum concentration (Cmax.) of nifedipine, a drug that is metabolised via CYP3A4. Nifedipine did not alter the plasma levels of Levitra when taken in combination. In these patients whose hypertension was controlled by nifedipine, Levitra 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mm Hg compared to placebo.

Alpha-blockers: When Levitra 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 ubstantial number of subjects. With simultaneous dosing of Levitra 10 mg and terazosin 10 mg, 6 of 8 subjects experienced a standing systolic blood pressure of less tha 85 mm Hg. With simultaneous dosing of Levitra 20 mg and terazosin 10 mg, 2 of 9 subjects experienced a standing systolic blood pressure of less than 85 mm Hg. When Levitra dosing was separated from terazosin 10 mg by 6 hours, 7 of 29 subjects who received 20 mg of Levitra experienced a decrease in standing systolic blood pressure below 85 mm Hg. In a similar study with tamsulosin in healthy volunteers, 1 or 24 subjects dosed with Levitra 20 mg and tamsulosin 0.4 separated by 6 hours experienced a standing systoloc blood pressure below 85 mm Hg. Two of 16 subjects dosed simultaneously with Levitra 10 mg and tamsulosin 0.4 mg experienced a standing systolic blood pressure below 85 mm Hg. The administration of lower doses of Levitra with alpha-blockers has not been completely evaluated to determine if they can be safely administered together. Based on these data, Levitra should not be used in patients o alpha-blockers therapy (see CONTRAINDICATIONS).

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 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: Levitra (10 mg and 20mg) 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).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Vardenafil was not carcinogenic in rats and mice when administered daily for 24 months. In these studies systemic drug exposures (AUCs) for unbound (free) vardenafil and its major metabolite were approximately 400- and170-fold for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 20 mg. Vardenafil was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward mutation assay in Chinese hamster V79 cells. Vardenafil was not clastogenic as assessed in either the in vitro chromosomal aberration test or the in vivo mouse micronucleus test. Vardenafil did not impair fertility in male and female rats administered doses up to 100 mg/kg/day for 29\8 days prior to mating in male, and for 14 days prior to mating and through day 7 of gestation in females. In a corresponding 1-month rat toxicity study, this dose produces and AUC value for unbound vardenafil 200 fold greater than AUC in humans at the MRHD of 20 mg.

There was no effect on sperm motility or morphology after a single 20 mg oral doses of vardenafil in healthy volunteers.

Pregnancy, Nursing Mothers and Pediatric

Levitra is not indicated for use in women, newborns, or children. Vardenafil was secreted into milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma. Following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours. It is not known if vardenafil is excreted inhuman breast milk.

Pregnancy Category B: 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 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 8mg/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. There are know adequate and well-controlled trials of vardenafil in pregnant women.

Geriatric Use

Elderky males aged 65 years and older have higher vardenafil plasma concentrations than younger males (18 – 45 years), mean Cmax and AUC were 34% and 52% higher, respectively (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, and DOSAGE AND ADMINISTRATION). Phase 3 clinical trials included more than 834 elderly patients, and no differences in safety or effectiveness of Levitra 5, 10, or 20 mg were noted when these elderly patients were compared to younger patients. However, due to increased vardenafil concentrations in the elderly, a starting dose of 5 mg Levitra should be considered in patients =65 years in age.

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