Levitra Side Effects, and Drug Interactions - Vardenafil HCl

Levitra Side Effects, and Drug Interactions - Vardenafil HCl

SIDE EFFECTS

LEVITRA was administered to over 4430 men (mean age 56, range 18-89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2200 patients were treated for 6 months or longer, and 880 patients were treated for at least 1 year.

In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for LEVITRA compared to 1.1% for placebo.

When LEVITRA was taken as recommended in placebo-controlled clinical trials, the following adverse events were reported (see Table 2).

Back pain was reported in 2.0% of patients treated with LEVITRA and 1.7% of patients on placebo.

Placebo-controlled trials suggested a dose effect in the incidence of some adverse events (headache, flushing, dyspepsia, nausea, rhinitis) over the 5 mg, 10 mg, and 20 mg doses of LEVITRA. The following section identifies additional, less frequent events (<2%) reported during the clinical development of LEVITRA. Excluded from this list are those events that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated with the drug.

BODY AS A WHOLE: anaphylactic reaction (including laryngeal edema), asthenia, face edema, pain

AUDITORY: tinnitus

CARDIOVASCULAR: angina pectoris, chest pain, hypertension, hypotension, myocardial ischemia, myocardial infarction, palpitation, postural hypotension, syncope, tachycardia

DIGESTIVE: abdominal pain, abnormal liver function tests, diarrhea, dry mouth, dysphagia, esophagitis, gastritis, gastroesophageal reflux, GGTP increased, vomiting

MUSCULOSKELETAL: arthralgia, back pain, myalgia, neck pain

NERVOUS: hypertonia, hypesthesia, insomnia, paresthesia, somnolence, vertigo RESPIRATORY: dyspnea, epistaxis, pharyngitis

SKIN AND APPENDAGES: photosensitivity reaction, pruritus, rash, sweating

OPHTHALMOLOGIC: abnormal vision, blurred vision, chromatopsia, changes in color vision, conjunctivitis (increased redness of the eye), dim vision, eye pain, glaucoma, photophobia, watery eyes

UROGENITAL: abnormal ejaculation, priapism (including prolonged or painful erections)

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 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 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 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 substantial 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 than 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 28 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 of 24 subjects dosed with LEVITRA 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 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 on alpha-blocker therapy (see CONTRAINDICATIONS).

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).