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.

WARNINGS

Cardiovascular effects
General: Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. In men for whom sexual activity is not recommended because of their underlying cardiovascular status, any treatment for erectile dysfunction, including LEVITRA, generally should not be used.

Left Ventricular Outflow Obstruction: Patients with left ventricular outflow obstruction, e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators, including Type 5 phosphodiesterase inhibitors.

Blood Pressure Effects: LEVITRA has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mm Hg systolic and 8 mm Hg diastolic) (see CLINICAL PHARMACOLOGY, Pharmacodynamics). While this normally would be expected to be of little consequence in most patients, prior to prescribing LEVITRA, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.

Effect of Co-administration of Strong CYP3A4 inhibitors
Long-term safety information is not available on the concomitant administration of vardenafil HCl with HIV protease inhibitors. Concomitant administration with ritonavir or indinavir substantially increases plasma concentrations of vardenafil HCl. To decrease the chance of adverse events in patients concomitantly taking ritonavir or indinavir, which are strong inhibitors of CYP3A4 metabolism, a maximum single dose of 2.5-mg LEVITRA should not be exceeded. Because ritonavir prolongs LEVITRA elimination half-life (5-6-fold), no more than a single 2.5-mg dose of LEVITRA should be taken in a 72-hour period by patients also taking ritonavir. Patients taking indinavir, ketoconazole 400-mg daily, or itraconazole 400-mg daily should not exceed LEVITRA 2.5-mg once daily. For patients taking ketoconazole or itraconazole 200-mg daily, a single dose of 5-mg LEVITRA should not be exceeded in a 24-hour period (see PRECAUTIONS, Drug Interactions and DOSAGE AND ADMINISTRATION).

Other Effects
There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds, including vardenafil HCl. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Patient Subgroups Not Studied in Clinical Trials
There are no controlled clinical data on the safety or efficacy of LEVITRA in the following patients; and therefore its use is not recommended until further information is available.

Unstable angina; hypotension (resting systolic blood pressure of <90 mm Hg); uncontrolled hypertension (>170/110 mm Hg) Recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months) Severe cardiac failure Severe hepatic impairment (Child-Pugh C) End stage renal disease requiring dialysis Known hereditary degenerative retinal disorders, including retinitis pigmentosa

PRECAUTIONS

The evaluation of erectile dysfunction should include a determination of potential underlying causes, a medical assessment, and the identification of appropriate treatment.

Before prescribing LEVITRA, it is important to note the following:

Alpha-blockers: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase Type 5 (PDE5) inhibitors, including LEVITRA, 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. In some patients, concomitant use of these two drug classes can lower blood pressure significantly (see PRECAUTIONS, Drug Interactions) leading to symptomatic hypotension (e.g., fainting).

Consideration should be given to the following:

Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose (see DOSAGE and ADMINISTRATION). In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor. Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

Hepatic Insufficiency: In volunteers with moderate impairment (Child-Pugh B), the C_max and AUC following a 10-mg vardenafil HCl dose were increased 130% and 160%, respectively, compared to healthy control subjects. Consequently, a starting dose of 5-mg is recommended for patients with moderate hepatic impairment and the maximum dose should not exceed 10-mg (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, and DOSAGE AND ADMINISTRATION). Vardenafil HCl has not been evaluated in patients with severe hepatic impairment (Child-Pugh C).

Congenital or Acquired QT Prolongation: In a study of the effect of LEVITRA on QT interval in 59 healthy males (see CLINICAL PHARMACOLOGY, Electrophysiology), therapeutic (10-mg) and supratherapeutic (80-mg) doses of LEVITRA and the active control moxifloxacin (400-mg) produced similar increases in QTc interval. This observation should be considered in clinical decisions when prescribing LEVITRA. Patients with congenital QT prolongation and those taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications should avoid using LEVITRA.

Renal Insufficiency: In patients with moderate (CL_cr = 30-50 ml/min) to severe (CL_cr <30 ml/min) renal impairment, the AUC of vardenafil HCl was 20-30% higher compared to that observed in a control group with normal renal function (CL_cr >80 ml/min) (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations). Vardenafil HCl pharmacokinetics have not been evaluated in patients requiring renal dialysis.

General: In humans, vardenafil HCl alone in doses up to 20 mg does not prolong the bleeding time. There is no clinical evidence of any additive prolongation of the bleeding time when vardenafil HCl is administered with aspirin. Vardenafil HCl has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore LEVITRA should be administered to these patients after careful benefit-risk assessment.

Treatment for erectile dysfunction should generally be used with caution by patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) or by patients who have conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

The safety and efficacy of LEVITRA used in combination with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Information for Patients
Physicians should discuss with patients the contraindication of LEVITRA with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of LEVITRA with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.

Physicians should inform their patients that in some patients concomitant use of PDE5 inhibitors, including LEVITRA, with alpha-blockers can lower blood pressure significantly leading to symptomatic hypotension (e.g., fainting). Patients prescribed LEVITRA who are taking alpha-blockers should be started on the lowest recommended starting dose of LEVITRA (see Drug Interactions and DOSAGE AND ADMINISTRATION). Patients should be advised of the possible occurrence of symptoms related to postural hypotension and appropriate countermeasures. Patients should be advised to contact the prescribing physician if other anti-hypertensive drugs or new medications that may interact with LEVITRA are prescribed by another healthcare provider.

Physicians should discuss with patients the appropriate use of LEVITRA and its anticipated benefits. It should be explained that sexual stimulation is required for an erection to occur after taking LEVITRA. LEVITRA should be taken approximately 60 minutes before sexual activity. Patients should be counseled regarding the dosing of LEVITRA. Patients should be advised to contact their healthcare provider for dose modification if they are not satisfied with the quality of their sexual performance with LEVITRA or in the case of an unwanted effect. Patients should be advised to contact the prescribing physician if new medications that may interact with LEVITRA are prescribed by another healthcare provider.

Physicians should advise patients to stop use of all PDE5 inhibitors, including LEVITRA, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be a sign of nonarteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events were related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors (see POST-MARKETING EXPERIENCE, Ophthalmologic).

Physicians should discuss with patients the potential cardiac risk of sexual activity for patients with preexisting cardiovascular risk factors.

The use of LEVITRA offers no protection against sexually transmitted diseases. Counseling of patients about protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.

Physicians should inform patients that there have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for LEVITRA and this class of compounds. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Drug Interactions

Effect of other drugs on LEVITRA

In vitro studies: Studies in human liver microsomes showed that vardenafil HCl 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 HCl clearance (see WARNINGS and DOSAGE AND ADMINISTRATION).

In vivo studies: Cytochrome P450 Inhibitors

Cimetidine (400-mg b.i.d.) had no effect on vardenafil HCl bioavailability (AUC) and maximum concentration (C_max) of vardenafil HCl when co-administered with 20-mg LEVITRA in healthy volunteers.

Erythromycin (500-mg t.i.d) produced a 4-fold increase in vardenafil HCl 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 HCl 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 HCl AUC, a 7-fold increase in vardenafil HCl C_max and a 2-fold increase in vardenafil HCl 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 HCl AUC and a 13-fold increase in vardenafil HCl C_max. The interaction is a consequence of blocking hepatic metabolism of vardenafil HCl by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil HCl 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 HCl and the following drugs: glyburide, warfarin, digoxin, Maalox, and ranitidine. In the warfarin study, vardenafil HCl had no effect on the prothrombin time or other pharmacodynamic parameters.

Effects of LEVITRA on other drugs
In vitro studies:

Vardenafil HCl 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 HCl 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 HCl 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 HCl 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:
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 HCl 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 HCl 5-mg or placebo administered simultaneously with the alpha-blocker and vardenafil HCl 5-mg or placebo administered 6 hours after the alpha-blocker. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil HCl dosing. For BP results see Table 2. One patient after simultaneous treatment with 5-mg vardenafil HCl and 10-mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mm Hg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil HCl and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mm Hg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil HCl 5-mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil HCl 5-mg and tamsulosin, two patients had a standing SBP of <85 mm Hg; two and one patient (vardenafil HCl and placebo, respectively) had a decrease in standing SBP of >30 mm Hg. When tamsulosin and vardenafil HCl 5-mg were separated by 6 hours, two patients had a standing SBP <85 mm Hg and one patient had a decrease in SBP of >30 mm Hg. 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 (mm Hg) following vardenafil HCl 5-mg in BPH patients on stable alpha-blocker therapy

Alpha-Blocker		Simultaneous dosing of Vardenafil HCl 5-mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil HCl 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	-6 (-9.9, -2.1)	-4 (-8.3, -0.5)
	Supine SBP	-4 (-7.0, -0.8)	-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 HCl 5-mg or placebo, or following administration of vardenafil HCl 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 HCl 5-mg or placebo, or following administration of vardenafil HCl 5-mg or placebo separated by 6 hours, are shown in Figure 4.

Figure 3: Mean change from baseline in standing systolic blood pressure (mm Hg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil HCl 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 (mm Hg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil HCl 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 HCl (stage 1) and 20-mg vardenafil HCl (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 HCl or placebo was given simultaneously with tamsulosin. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil HCl dosing. For BP results see Table 3. One patient experienced a decrease from baseline in standing SBP of >30 mm Hg following vardenafil HCl 10-mg. There were no other instances of outlier blood pressure values (standing SBP <85 mm Hg or decrease from baseline in standing SBP of >30 mm Hg). Three patients reported dizziness following vardenafil HCl 20-mg. There were no cases of syncope.

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

	Vardenafil HCl 10-mg Placebo-subtracted	Vardenafil HCl 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 HCl 20-mg or placebo, or following administration of vardenafil HCl 20-mg or placebo separated by 6 hours are shown in Figure 5.

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

Concomitant treatment with vardenafil HCl 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 mm Hg and/or a decrease from baseline of standing SBP >30 mm Hg) were observed in 9/24 subjects receiving tamsulosin and 19/29 receiving terazosin. The incidence of subjects with standing SBP <85 mm Hg given vardenafil HCl 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 mm Hg were not associated with symptoms. Among subjects treated with terazosin, outlier values were observed more frequently when vardenafil HCl 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 HCl. 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 (mm Hg) following vardenafil HCl 10 and 20-mg in healthy volunteers on daily alpha-blocker therapy

		Dosing of Vardenafil HCl and Alpha-Blocker Separated by 6 Hours		Simultaneous dosing of Vardenafil HCl and Alpha-Blocker
Alpha-blocker		Vardenafil HCl 10-mg Placebo-Subtracted	Vardenafil HCl 20-mg Placebo-Subtracted	Vardenafil HCl 10-mg Placebo-Subtracted	Vardenafil HCl 20-mg Placebo-Subtracted
Terazosin 10-mg daily	Standing SBP	-7 (-10, -3)	-11 (-14, -7)	-23 (-31, 16)*	-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)

* Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference.

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

Figure 7: Mean change from baseline in standing systolic blood pressure
(mm Hg) over 6 hour interval following simultaneous or 6 hr separation
administration of vardenafil HCl 10-mg, vardenafil HCl 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 HCl 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).

Carcinogenesis, Mutagenesis, Impairment of Fertility
Vardenafil HCl was not carcinogenic in rats and mice when administered daily for 24 months. In these studies systemic drug exposures (AUCs) for unbound (free) vardenafil HCl and its major metabolite were approximately 400- and 170-fold for male and female rats, respectively, and 21- and 37-fold for male and female mice, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 20-mg. Vardenafil HCl was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward mutation assay in Chinese hamster V79 cells. Vardenafil HCl was not clastogenic as assessed in either the in vitro chromosomal aberration test or the in vivo mouse micronucleus test. Vardenafil HCl did not impair fertility in male and female rats administered doses up to 100-mg/kg/day for 28 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 produced an AUC value for unbound vardenafil HCl 200-fold greater than AUC in humans at the MRHD of 20-mg.

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

Pregnancy, Nursing Mothers and Pediatric Use
LEVITRA is not indicated for use in women, newborns, or children. Vardenafil HCl was secreted into the 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 HCl is excreted in human breast milk.

Pregnancy Category B: No evidence of specific potential for teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits that received vardenafil HCl 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 HCl 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, 1mg/kg/day in the pregnant rat is estimated to produce total AUC values for unbound vardenafil HCl and its major metabolite comparable to the human AUC at the MRHD of 20-mg. There are no adequate and well-controlled trials of vardenafil HCl in pregnant women.

Geriatric Use
Elderly males age 65 years and older have higher vardenafil HCl plasma concentrations than younger males (18-45 years), mean C_max 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 HCl concentrations in the elderly, a starting dose of 5-mg LEVITRA should be considered in patients >65 years of age.

ADVERSE REACTIONS
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 5).

Table 5: Adverse Events Reported By ≥2% of Patients Treated with LEVITRA and More Frequent on Drug than Placebo in Fixed and Flexible* Dose Randomized, Controlled Trials of 5-mg, 10-mg, or 20-mg Vardenafil HCl

Adverse Event		Percentage of Patients Reporting Event
		Placebo N = 1199	LEVITRA N = 2203
Headache		4%	15%
Flushing		1%	11%
Rhinitis		3%	9%
Dyspepsia		1%	4%
Accidental Injury†		2%	3%
Sinusitis		1%	3%
Flu Syndrome		2%	3%
Dizziness		1%	2%
Increased Creatine Kinase		1%	2%
Nausea		1%	2%

* Flexible dose studies started all patients at LEVITRA 10-mg and allowed decrease in dose to 5-mg or increase in dose to 20-mg based on side effects and efficacy.
† All the events listed in the above table were deemed to be adverse drug reactions with the exception of accidental injury.

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)

POST-MARKETING EXPERIENCE
Ophthalmologic
Nonarteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including LEVITRA. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup-to-disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors (see PRECAUTIONS, Information for Patients).

Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal vein occlusion, and reduced visual acuity, have also been reported rarely in post-marketing experience. It is not possible to determine whether these events are related directly to the use of LEVITRA.

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 HCl is highly bound to plasma proteins and is not significantly eliminated in the urine.

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