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When 40 mg of vardenafil was administered twice daily, cases of severe back pain were observed.

In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to

accelerate

Administration of LEVITRA with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated [see CLINICAL PHARMACOLOGY ]. Consistent with

the

Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles.

During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum.

The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the

rates

Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation.

In vitro studies have shown that vardenafil is a selective inhibitor of PDE5.

The inhibitory effect of vardenafil is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).

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.

Vardenafil may add to the blood pressure lowering effects of antihypertensive agents [see DRUG INTERACTIONS ]. Effects On Blood Pressure And Heart Rate When LEVITRA Is Combined With Nitrates.

A study was conducted in which the blood pressure and heart rate response to 0.4 mg nitroglycerin (NTG) sublingually was evaluated in 18 healthy subjects following pretreatment with LEVITRA 20 mg at various times before NTG administration.

LEVITRA 20 mg caused an additional time-related reduction in blood pressure and increase in heart rate in association with NTG administration.

The blood pressure effects were observed when LEVITRA 20 mg was dosed 1 or 4 hours before NTG and the heart rate effects were observed when 20 mg was dosed 1, 4, or 8 hours before NTG.

Additional blood pressure and heart rate changes were not

detected

(See Figure 1.) Figure 1: Placebo-subtracted point estimates (with 90% CI) of mean maximal blood pressure and heart rate effects of pre-dosing with vardenafil 20 mg at 24, 8, 4, sildenafil pills online and 1 hour before 0.4 mg NTG sublingually. Because the disease state of patients requiring nitrate therapy is anticipated to increase the likelihood of hypotension, the use of vardenafil by patients on nitrate therapy or on nitric oxide donors is contraindicated [see CONTRAINDICATIONS ]. Blood Pressure Effects In Patients On Stable Alpha-Blocker Treatment.

Three clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment, consisting of alfuzosin, tamsulosin or terazosin.

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

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 sildenafil pills online a standing SBP of 30 mmHg was observed in two patients on tamsulosin receiving simultaneous vardenafil and in one patient receiving simultaneous placebo treatment.

When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP 30 mmHg.

There were no severe adverse events related to hypotension reported during the study. Table 2: Mean (95% C.I.) maximal change from

baseline

men

therapy

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 6hour interval after vardenafil dosing.

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 30 mmHg). Three patients reported dizziness following vardenafil 20 mg.

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 of tamsulosin 0.4 mg following simultaneous administration of vardenafil 10 mg, vardenafil 20 mg or placebo are shown in Figure 4. Figure 4: 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

The design was a randomized, double blind, 3period cross-over study. Vardenafil or placebo was administered 4 hours after the administration of alfuzosin. Blood pressure and pulse were evaluated over a 10-hour interval after dosing of vardenafil or placebo.

Table 4: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 and 10 mg in BPH patients on stable alpha-blocker therapy

with

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 30 mmHg) were observed in 9/24 subjects receiving tamsulosin and 19/29 receiving terazosin. The incidence of subjects with standing

SBP

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

The effect of 10 mg and 80 mg vardenafil on QT interval was evaluated in a single-dose, double-blind, randomized, placebo-and active-controlled (moxifloxacin 400 mg) crossover study in 59 healthy males (81% White, 12% Black, 7% Hispanic) aged 45-60 years.

The QT interval was measured at one hour post dose because this time point approximates the average time of peak vardenafil concentration.

The sildenafil pills online 80 mg dose of LEVITRA (four times the highest recommended dose) was chosen because this dose yields plasma concentrations covering those observed upon co-administration of a low-dose of LEVITRA (5 mg) and 600 mg BID of ritonavir. Of the CYP3A4 inhibitors that have been studied, ritonavir causes the most significant drug-drug interaction with vardenafil. Table 6 summarizes the effect on mean uncorrected QT and mean corrected QT interval (QT c ) with different methods of correction (Fridericia and a linear individual correction method) at one hour post-dose. No single correction method is known to be more valid than the other. In this study, the mean increase in heart rate associated with a 10 mg dose of LEVITRA compared to placebo was 5 beats/minute and with an 80 mg dose of LEVITRA the mean increase was 6 beats/minute.

Mean QT and QT c changes in msec (90% CI) from baseline relative to placebo at 1 hour post-dose with different methodologies to correct for the

effect

In a separate postmarketing study of 44 healthy volunteers, single doses of 10 mg LEVITRA resulted in a placebo- subtracted mean change from baseline of QT c F (Fridericia correction) of 5 msec (90% CI: 2,8). Single doses of gatifloxacin 400mg resulted in a placebo-subtracted mean change from baseline QTcF of 4 msec (90% CI: 1,7). When LEVITRA 10mg and gatifloxacin 400 mg were co-administered, the mean QTcF change from baseline was additive when compared to either drug alone and produced a mean QTcF change of 9 msec from baseline (90% CI: 6,11).

The clinical impact of these QT changes is unknown [see WARNINGS AND PRECAUTIONS ].

Effects On Exercise Treadmill Test In Patients With Coronary Artery Disease (CAD) In two independent trials that assessed 10 mg (n=41) and 20 mg (n=39) vardenafil, respectively, vardenafil did not alter the total treadmill exercise time compared to placebo.

The patient population included men aged 40-80 years with stable exercise-induced angina documented by at least one of the following: 1) prior history of myocardial infarction (MI), coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA), or stenting (not within 6 months); 2) positive coronary angiogram showing at least 60% narrowing of the diameter of at least one major coronary artery; or 3) a positive stress echocardiogram or stress nuclear

perfusion

seconds

The total time to angina was not altered by LEVITRA when compared to placebo (10 mg LEVITRA vs.

placebo: 291±123 and 292±110 seconds; 20 mg LEVITRA vs.

placebo: 354±137 and 347±143 seconds, respectively). The total time to 1 mm or greater ST-segment depression was similar to placebo in both the 10 mg and the 20 mg LEVITRA groups (10 mg LEVITRA vs. placebo: 380±108 and 334±108 seconds; 20 mg LEVITRA vs. placebo: 364±101 and 366±105 seconds, respectively). Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green) using the Farnsworth-Munsell 100-hue test and reductions in electroretinogram (ERG) b-wave amplitudes, with peak effects near the time of peak plasma levels. These findings are consistent with the inhibition of PDE6 in rods and cones, which is involved in phototransduction in the retina. The findings were most evident one hour after administration, diminishing but still present 6 hours after administration.

In a single dose study in 25 normal males, LEVITRA 40 mg, twice the maximum daily recommended dose, did not alter visual acuity, intraocular pressure, fundoscopic and slit lamp findings.

In another double-blind, placebo controlled clinical trial, at least 15 doses of 20 mg vardenafil were administered over 8 weeks versus placebo to 52 males. Thirty-two (32) males (62%) of the patients completed the trial.

Retinal function was measured by ERG and FM-100 test 2, 6 and 24 hours after dosing. The trial was designed to detect changes in retinal function that might occur in more than 10% of patients.

Vardenafil did not produce clinically significant ERG or FM-100 effects in healthy men compared to placebo. Two patients on vardenafil in the trial reported episodes of transient cyanopsia (objects appear blue).

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

The pharmacokinetics of vardenafil are approximately dose proportional over the recommended dose range..

Mean vardenafil plasma concentrations measured after the administration of a single oral dose of 20 mg to healthy male volunteers are depicted in Figure 8.