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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 when LEVITRA 20 mg was dosed 24 hours before NTG. (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, 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 evaluated over the 6-hour interval after vardenafil dosing. 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 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 in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1) Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted Terazosin Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5) 5 or 10 mg daily Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7) Tamsulosin Standing SBP -6 (-9.9, -2.1) -4 (-8.3, -0.5) 0.4 mg daily Supine SBP -4 (-7, -0.8) -5 (-7.9, -1.7) Blood pressure effects (standing SBP) in normotensive men on stable dose of

tamsulosin

Figure 2: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following non prescription sildenafil citrate simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 1) Figure 3: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose terazosin (5 or 10 mg) in normotensive BPH patients (Study 1) This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg vardenafil (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 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 patients (Study 2) This study was designed to evaluate the effect of single doses of 5 mg vardenafil (stage 1) and 10 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=24) on stable therapy with alfuzosin 10 mg daily for at least four weeks. 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 non prescription sildenafil citrate 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

Blood Pressure Effects In Normotensive Men After Forced Titration With Alpha-Blockers.

Two randomized, double blind, placebo-controlled non prescription sildenafil citrate 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 non prescription sildenafil citrate incidence of subjects with standing SBP Alpha-Blocker Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours Simultaneous dosing of Vardenafil and Alpha-Blocker Vardenafil 10 mg Placebo-Subtracted Vardenafil 20 mg Placebo-Subtracted Vardenafil 10 mg Placebo-Subtracted Vardenafil 20 mg Placebo-Subtracted Terazosin 10 mg daily Standing SBP -7 (-10, -3) -11 (-14, -7) -23 (-31, 16) a -14 (-33, 11) a Supine SBP -5 (-8, -2) -7 (-11, -4) -7 (-25, 19) a -7 (-31, 22) a 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) a) Due to the sample size, confidence intervals may not be an accurate measure for these data.