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Thereafter, 17 subjects were treated with VIAGRA 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects).

For the 17 subjects who received VIAGRA 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg Supine 7.4 (-0.9 , 15.7) Standing 6.0 (-0.8, 12.8) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg VIAGRA or matching placebo are shown in Figure 2. Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline. Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after VIAGRA or matching placebo.

Outliers were defined as subjects with a standing systolic blood pressure of 30 mmHg at one or more timepoints. There were no subjects treated with VIAGRA 25 mg who had a standing SBP 30mmHg following VIAGRA 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.

Of the four subjects who received VIAGRA 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with VIAGRA with symptoms lasting for 8 hours), and mild adverse

events

For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively.

Two of these subjects had a standing SBP Study 2: VIAGRA with Doxazosin.

In the second study, a single oral dose of VIAGRA 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH.

Following at least 14 consecutive days of doxazosin, VIAGRA 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects).

Twenty subjects received VIAGRA 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with VIAGRA 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study.

For the 19 subjects who received both VIAGRA and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI) Supine 9.08 (5.48, 12.68) Standing 11.62 (7.34, 15.90) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg VIAGRA or matching placebo are shown in Figure 3. Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline. Blood pressure was measured after administration of VIAGRA at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of 30mmHg following VIAGRA 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study. In the third study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH.

In dose period 1, subjects were administered open-label doxazosin and a single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of doxazosin.

If a subject did not successfully complete this first dosing period, he was discontinued from the study.

Subjects who had successfully completed the previous doxazosin interaction study (using VIAGRA 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1.

Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label VIAGRA 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using VIAGRA 50 mg).

For the 20 subjects who received VIAGRA 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg Supine 7.9 (4.6, 11.1) Standing 4.3 (-1.8,10.3) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg VIAGRA or matching placebo are shown in Figure 4.

Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline. Blood pressure was measured after administration of VIAGRA at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of 30 mmHg following VIAGRA 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both VIAGRA 50 mg and 100 mg. There were no episodes of syncope reported in this study. Effect of VIAGRA on Blood Pressure When Co-administered with Anti-hypertensives: When VIAGRA 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. Effect of VIAGRA on Blood Pressure When Co-administered with Alcohol: VIAGRA (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

The maximum observed decrease in systolic blood pressure was -18.5 mmHg when sildenafil was co-administered with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum observed decrease in diastolic blood pressure was -17.2 mmHg when sildenafil was co-administered with alcohol versus -11.1 mmHg when alcohol was administered alone. There were no reports of postural dizziness or orthostatic hypotension. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [ see Drug Interactions (7.5) ].

Effects of VIAGRA on Cardiac Parameters: Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of VIAGRA on cardiac output.

In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization.

A total dose of 40 mg sildenafil was administered by four intravenous infusions. The results from this pilot study are shown in Table 3; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients.

Mean resting values for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressure and cardiac output decreased by 28%, 28%, 20% and 7% respectively.

Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients.

Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil Means ± SD At rest After 4 minutes of exercise N Baseline (B2) n Sildenafil (D1) n Baseline n Sildenafil PAOP (mmHg) 8 8.1 ± 5.1 8 6.5 ± 4.3 8 36.0 ± 13.7 8 27.8 ± 15.3 Mean PAP (mmHg) 8 16.7 ± 4 8 12.1 ± 3.9 8 39.4 ± 12.9 8 31.7 ± 13.2 Mean RAP (mmHg) 7 5.7 ± 3.7 8 4.1 ± 3.7 - - - - Systolic SAP (mmHg) 8 150.4 ± 12.4 8 140.6 ± 16.5 8 199.5 ± 37.4 8 187.8 ± 30.0 Diastolic SAP (mmHg) 8 73.6 ± 7.8 8 65.9 ± 10 8 84.6 ± 9.7 8 79.5 ± 9.4 Cardiac output (L/min) 8 5.6 ± 0.9 8 5.2 ± 1.1 8 11.5 ± 2.4 8 10.2 ± 3.5 Heart rate (bpm) 8 67 ± 11.1 8 66.9 ± 12 8 101.9 ± 11.6 8 99.0 ± 20.4.

In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or VIAGRA 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort.

The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (N=70) and placebo, respectively.

These results demonstrated that the effect of VIAGRA sildenafil without rx on the primary endpoint was statistically non-inferior to placebo. Effects of VIAGRA on Vision: At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. Subjects in the study reported this finding as difficulties in discriminating blue/green.

An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry.

Effects of VIAGRA on Sperm : There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRA in healthy volunteers. VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25–63%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range.

It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil.

Both sildenafil and the metabolite have terminal half lives of about 4 hours.

Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below: Figure 5: Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers.

Absorption and Distribution: VIAGRA is rapidly absorbed.

Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When VIAGRA is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues.

Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.

Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients. Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes.

The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized.

This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug.

Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects.

After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach.

Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18–45 years).

Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [ see Dosage and Administration (2.5), and Use in Specific Populations (8.5) ] Renal Impairment: In volunteers with mild (CLcr=50–80 mL/min) and moderate (CLcr=30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr max compared to age-matched volunteers with no renal impairment [ see Dosage and Administration (2.5), and Use in Specific Populations (8.6) ].

In addition, N-desmethyl metabolite AUC and C max values significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment: In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C max (47%) compared to age-matched volunteers with no hepatic impairment.

The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [ see Dosage and Administration (2.5), and Use in Specific Populations (8.7) ].

Therefore, age >65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. A starting oral dose of 25 mg should be considered in those patients [ see Dosage and Administration (2.5) ] .

Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.