16 HOW SUPPLIED/STORAGE AND HANDLING

The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.

8.6 Patients with Hepatic Impairment

The mean subject age in this study was 63.9 years. Twenty subjects received sildenafil citrate 50 mg, but only 19 subjects received matching placebo. This patient had been taking minoxidil, a potent vasodilator, during the study. For the 19 subjects who received both sildenafil citrate and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg sildenafil citrate or buy sildenafil citrate online canada matching placebo are shown in Figure 3. Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of sildenafil citrate at the same times as those specified for the first doxazosin study.

Patient resources

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 sildenafil citrate 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. The mean subject age in this study was 66.4 years. 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 sildenafil citrate 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 sildenafil citrate 50 mg).

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For the 20 subjects who received sildenafil citrate 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil citrate or matching placebo are shown in Figure 4. Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration sildenafil pricing of sildenafil citrate at the same times as those specified for the previous doxazosin studies. There were no episodes of syncope reported in this study. Effect of Sildenafil citrate on Blood Pressure When Co-administered with Anti-hypertensives:When sildenafil citrate 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 Sildenafil citrate on Blood Pressure When Co-administered with Alcohol:Sildenafil citrate (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%. Effects of Sildenafil citrate on Blood Pressure:Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). Larger effects were recorded among patients receiving concomitant nitrates [ see Contraindications (4.1)]. Figure 1: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers. Effects of Sildenafil citrate on Blood Pressure When Nitroglycerin is Subsequently Administered:Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Contraindications (4.1)].

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Effects of Sildenafil citrate on Blood Pressure When Co-administered with Alpha-Blockers:Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of Sildenafil citrate with doxazosin, an alpha-adrenergic blocking agent. In the first study, a single oral dose of Sildenafil citrate 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH).

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The mean subject age was 66.5 years. For the 17 subjects who received sildenafil citrate 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg Sildenafil citrate 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 sildenafil citrate or matching placebo. No severe adverse events potentially related to blood pressure effects were reported in this group. Of the four subjects who received sildenafil citrate 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 sildenafil citrate with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing).

4.3 Concomitant Guanylate Cyclase (GC) Stimulators

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. 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).

What are the most common side effects of sildenafil?

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 to 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 to 80 mL/min) and moderate (CLcr=30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil citrate (50 mg) were not altered.

Who should not take sildenafil?

Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension. In the second study, a single oral dose of sildenafil citrate 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. The mean subject age in this study was 63.9 years.

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Twenty subjects received sildenafil citrate 50 mg, but only 19 subjects received matching placebo. This patient had been taking minoxidil, a potent vasodilator, during the study. For the 19 subjects who received both sildenafil citrate and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg sildenafil citrate or buy sildenafil citrate online canada matching placebo are shown in Figure 3. Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of sildenafil citrate at the same times as those specified for the first doxazosin study. 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 sildenafil citrate 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. The mean subject age in this study was 66.4 years. 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 sildenafil citrate 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 sildenafil citrate 50 mg).

• Sildenafil tablets 125 mg are generally well-tolerated.
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For the 20 subjects who received sildenafil citrate 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil citrate or matching placebo are shown in Figure 4. Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration sildenafil pricing of sildenafil citrate at the same times as those specified for the previous doxazosin studies.

5.7 Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies

There were no episodes of syncope reported in this study. Effect of Sildenafil citrate on Blood Pressure When Co-administered with Anti-hypertensives:When sildenafil citrate 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 Sildenafil citrate on Blood Pressure When Co-administered with Alcohol:Sildenafil citrate (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 recommended dose of 100 mg sildenafil was not evaluated in this study [ see Drug Interactions (7.5)]. Effects of Sildenafil citrate on Cardiac Parameters:Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers.

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The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [ see Drug Interactions (7.5)]. Effects of Sildenafil citrate 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 sildenafil citrate on cardiac output. 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.

Interactions that increase your risk for side effects

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. In a double-blind study, 144 patients with erectile dysfunction and chronic stable canada sildenafil angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil citrate 100 mg 1 hour prior to exercise testing. These results demonstrated that the effect of sildenafil citrate on the primary endpoint was statistically non-inferior to placebo. Effects of Sildenafil citrate 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. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry.

Prior authorization

Effects of Sildenafil citrate on Sperm:There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil citrate in healthy volunteers. Sildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%). 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:Sildenafil citrate is rapidly absorbed. Studies have produced relevant data on the effects of sildenafil citrate on cardiac output. A total dose of 40 mg sildenafil was administered by four intravenous infusions.

Mechanism of action

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.

Condition	Risk Factors	Recommendations
Nitrate use	Severe hypotension	Do not combine with nitrates
Severe Cardiovascular Disease	Increased risk of heart attack or stroke	Medical consultation before use
Retinal Disorders	Potential for vision problems	Caution advised
Severe Liver Impairment	Reduced drug metabolism	Dose adjustment or avoid

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. In a double-blind study, 144 patients with erectile dysfunction and chronic stable canada sildenafil angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil citrate 100 mg 1 hour prior to exercise testing. These results demonstrated that the effect of sildenafil citrate on the primary endpoint was statistically non-inferior to placebo. Effects of Sildenafil citrate 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. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry. Effects of Sildenafil citrate on Sperm:There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil citrate in healthy volunteers. Sildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%). Both sildenafil and the metabolite have terminal half lives of about 4 hours.

Conflict of interest statement

The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Effects of Sildenafil citrate on Blood Pressure:Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). Larger effects were recorded among patients receiving concomitant nitrates [ see Contraindications (4.1)]. Figure 1: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers. Effects of Sildenafil citrate on Blood Pressure When Nitroglycerin is Subsequently Administered:Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL).

Warnings and Precautions

Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Contraindications (4.1)]. Effects of Sildenafil citrate on Blood Pressure When Co-administered with Alpha-Blockers:Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of Sildenafil citrate with doxazosin, an alpha-adrenergic blocking agent. In the first study, a single oral dose of Sildenafil citrate 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). The mean subject age was 66.5 years. For the 17 subjects who received sildenafil citrate 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg Sildenafil citrate or matching placebo are shown in Figure 2.

Dosage adjustments

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 sildenafil citrate or matching placebo. No severe adverse events potentially related to blood pressure effects were reported in this group. Of the four subjects who received sildenafil citrate 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 sildenafil citrate with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension. In the second study, a single oral dose of sildenafil citrate 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. 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:Sildenafil citrate is rapidly absorbed.

Frequently asked questions

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. 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 to 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 to 80 mL/min) and moderate (CLcr=30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil citrate (50 mg) were not altered.

• Sildenafil is sometimes used off-label for other health issues.
• Its interaction with blood thinners should be monitored.
• Men with retinitis pigmentosa should avoid sildenafil.
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