5 WARNINGS AND PRECAUTIONS

Studies in vitro have shown that sildenafil is selective for PDE5.

Proper Use

Studies in vitro have shown that sildenafil is selective for PDE5. This lower selectivity is thought to be the basis for abnormalities related to color vision [ see Clinical Pharmacology (12.2)]. In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo. Effects of Sildenafil citrate on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan ®), after sildenafil citrate administration compared with placebo.

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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).

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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. This lower selectivity is thought to be the basis for abnormalities related to color vision [ see Clinical Pharmacology (12.2)]. In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo. Effects of Sildenafil citrate on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan ®), after sildenafil citrate administration compared with placebo. 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).

Common Side Effect	Frequency	Severity	Notes
Headache	Very common	Mild to moderate	Usually transient
Flushing	Common	Mild	Often resolves quickly
Dyspepsia / Indigestion	Common	Mild	Can be managed with antacids
Visual Disturbances	Less common	Mild	Changes in color perception
Priapism	Rare	Serious	Medical emergency, requires immediate attention

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.

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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)].

• The onset of action is usually within 30 minutes.
• Peak effect occurs around 1 hour after ingestion.
• The duration of action can last up to 4-6 hours.

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.

8.7 Hepatic Impairment

For the 20 subjects who received sildenafil citrate 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% sildenafil citrate tablet 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 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%.

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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.

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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 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. 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.

8.1 Pregnancy

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.

Further information

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.

Usual Adult Dose for:

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 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.

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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). The mean subject age in this study was 63.9 years.

5.6 Adverse Reactions with the Concomitant Use of Ritonavir

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 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.

• Sildenafil is not an aphrodisiac and needs sexual stimulation.
• It does not increase libido directly.
• Effectiveness varies between individuals.

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). For the 20 subjects who received sildenafil citrate 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% sildenafil citrate tablet 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.

Form	Dose Range per Tablet	Typical Strengths	Administration Route	Manufacturer Examples
Oral Tablets	25 mg - 100 mg	25 mg, 50 mg, 100 mg	Oral (once or as needed)	Pfizer, Teva, Cipla
Chewable Tablets	50 mg	50 mg	Oral (chewed)	Generic brands
Sublingual Tablets	50 mg	50 mg	Sublingual	Experimental formulations

Figure 4: 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 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.

Condition	Risk	Recommendations
Concomitant Nitrate Use	Severe hypotension	Avoid combination
Cardiac Conditions	Risk of myocardial infarction or arrhythmia	Consult cardiologist
Severe Liver Impairment	Altered drug metabolism	Dose adjustment needed
Hypotension (low BP)	Further blood pressure reduction	Use with caution

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. 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. 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 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.

What special precautions should I follow?

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%).

Dosage And Administration

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.

Risk Summary

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.

Label Warnings

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.

• Typical sildenafil dose ranges from 25 to 100 mg.
• It should be taken 30-60 minutes before activity.
• Do not exceed one dose within 24 hours.

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.