4 CONTRAINDICATIONS

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionThe physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation.

• Sildenafil citrate tablets 50mg are used to treat erectile dysfunction.
• These tablets work by increasing blood flow to the penis.
• Take sildenafil 50mg approximately 30 minutes before activity.
• Do not exceed one dose in a 24-hour period.
• Common side effects include headache and flushing.
• Sildenafil can interact with nitrates, causing dangerous drops in blood pressure.
• Store tablets in a cool, dry place away from direct sunlight.
• Consult a doctor before use, especially if you have heart conditions.

NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum.

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Following at least 14 consecutive days of doxazosin, sildenafil citrate 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). 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. One patient discontinued the study prematurely due to an adverse event sildenafil 100mg hexal of hypotension following dosing with sildenafil citrate 50 mg. 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 BaselineBlood pressure was measured after administration of sildenafil citrate at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of < 85 mmHg.

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In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of sildenafil citrate 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP >30mmHg following sildenafil citrate 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil citrate 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study.Study 3: Sildenafil citrate with DoxazosinIn 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.

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When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.Binding CharacteristicsStudies in vitrohave shown that sildenafil is selective for PDE5.

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Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. 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 vivoand peripheral arterial-venous dilatation in vivo.12.2 PharmacodynamicsEffects 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. Most studies assessed the efficacy of sildenafil citrate approximately 60 minutes post dose. The erectile response, as assessed by sildenafil 130mg RigiScan ®, generally increased with increasing sildenafil dose and plasma concentration. 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). The decrease in sitting blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of Sildenafil citrate, therefore the effects are not related to dose or plasma levels within this dosage range. 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).

Side Effect	Incidence Rate	Severity	Comments
Headache	20-30%	Mild to moderate	Usually resolves within hours
Flushing	15-25%	Mild	Facial redness
Indigestion	10-15%	Mild to moderate	Related to vasodilation
Nasal Congestion	10%	Mild	Due to blood vessel dilation
Vision Changes	2-3%	Mild to moderate	Blue tint or blurred vision

In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers.

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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). In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. 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.Study 1: Sildenafil citrate with DoxazosinIn 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). Following at least 14 consecutive daily doses of doxazosin, Sildenafil citrate 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the sildenafil citrate dose was reduced to 25 mg.

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Thereafter, 17 subjects were treated with Sildenafil citrate 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). 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 BaselineBlood pressure was measured immediately pre-dose sildenafil 100 mg tab 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. Outliers were defined as subjects with a standing systolic blood pressure of <85 mmHg or a decrease from baseline in standing systolic blood pressure of >30 mmHg at one or more timepoints. There were no subjects treated with sildenafil citrate 25 mg who had a standing SBP < 85mmHg. There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following sildenafil citrate 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 sildenafil citrate and placebo.

Sildenafil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

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). There were no reports of syncope among these patients. 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 < 85mmHg. Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension.Study 2: Sildenafil citrate with DoxazosinIn 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. 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.Study 1: Sildenafil citrate with DoxazosinIn 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). Following at least 14 consecutive daily doses of doxazosin, Sildenafil citrate 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the sildenafil citrate dose was reduced to 25 mg. Thereafter, 17 subjects were treated with Sildenafil citrate 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). 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 BaselineBlood pressure was measured immediately pre-dose sildenafil 100 mg tab 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. Outliers were defined as subjects with a standing systolic blood pressure of <85 mmHg or a decrease from baseline in standing systolic blood pressure of >30 mmHg at one or more timepoints.

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12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionThe physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.Binding CharacteristicsStudies in vitrohave shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11).

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Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. 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 vivoand peripheral arterial-venous dilatation in vivo.12.2 PharmacodynamicsEffects 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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Most studies assessed the efficacy of sildenafil citrate approximately 60 minutes post dose. The erectile response, as assessed by sildenafil 130mg RigiScan ®, generally increased with increasing sildenafil dose and plasma concentration. 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). The decrease in sitting blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of Sildenafil citrate, therefore the effects are not related to dose or plasma levels within this dosage range. There were no subjects treated with sildenafil citrate 25 mg who had a standing SBP < 85mmHg.

• Sildenafil citrate 50mg can be used in combination therapy for ED.
• It is vital to follow your doctor’s exact dose and timing instructions.
• Do not take sildenafil if you have a history of allergic reactions.
• Exercise caution if you experience chest pains while on the medication.
• Keep track of any side effects experienced and report them.
• Avoid physical activity immediately after taking the tablet if feeling dizzy.
• The medication does not protect against STDs; use barrier protection.
• Always inform your healthcare provider of all ongoing treatments and medications.

There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following sildenafil citrate 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 sildenafil citrate and 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). There were no reports of syncope among these patients.

• The use of sildenafil citrate 50mg is often combined with psychological counseling.
• Alcohol and large meals can delay the medication’s effectiveness.
• Do not use sildenafil if you are pregnant or nursing.
• Patients with severe vision problems should consult their doctor before use.
• Sildenafil may cause flushing, nasal congestion, or diarrhea.
• Discontinuation may be advised if adverse reactions occur.
• Use caution in men over the age of 65, as side effects may increase.
• Always follow the instructions provided by your medical professional.

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 < 85mmHg. Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension.Study 2: Sildenafil citrate with DoxazosinIn 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. Following at least 14 consecutive days of doxazosin, sildenafil citrate 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). 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. One patient discontinued the study prematurely due to an adverse event sildenafil 100mg hexal of hypotension following dosing with sildenafil citrate 50 mg. 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 BaselineBlood 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 two subjects who had a standing SBP of < 85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of sildenafil citrate 50 mg and resolving after approximately 7.5 hours.

• Sildenafil 50mg is a phosphodiesterase inhibitor for ED treatment.
• The medication is not a cure but helps achieve an erection on demand.
• Avoid combining sildenafil with recreational drugs or alcohol.
• It is important to follow the timing recommended by your doctor.
• The medication may cause a temporary decrease in blood pressure.
• Use with caution in individuals with kidney or liver impairment.
• Always read the patient information leaflet that accompanies the medicine.
• Regular medical check-ups are advised when using sildenafil long-term.

There was one subject with a decrease from baseline in standing systolic BP >30mmHg following sildenafil citrate 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil citrate 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study.Study 3: Sildenafil citrate with DoxazosinIn 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.