DOSAGE FORMS AND STRENGTHS

There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following sildenafil citrate 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 sildenafil citrate 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 sildenafil citrate 50 mg and 100 mg.

Side Effects

In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C maxcompared 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 maxvalues 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)].Drug Interaction StudiesEffects of Other Drugs on Sildenafil citrateSildenafil 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. The concomitant use of erythromycin or strong CYP3A4 inhibitors (e.g., saquinavir, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil [ see Dosage and Administration (2.4)].In vivostudies:Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil citrate (50 mg) to healthy volunteers.When a single 100 mg dose of sildenafil citrate was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C maxand a 182% increase in sildenafil AUC.

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In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with sildenafil citrate (100 mg single dose) resulted in a 140% increase in sildenafil C maxand a 210% increase in sildenafil AUC.

Sildenafil Tablets for ED

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 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 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. 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.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. The primary endpoint was time to limiting angina in the sildenafil tables 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 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. 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 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.12.3 PharmacokineticsSildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%).

5.8 Effects on Bleeding

There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following sildenafil citrate 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 sildenafil citrate 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 sildenafil citrate 50 mg and 100 mg. 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 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.

What should I know about sildenafil before taking it?

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 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. 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.

Less common

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. The primary endpoint was time to limiting angina in the sildenafil tables 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 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. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly sildenafil citrate tablets 50 mg CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil.

• Sildenafil citrate 50mg may cause priapism, a prolonged erection needing medical attention.
• Use with caution in men taking blood pressure medications.
• Check for contraindications: heart disease, stroke history, or liver issues.
• Avoid taking sildenafil with fatty meals to improve absorption time.
• The drug's effectiveness can be reduced if taken with certain drugs.
• Patients should inform their doctor of all medications they are taking.
• The medication does not protect against sexually transmitted infections.
• Follow the prescribed dosage schedule strictly to avoid adverse reactions.

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.

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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 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.12.3 PharmacokineticsSildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly sildenafil citrate tablets 50 mg 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:Sildenafil citrate is rapidly absorbed.

4. Ethical Manufacturing Practices

Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T maxof 60 minutes and a mean reduction in C maxof 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.

What does SILDENAFIL CITRATE (Generic for REVATIO) look like?

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 vitropotency 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.Pharmacokinetics in Special PopulationsGeriatrics: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 sildenafil 10mg pharmacokinetics of a single oral dose of sildenafil citrate (50 mg) were not altered. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T maxof 60 minutes and a mean reduction in C maxof 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.

8.4 Pediatric Use

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 vitropotency 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.Pharmacokinetics in Special PopulationsGeriatrics: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).

What should I know about storage and disposal of this medication?

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 sildenafil 10mg pharmacokinetics of a single oral dose of sildenafil citrate (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C maxcompared 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 maxvalues 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 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.

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.

• 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.

A starting oral dose of 25 mg should be considered in those patients [ see Dosage and Administration (2.5)].Drug Interaction StudiesEffects of Other Drugs on Sildenafil citrateSildenafil 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. The concomitant use of erythromycin or strong CYP3A4 inhibitors (e.g., saquinavir, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil [ see Dosage and Administration (2.4)].In vivostudies:Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil citrate (50 mg) to healthy volunteers.When a single 100 mg dose of sildenafil citrate was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C maxand a 182% increase in sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with sildenafil citrate (100 mg single dose) resulted in a 140% increase in sildenafil C maxand a 210% increase in sildenafil AUC.

• 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.