Bioequivalence and Bioavailability of an Orodispersible Tablet of Sildenafil Citrate in Healthy Chinese Male Subjects

The overall frequency of discontinuation in sildenafil-treated patients was 3% (20 mg and 40 mg three times a day) and 8% (80 mg three times a day). Most Common Adverse Reactions in Patients Treated with Sildenafil 20 mg, 40 mg, 80 mg and Placebo Three Times Per Day in SUPER-1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients) In a placebo-controlled fixed dose titration study (PACES-1) of sildenafil (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined sildenafil + epoprostenol group compared with 13% of subjects in the epoprostenol group [see Clinical Studies (14)]. In a study to assess the effects of multiple doses of sildenafil on mortality in adults with PAH (StudyA1481324), the lower dose 5 mg TID group showed a higher observed number of deaths (all related to underlying disease/disease under study), serious adverse events, and severe adverse events than the 20 mg and 80 mg TID groups [see Clinical Studies (14)]. Sildenafil was studied in a total of 234 PAH pediatric patients 1 to 17 years of age in a 16-week, double-blind placebo-controlled study (STARTS-1); 220 patients continued in a long-term extension study (STARTS-2). Adverse events with sildenafil injection were similar to those seen with oral tablets. Concomitant use of sildenafil with nitrates in any form is contraindicated [see Contraindications (4)]. Concomitant use of sildenafil with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)]. Concomitant use of sildenafil with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of sildenafil may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of sildenafil to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

Publication types

Improvements were observed with cardiac index in all three sildenafil dose groups over placebo. Data on other hemodynamic measures for the sildenafil low, medium and high dose groups compared to placebo is displayed in Table 3. Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4)]. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively.

What should I do if I miss a dose of sildenafil?

After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. Sildenafil Injection: The pharmacokinetic profile of sildenafil has been characterized following intravenous administration.

Binding Characteristics

A 10 mg dose of sildenafil injection is predicted to provide a pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg oral dose. Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. Pediatric Patients Body weight was shown to be a good predictor of drug exposure in children. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function. Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data). No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis). Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation. The safety and efficacy of sildenafil have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underlie improvements in exercise. Use of sildenafil for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)]. The safety and effectiveness of sildenafil have not been established in pediatric patients younger than 1 year of age. During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies (14)], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients > 45 kg up to a maximum of 40 mg three times a day. Clinical studies of sildenafil did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. Severe impairment has not been studied [see Clinical Pharmacology (12.3)]. No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)]. Sildenafil for oral suspension is supplied as white to off-white granular powder containing 1.57 g of sildenafil citrate USP (equivalent to 1.12 g sildenafil) in an amber PET bottle intended for reconstitution.

• Sildenafil tablets 125 mg are manufactured by various brands.
• Always verify the authenticity of medication sources.
• Use only FDA-approved or certified pharmacies.
• Cost can vary based on brand and location.
• Generic versions are typically more affordable.
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• Read customer reviews before purchasing online.
• Consult your doctor about the best brand for you.

Following reconstitution with 90 mL water, the volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil.

In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (with 1 mL and 2 mL dose markings) buy pills sildenafil are provided.

7.1 Nitrates

Effects of Other Drugs on Sildenafil Pharmacokinetics Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reduction in sildenafil clearance when co-administered with beta-blockers. Sildenafil Injection: Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less than those observed after oral sildenafil administration. SUPER-1 (NCT00644605) - Sildenafil Monotherapy [20 mg, 40 mg, and 80 mg Three Times a Day] A randomized, double-blind, placebo-controlled study of sildenafil (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure ≥ 25 mmHg at rest with a pulmonary capillary wedge pressure < 15 mmHg). Patients were randomized to receive placebo (n = 70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil.

Drug Interactions

These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. SUPER-2 (NCT00159887) Long-Term Treatment of PAH In a long-term follow-up of patients who were treated with sildenafil (n = 277), K-M estimates of survival at 1, 2, and 3 years were 94%, 88% , and 79%, respectively. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2)]. Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies (14)]. Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 2. Patients on sildenafil medium and high dose groups achieved dose related improvements in pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies (14)]. Improvements were observed with cardiac index in all three sildenafil dose groups over placebo. Data on other hemodynamic measures for the sildenafil low, medium and high dose groups compared to placebo is displayed in Table 3. Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4)]. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively.

2.1 Recommended Dosage in Adults

Use of sildenafil for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)]. The safety and effectiveness of sildenafil have not been established in pediatric patients younger than 1 year of age. During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies (14)], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients > 45 kg up to a maximum of 40 mg three times a day. Clinical studies of sildenafil did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Comparing Sildenafil vs. Tadalafil Dosage

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. Severe impairment has not been studied [see Clinical Pharmacology (12.3)]. No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)]. Sildenafil for oral suspension is supplied as white to off-white granular powder containing 1.57 g of sildenafil citrate USP (equivalent to 1.12 g sildenafil) in an amber PET bottle intended for reconstitution. Following reconstitution with 90 mL water, the volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil.

Who should not take sildenafil?

In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (with 1 mL and 2 mL dose markings) buy pills sildenafil are provided. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2)]. Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies (14)]. Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 2. Patients on sildenafil medium and high dose groups achieved dose related improvements in pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies (14)]. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively.

• Sildenafil tablets 125 mg can be part of a broader ED treatment plan.
• Psychological counseling may enhance effectiveness.
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• Lifestyle modifications include weight management and exercise.
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• Vasodilator drugs should be avoided when using sildenafil.
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An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. Sildenafil Injection: The pharmacokinetic profile of sildenafil has been characterized following intravenous administration. A 10 mg dose of sildenafil injection is predicted to provide a pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg oral dose. Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. Pediatric Patients Body weight was shown to be a good predictor of drug exposure in children. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function.

Effects of Other Drugs on Sildenafil Pharmacokinetics Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reduction in sildenafil clearance when co-administered with beta-blockers. Sildenafil Injection: Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less than those observed after oral sildenafil administration. SUPER-1 (NCT00644605) - Sildenafil Monotherapy [20 mg, 40 mg, and 80 mg Three Times a Day] A randomized, double-blind, placebo-controlled study of sildenafil (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure ≥ 25 mmHg at rest with a pulmonary capillary wedge pressure < 15 mmHg). Patients were randomized to receive placebo (n = 70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. SUPER-2 (NCT00159887) Long-Term Treatment of PAH In a long-term follow-up of patients who were treated with sildenafil (n = 277), K-M estimates of survival at 1, 2, and 3 years were 94%, 88% , and 79%, respectively.

Related/similar drugs

The overall frequency of discontinuation in sildenafil-treated patients was 3% (20 mg and 40 mg three times a day) and 8% (80 mg three times a day). Most Common Adverse Reactions in Patients Treated with Sildenafil 20 mg, 40 mg, 80 mg and Placebo Three Times Per Day in SUPER-1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients) In a placebo-controlled fixed dose titration study (PACES-1) of sildenafil (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined sildenafil + epoprostenol group compared with 13% of subjects in the epoprostenol group [see Clinical Studies (14)]. In a study to assess the effects of multiple doses of sildenafil on mortality in adults with PAH (StudyA1481324), the lower dose 5 mg TID group showed a higher observed number of deaths (all related to underlying disease/disease under study), serious adverse events, and severe adverse events than the 20 mg and 80 mg TID groups [see Clinical Studies (14)]. Sildenafil was studied in a total of 234 PAH pediatric patients 1 to 17 years of age in a 16-week, double-blind placebo-controlled study (STARTS-1); 220 patients continued in a long-term extension study (STARTS-2). Adverse events with sildenafil injection were similar to those seen with oral tablets.

5.5 Hearing Loss

Concomitant use of sildenafil with nitrates in any form is contraindicated [see Contraindications (4)]. Concomitant use of sildenafil with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)]. Concomitant use of sildenafil with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of sildenafil may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of sildenafil to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

Missed Dose

Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data). No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis). Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation. The safety and efficacy of sildenafil have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underlie improvements in exercise.