6 ADVERSE REACTIONS

Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval)Key:PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil tablets. Without a control group, these data must be interpreted cautiously.Study 2 (Sildenafil tablets co-administered with epoprostenol)A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients were randomized to placebo or sildenafil tablets (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy.At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian.There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil tablets group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil tablets group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009).Patients on sildenafil tablets achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil tablets (95% CI: -5.7, -2.1) (p = 0.00003).Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than the sildenafil tablets-treated patients and that sildenafil tablets-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11.Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH (in Study 2)Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil tablets compared to placebo. More than twice as many sildenafil tablets-treated patients (36%) as the placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.Study 3 (Sildenafil tablets monotherapy (1 mg, 5 mg, and 20 mg three times a day))A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were randomized to 1 of 3 doses of Sildenafil tablets: 1 mg, 5 mg, and 20 mg, three times a day.At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian.The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Similar increases in walk distance (mean increase of 38-41 meters) were observed in the 5 and 20 mg dose groups. These increases were significantly better than those observed in the 1 mg dose group (Figure 12).Figure 12. Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 - ITT Population Sildenafil Protocol A1481244Study 4 (Sildenafil Tablets added to bosentan therapy - lack of effect on exercise capacity)A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a sildenafil 25mg tablets day) in combination with bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD. Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil tablets monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil tablets (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were randomized to receive placebo (n=70) or sildenafil tablets, 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18–81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343).

5.2 Worsening Pulmonary Vascular Occlusive Disease

These increases were significantly better than those observed in the 1 mg dose group (Figure 12).Figure 12. Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 - ITT Population Sildenafil Protocol A1481244Study 4 (Sildenafil Tablets added to bosentan therapy - lack of effect on exercise capacity)A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a sildenafil 25mg tablets day) in combination with bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD.

Warnings and Precautions

Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil tablets monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil tablets (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were randomized to receive placebo (n=70) or sildenafil tablets, 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18–81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval) Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age and hemodynamic parameters. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval) Key:PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.

Dosage for pulmonary arterial hypertension (PAH)

Study 2 (Sildenafil tablets co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking sildenafil for women stable doses of intravenous epoprostenol. Patients were randomized to placebo or sildenafil tablets (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil tablets group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil tablets group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil tablets achieved a statistically significant reduction in mPAP compared to those on placebo. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval) Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age and hemodynamic parameters. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval) Key:PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.

Study 2 (Sildenafil tablets co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking sildenafil for women stable doses of intravenous epoprostenol. Patients were randomized to placebo or sildenafil tablets (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil tablets group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil tablets group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009).

• Sildenafil 20 mg is a prescription medication used for erectile dysfunction.
• It helps increase blood flow to the penis during sexual activity.
• Typically prescribed for men with ED to improve sexual performance.

Patients on sildenafil tablets achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil tablets (95% CI: -5.7, -2.1) (p = 0.00003).

2.1 Sildenafil Tablets

Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval)Key:PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil tablets. Without a control group, these data must be interpreted cautiously.Study 2 (Sildenafil tablets co-administered with epoprostenol)A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients were randomized to placebo or sildenafil tablets (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy.At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian.There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil tablets group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil tablets group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009).Patients on sildenafil tablets achieved a statistically significant reduction in mPAP compared to those on placebo.

More common

A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil tablets (95% CI: -5.7, -2.1) (p = 0.00003).Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than the sildenafil tablets-treated patients and that sildenafil tablets-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11.Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH (in Study 2)Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil tablets compared to placebo. More than twice as many sildenafil tablets-treated patients (36%) as the placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.Study 3 (Sildenafil tablets monotherapy (1 mg, 5 mg, and 20 mg three times a day))A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH.

Sildenafil Tablets for ED

This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were randomized to 1 of 3 doses of Sildenafil tablets: 1 mg, 5 mg, and 20 mg, three times a day.At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian.The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Similar increases in walk distance (mean increase of 38-41 meters) were observed in the 5 and 20 mg dose groups. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH (in Study 2) Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil tablets compared to placebo. More than twice as many sildenafil tablets-treated patients (36%) as the placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study 3 (Sildenafil tablets monotherapy (1 mg, 5 mg, and 20 mg three times a day)) A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH.

• Common side effects of sildenafil include headaches, flushing, and nasal congestion.
• Serious side effects are rare but require immediate medical attention.
• Patients should report any adverse reactions to their healthcare provider.

Patients were randomized to 1 of 3 doses of Sildenafil tablets: 1 mg, 5 mg, and 20 mg, three times a day.

7. Drug Interactions

Sildenafil Tablets, USP 20 mg are supplied as white round, biconvex film coated tablets debossed with "R" on one side and "20" on the other side, containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: Recommended Storage for Sildenafil Tablets, USP: Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information).Inform patients of contraindication of sildenafil tablets with regular and/or intermittent use of organic nitrates.Inform patients that sildenafil tablets is also marketed as VIAGRA for erectile dysfunction. At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian. These increases were significantly better than those observed in the 1 mg dose group (Figure 12). Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 - ITT Population Sildenafil Protocol A1481244 Study 4 (Sildenafil Tablets added to bosentan therapy - lack of effect on exercise capacity) A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months.

When to See a Doctor

A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil tablets (95% CI: -5.7, -2.1) (p = 0.00003). Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH (in Study 2) Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil tablets compared to placebo. More than twice as many sildenafil tablets-treated patients (36%) as the placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study 3 (Sildenafil tablets monotherapy (1 mg, 5 mg, and 20 mg three times a day)) A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. Patients were randomized to 1 of 3 doses of Sildenafil tablets: 1 mg, 5 mg, and 20 mg, three times a day.

Starting Sildenafil: Recommended First-Time Dosage

At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian. These increases were significantly better than those observed in the 1 mg dose group (Figure 12). Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 - ITT Population Sildenafil Protocol A1481244 Study 4 (Sildenafil Tablets added to bosentan therapy - lack of effect on exercise capacity) A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. HOW SUPPLIED/STORAGE AND HANDLING Sildenafil Tablets, USP 20 mg are supplied as white round, biconvex film coated tablets debossed with "R" on one side and "20" on the other side, containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows:Recommended Storage for Sildenafil Tablets, USP: Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. HOW SUPPLIED/STORAGE AND HANDLING Sildenafil Tablets, USP 20 mg are supplied as white round, biconvex film coated tablets debossed with "R" on one side and "20" on the other side, containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows:Recommended Storage for Sildenafil Tablets, USP: Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].

• Sildenafil 20 mg tablets should be taken about 30 to 60 minutes before sexual activity.
• It’s important not to take more than one dose in 24 hours.
• Do not crush or chew the medication; swallow it whole with water.

Sildenafil Tablets, USP 20 mg are supplied as white round, biconvex film coated tablets debossed with "R" on one side and "20" on the other side, containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: Recommended Storage for Sildenafil Tablets, USP: Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information).Inform patients of contraindication of sildenafil tablets with regular and/or intermittent use of organic nitrates.Inform patients that sildenafil tablets is also marketed as VIAGRA for erectile dysfunction.