Label: SILDENAFIL- sildenafil tablet, film coated

Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4)] . Sildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers.

Country/Region	Legal Status	Regulatory Agency	Prescription Needed	Notes
United States	Prescription-only	FDA	Yes	Class II controlled substance
European Union	Prescription-required	EMA	Yes	Regulated as prescription drug
India	Available both OTC and RX	CDSCO	Prescription recommended	Varies by state
Australia	Prescription-only	TGA	Yes	Controlled medicine

In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50greater than 150 µM). 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.

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The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone.Study A1481324 (NCT02060487) - Study to Assess the Effects of Sildenafil on Mortality in Adults with PAHA study to assess the effects of multiple doses of sildenafil on mortality in adults with PAH was conducted following the observation of a higher risk of mortality in pediatric patients taking a high dose of sildenafil TID, based on body weight, compared to those taking a lower dose of sildenafil in the long-term extension of the pediatric clinical trial.The study was a randomized, double-blind, parallel-group study in 385 adults with PAH. Patients were randomly assigned 1:1:1 to one of three treatment groups (5, 20, and 80 mg TID). Most patients were PAH treatment naïve (83%). For most patients the etiology canada sildenafil of PAH was idiopathic (72%). The most common WHO Functional Class was Class III (58% of patients).

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Treatment groups were well balanced with respect to baseline demographics of strata history of PAH treatment and etiology of PAH, as well as the WHO Functional Class categories.The primary objective of the study was to compare sildenafil 80 mg TID versus 5 mg TID for mortality, with success defined by ruling out twice the mortality at 80 mg.The key secondary efficacy endpoint was time to first event of clinical worsening, defined as a composite endpoint of all-cause mortality, hospitalization for worsening PAH or disease progression. An additional secondary endpoint was 6MWD at Months 6 and 12.Overall SurvivalAt the time of a planned interim analysis (50% deaths) it was identified that the primary efficacy objective of this protocol was met and therefore the study was stopped. Based on the primary efficacy endpoint (mortality), the non-inferiority of sildenafil 80 mg TID arm versus 5 mg TID arm was met using a 2-sided significance level of 0.003 for the interim analysis. Primary comparison of the 80 mg TID group to the 5 mg TID group yielded the HR (99.7% CI) = 0.51 (0.22, 1.21); i.e., non-inferiority was established.Table 6. Hazard Ratios for Overall Survival, Assessed in the Proportional Hazards Model – Intent To Treat Populationa. The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. 14 CLINICAL STUDIES SUPER-1 (NCT00644605) - Sildenafil citrate Monotherapy [20 mg, 40 mg, and 80 mg Three Times a Day]A randomized, double-blind, placebo-controlled study of sildenafil citrate (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).

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Patients were predominantly WHO Functional Classes II-III. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.Patients were randomized to receive placebo (n=70) or sildenafil tablet 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks.

7.3 Amlodipine

On treatment deaths: Any death within 7 days of last dose was regarded as “On treatment”, thus might include deaths occurred after discontinuation from study treatment.b. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH.Kaplan-Meier estimates of survival at 3 years were 66%, 79%, and 85% in the 5-, 20-, and 80- mg TID dose groups, respectively.Clinical WorseningSildenafil 80 mg was also superior to 5 mg for time to first event of clinical worsening with HR (99.7% CI) = 0.44 (0.22, 0.89).Table 7. Hazard Ratios for Time to First Event of Clinical Worsening – Intent To Treat PopulationNote: Sildenafil 5 mg is not an approved dosage.Abbreviations: 6MWD = 6-minute walk distance; CI = confidence interval; PAH = pulmonary arterial hypertension.a. Clinical worsening events were defined as reduction from baseline in the 6MWD test by at least 15% and worsening functional class from baseline, both confirmed by a second test/evaluation within 2 weeks.b. Count of cases of disease progression as the first event of clinical worsening.c.

How it works for PAH

Count of non-elective hospital stays for worsening PAH as the first event of clinical worsening.d. Count of deaths as the first event of clinical worsening.e. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. P-value from the Wald test.6MWD at Months 6 and 12At baseline, the median of 6MWD for the intent-to-treat (ITT) population was 332 to 352 m. At Month 6, the median change from baseline was highest for sildenafil 80 mg TID with 28 m compared to 18 m and 19 m for sildenafil 5 mg TID and sildenafil 20 mg TID groups, respectively.The same was seen at Month 12, the median change from baseline for sildenafil 80 mg TID group was 33 m compared to 17 m for sildenafil 5 mg TID and 31 m in sildenafil 20 mg TID groups.Overall, the safety data for sildenafil 20 mg TID and for the higher sildenafil 80 mg TID dose were consistent with the established safety profile of sildenafil in previous adult PAH studies [see Adverse Reactions (6.1)].Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. Placebo-Corrected Change from Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-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.SUPER-2 (NCT00159887) Long-Term Treatment of PAHIn 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.

Overdose/Missed Dose

Patients were randomized to placebo or sildenafil citrate (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 citrate group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil tablet 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 citrate achieved a statistically significant reduction in mPAP compared to those on placebo.

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Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4)] . Sildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function.

Does sildenafil interact with foods or drinks?

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50greater than 150 µM). 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. The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. 14 CLINICAL STUDIES SUPER-1 (NCT00644605) - Sildenafil citrate Monotherapy [20 mg, 40 mg, and 80 mg Three Times a Day]A randomized, double-blind, placebo-controlled study of sildenafil citrate (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 predominantly WHO Functional Classes II-III. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil tablet (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).

8.5 Geriatric Use

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 sildenafil citrate -treated patients and that sildenafil citrate -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 5.Figure 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1Improvements in WHO Functional Class for PAH were also demonstrated in patients on sildenafil tablet compared to placebo. More than twice as many sildenafil citrate-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.Study A1481243 (NCT00323297) – Sildenafil citrate Added to Bosentan Therapy – Lack of Effect on Exercise CapacityA randomized, double-blind, placebo-controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of 3 months. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone.Study A1481324 (NCT02060487) - Study to Assess the Effects of Sildenafil on Mortality in Adults with PAHA study to assess the effects of multiple doses of sildenafil on mortality in adults with PAH was conducted following the observation of a higher risk of mortality in pediatric patients taking a high dose of sildenafil TID, based on body weight, compared to those taking a lower dose of sildenafil in the long-term extension of the pediatric clinical trial.The study was a randomized, double-blind, parallel-group study in 385 adults with PAH. Patients were randomly assigned 1:1:1 to one of three treatment groups (5, 20, and 80 mg TID). Most patients were PAH treatment naïve (83%). For most patients the etiology canada sildenafil of PAH was idiopathic (72%). The most common WHO Functional Class was Class III (58% of patients).

• Sildenafil is classified as a prescription medication in most countries.
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Treatment groups were well balanced with respect to baseline demographics of strata history of PAH treatment and etiology of PAH, as well as the WHO Functional Class categories.The primary objective of the study was to compare sildenafil 80 mg TID versus 5 mg TID for mortality, with success defined by ruling out twice the mortality at 80 mg.The key secondary efficacy endpoint was time to first event of clinical worsening, defined as a composite endpoint of all-cause mortality, hospitalization for worsening PAH or disease progression. An additional secondary endpoint was 6MWD at Months 6 and 12.Overall SurvivalAt the time of a planned interim analysis (50% deaths) it was identified that the primary efficacy objective of this protocol was met and therefore the study was stopped. Based on the primary efficacy endpoint (mortality), the non-inferiority of sildenafil 80 mg TID arm versus 5 mg TID arm was met using a 2-sided significance level of 0.003 for the interim analysis. Primary comparison of the 80 mg TID group to the 5 mg TID group yielded the HR (99.7% CI) = 0.51 (0.22, 1.21); i.e., non-inferiority was established.Table 6. Hazard Ratios for Overall Survival, Assessed in the Proportional Hazards Model – Intent To Treat Populationa. On treatment deaths: Any death within 7 days of last dose was regarded as “On treatment”, thus might include deaths occurred after discontinuation from study treatment.b. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH.Kaplan-Meier estimates of survival at 3 years were 66%, 79%, and 85% in the 5-, 20-, and 80- mg TID dose groups, respectively.Clinical WorseningSildenafil 80 mg was also superior to 5 mg for time to first event of clinical worsening with HR (99.7% CI) = 0.44 (0.22, 0.89).Table 7. Hazard Ratios for Time to First Event of Clinical Worsening – Intent To Treat PopulationNote: Sildenafil 5 mg is not an approved dosage.Abbreviations: 6MWD = 6-minute walk distance; CI = confidence interval; PAH = pulmonary arterial hypertension.a. Clinical worsening events were defined as reduction from baseline in the 6MWD test by at least 15% and worsening functional class from baseline, both confirmed by a second test/evaluation within 2 weeks.b. Count of cases of disease progression as the first event of clinical worsening.c.

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SUPER-1 (NCT00644605) - Sildenafil citrate Monotherapy [20 mg, 40 mg, and 80 mg Three Times a Day] A randomized, double-blind, placebo-controlled study of sildenafil citrate (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).

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Count of non-elective hospital stays for worsening PAH as the first event of clinical worsening.d. Count of deaths as the first event of clinical worsening.e.

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Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. P-value from the Wald test.6MWD at Months 6 and 12At baseline, the median of 6MWD for the intent-to-treat (ITT) population was 332 to 352 m. At Month 6, the median change from baseline was highest for sildenafil 80 mg TID with 28 m compared to 18 m and 19 m for sildenafil 5 mg TID and sildenafil 20 mg TID groups, respectively.The same was seen at Month 12, the median change from baseline for sildenafil 80 mg TID group was 33 m compared to 17 m for sildenafil 5 mg TID and 31 m in sildenafil 20 mg TID groups.Overall, the safety data for sildenafil 20 mg TID and for the higher sildenafil 80 mg TID dose were consistent with the established safety profile of sildenafil in previous adult PAH studies [see Adverse Reactions (6.1)].Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets.

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Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.Patients were randomized to receive placebo (n=70) or sildenafil tablet 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 Change from Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-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.SUPER-2 (NCT00159887) Long-Term Treatment of PAHIn 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. Patients were randomized to placebo or sildenafil citrate (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 citrate group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil tablet 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 citrate 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 tablet (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).

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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 sildenafil citrate -treated patients and that sildenafil citrate -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 5.Figure 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1Improvements in WHO Functional Class for PAH were also demonstrated in patients on sildenafil tablet compared to placebo. More than twice as many sildenafil citrate-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.Study A1481243 (NCT00323297) – Sildenafil citrate Added to Bosentan Therapy – Lack of Effect on Exercise CapacityA randomized, double-blind, placebo-controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of 3 months. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). SUPER-1 (NCT00644605) - Sildenafil citrate Monotherapy [20 mg, 40 mg, and 80 mg Three Times a Day] A randomized, double-blind, placebo-controlled study of sildenafil citrate (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).