|Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC code: G04BE03|
Mechanism of actionSildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5), the enzyme that is responsible for degradation of cGMP. Apart from the presence of this enzyme in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Pharmacodynamic effectsStudies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-fold selectivity over PDE1, and over 700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mm Hg respectively. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen.Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported.In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9 %. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries.Mild and transient differences in colour discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, colour discrimination simulated traffic light, Humphrey perimeter and photostress).
Clinical efficacy and safety
Efficacy in adult patients with pulmonary arterial hypertension (PAH)A randomised, double-blind, placebo-controlled study was conducted in 278 patients with primary pulmonary hypertension, PAH associated with connective tissue disease, and PAH following surgical repair of congenital heart lesions. Patients were randomised to one of four treatment groups: placebo, sildenafil 20 mg, sildenafil 40 mg or sildenafil 80 mg, three times a day. Of the 278 patients randomised, 277 patients received at least 1 dose of study drug. The study population consisted of 68 (25 %) men and 209 (75 %) women with a mean age of 49 years (range: 18-81 years) and baseline 6-minute walk test distance between 100 and 450 metres inclusive (mean: 344 metres). 175 patients (63 %) included were diagnosed with primary pulmonary hypertension, 84 (30 %) were diagnosed with PAH associated with connective tissue disease and 18 (7 %) of the patients were diagnosed with PAH following surgical repair of congenital heart lesions. Most patients were WHO Functional Class II (107/277, 39 %) or III (160/277, 58 %) with a mean baseline 6 minute walking distance of 378 meters and 326 meters respectively; fewer patients were Class I (1/277, 0.4 %) or IV (9/277, 3 %) at baseline. Patients with left ventricular ejection fraction < 45 % or left ventricular shortening fraction < 0.2 were not studied.Sildenafil (or placebo) was added to patients' background therapy which could have included a combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as add-on therapy, and neither was arginine supplementation. Patients who previously failed bosentan therapy were excluded from the study.The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance (6MWD). A statistically significant increase in 6MWD was observed in all 3 sildenafil dose groups compared to those on placebo. Placebo corrected increases in 6MWD were 45 metres (p < 0.0001), 46 metres (p < 0.0001) and 50 metres (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID respectively. There was no significant difference in effect between sildenafil doses. For patients with a baseline 6MWD < 325 m improved efficacy was observed with higher doses (placebo-corrected improvements of 58 metres, 65 metres and 87 metres for 20 mg, 40 mg and 80 mg doses TID, respectively).When analysed by WHO functional class, a statistically significant increase in 6MWD was observed in the 20 mg dose group. For class II and class III, placebo corrected increases of 49 metres (p = 0.0007) and 45 metres (p = 0.0031) were observed respectively.The improvement in 6MWD was apparent after 4 weeks of treatment and this effect was maintained at weeks 8 and 12. Results were generally consistent in subgroups according to aetiology (primary and connective tissue disease-associated PAH), WHO functional class, gender, race, location, mean PAP and PVRI.Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) compared to those on placebo. Placebo-corrected treatment effects with mPAP were 2.7 mmHg (p = 0.04), -3.0 mm Hg (p = 0.01) and -5.1 mm Hg (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID respectively. Placebo-corrected treatment effects with PVR were -178 dyne.sec/cm5 (p=0.0051), -195 dyne.sec/cm5 (p=0.0017) and -320 dyne.sec/cm5 (p<0.0001) for sildenafil 20 mg, 40 mg and 80 mg TID, respectively. The percent reduction at 12 weeks for sildenafil 20 mg, 40 mg and 80 mg TID in PVR (11.2 %, 12.9 %, 23.3 %) was proportionally greater than the reduction in systemic vascular resistance (SVR) (7.2 %, 5.9 %, 14.4 %). The effect of sildenafil on mortality is unknown.A greater percentage of patients on each of the sildenafil doses (i.e. 28 %, 36 % and 42 % of subjects who received sildenafil 20 mg, 40 mg and 80 mg TID doses, respectively) showed an improvement by at least one WHO functional class at week 12 compared to placebo (7 %). The respective odds ratios were 2.92 (p=0.0087), 4.32 (p=0.0004) and 5.75 (p<0.0001).
Long-term survival data in naive populationPatients enrolled into the pivotal study were eligible to enter a long term open label extension study. At 3 years 87 % of the patients were receiving a dose of 80 mg TID. A total of 207 patients were treated with Revatio in the pivotal study, and their long term survival status was assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 year survival were 96 %, 91 % and 82 %, respectively. Survival in patients of WHO functional class II at baseline at 1, 2 and 3 years was 99 %, 91 %, and 84 % respectively, and for patients of WHO functional class III at baseline was 94 %, 90 %, and 81 %, respectively.
Efficacy in adult patients with PAH (when used in combination with epoprostenol)A randomised, double-blind, placebo controlled study was conducted in 267 patients with PAH who were stabilised on intravenous epoprostenol. The PAH patients included those with Primary Pulmonary Arterial Hypertension (212/267, 79 %) and PAH associated with connective tissue disease (55/267, 21 %). Most patients were WHO Functional Class II (68/267, 26 %) or III (175/267, 66 %); fewer patients were Class I (3/267, 1 %) or IV (16/267, 6 %) at baseline; for a few patients (5/267, 2 %), the WHO Functional Class was unknown. Patients were randomised to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) when used in combination with intravenous epoprostenol.The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance. There was a statistically significant benefit of sildenafil compared to placebo in 6-minute walk distance. A mean placebo corrected increase in walk distance of 26 metres was observed in favour of sildenafil (95 % CI: 10.8, 41.2) (p = 0.0009). For patients with a baseline walking distance ≥ 325 metres, the treatment effect was 38.4 metres in favour of sildenafil; for patients with a baseline walking distance < 325 metres, the treatment effect was 2.3 metres in favour of placebo. For patients with primary PAH, the treatment effect was 31.1 metres compared to 7.7 metres for patients with PAH associated with connective tissue disease. The difference in results between these randomisation subgroups may have arisen by chance in view of their limited sample size.Patients on sildenafil achieved a statistically significant reduction in mean Pulmonary Arterial Pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favour of sildenafil (95 % CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening was a secondary endpoint as defined as the time from randomisation 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). Treatment with sildenafil significantly delayed the time to clinical worsening of PAH compared to placebo (p = 0.0074). 23 subjects experienced clinical worsening events in the placebo group (17.6 %) compared with 8 subjects in the sildenafil group (6.0 %).
Long-term Survival Data in the background epoprostenol studyPatients enrolled into the epoprostenol add-on therapy study were eligible to enter a long term open label extension study. At 3 years 68 % of the patients were receiving a dose of 80 mg TID. A total of 134 patients were treated with Revatio in the initial study, and their long term survival status was assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 year survival were 92 %, 81 % and 74 %, respectively.
Efficacy and safety in adult patients with PAH (when used in combination with bosentan)A randomized, double-blind, placebo controlled study was conducted in 103 clinically stable subjects with PAH (WHO FC II and III) who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with connective tissue disease. Patients were randomized to placebo or sildenafil (20 mg three times a 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. The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil (20 mg three times a day) and placebo (13.62 m (95% CI: -3.89 to 31.12) and 14.08 m (95% CI: -1.78 to 29.95), respectively).Differences in 6MWD were observed between patients with primary PAH and PAH associated with connective tissue disease. For subjects with primary PAH (67 subjects), mean changes from baseline were 26.39 m (95% CI: 10.70 to 42.08) and 11.84 m (95% CI: -8.83 to 32.52) for the sildenafil and placebo groups, respectively. However, for subjects with PAH associated with connective tissue disease (36 subjects) mean changes from baseline were -18.32 m (95% CI: -65.66 to 29.02) and 17.50 m (95% CI: -9.41 to 44.41) for the sildenafil and placebo groups, respectively.Overall, the adverse events were generally similar between the two treatment groups (sildenafil plus bosentan vs. bosentan alone), and consistent with the known safety profile of sildenafil when used as monotherapy (see sections 4.4 and 4.5).
Paediatric populationA total of 234 subjects aged 1 to 17 years were treated in a randomized, double-blind, multi-centre, placebo controlled parallel group, dose ranging study. Subjects (38 % male and 62 % female) had a body weight ≥ 8 kg, and had primary pulmonary hypertension (PPH) [33 %], or PAH secondary to congenital heart disease [systemic-to-pulmonary shunt 37 %, surgical repair 30 %]. In this trial, 63 of 234 (27 %) patients were < 7 years old (sildenafil low dose = 2; medium dose = 17; high dose = 28; placebo = 16) and 171 of 234 (73 %) patients were 7 years or older (sildenafil low dose = 40; medium dose = 38; and high dose = 49; placebo = 44). Most subjects were WHO Functional Class I (75/234, 32 %) or II (120/234, 51 %) at baseline; fewer patients were Class III (35/234, 15 %) or IV (1/234, 0.4 %); for a few patients (3/234, 1.3 %), the WHO Functional Class was unknown.Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted in the study, and neither was arginine supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors. The primary objective of the study was to assess the efficacy of 16 weeks of chronic treatment with oral sildenafil in paediatric subjects to improve exercise capacity as measured by the Cardiopulmonary Exercise Test (CPET) in subjects who were developmentally able to perform the test, n = 115). Secondary endpoints included haemodynamic monitoring, symptom assessment, WHO functional class, change in background treatment, and quality of life measurements.Subjects were allocated to one of three sildenafil treatment groups, low (10 mg), medium (10-40 mg) or high dose (20-80 mg) regimens of Revatio given three times a day, or placebo. Actual doses administered within a group were dependent on body weight (see Section 4.8). The proportion of subjects receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (47.7 %) and the placebo treatment group (41.7 %). The primary endpoint was the placebo-corrected percentage change in peak VO2 from baseline to week 16 assessed by CPET testing in the combined dose groups (Table 2). A total of 106 out of 234 (45 %) subjects were evaluable for CPET, which comprised those children ≥ 7 years old and developmentally able to perform the test. Children < 7 years (sildenafil combined dose = 47; placebo = 16) were evaluable only for the secondary endpoints. Mean baseline peak volume of oxygen consumed (VO2) values were comparable across the sildenafil treatment groups (17.37 to 18.03 ml/kg/min), and slightly higher for the placebo treatment group (20.02 ml/kg/min). The results of the main analysis (combined dose groups versus placebo) were not statistically significant (p = 0.056) (see Table 2). The estimated difference between the medium sildenafil dose and placebo was 11.33 % (95 % CI: 1.72 to 20.94) (see Table 2).Table 2: Placebo Corrected % Change from Baseline in Peak VO2 by Active Treatment Group
|Treatment group||Estimated difference||95% confidence interval|
|Combined dose groups (n=77)||7.71
(p = 0.056)
n=29 for placebo groupEstimates based on ANCOVA with adjustments for the covariates baseline peak VO2, etiology and weight groupDose related improvements were observed with pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP). The sildenafil medium and high dose groups both showed PVRI reductions compared to placebo, of 18 % (95 % CI: 2 % to 32 %) and 27 % (95 % CI: 14 % to 39 %), respectively; whilst the low dose group showed no significant difference from placebo (difference of 2 %). The sildenafil medium and high dose groups displayed mPAP changes from baseline compared to placebo, of -3.5 mmHg (95 % CI: -8.9, 1.9) and -7.3 mmHg (95 % CI: -12.4, -2.1), respectively; whilst the low dose group showed little difference from placebo (difference of 1.6 mmHg). Improvements were observed with cardiac index with all three sildenafil groups over placebo, 10 %, 4 % and 15 % for the low, medium and high dose groups respectively.Significant improvements in functional class were demonstrated only in subjects on sildenafil high dose compared to placebo. Odds ratios for the sildenafil low, medium and high dose groups compared to placebo were 0.6 (95 % CI: 0.18, 2.01), 2.25 (95 % CI: 0.75, 6.69) and 4.52 (95 % CI: 1.56, 13.10), respectively.
Long term extension dataOf the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered the long-term extension study. Subjects who had been in the placebo group in the short-term study were randomly reassigned to sildenafil treatment; subjects weighing ≤ 20 kg entered the medium or high dose groups (1:1), while subjects weighing > 20 kg entered the low, medium or high dose groups (1:1:1). Of the total 229 subjects who received sildenafil, there were 55, 74, and 100 subjects in the low, medium and high dose groups, respectively. Across the short-term and long-term studies, the overall duration of treatment from start of double-blind for individual subjects ranged from 3 to 3129 days. By sildenafil treatment group, median duration of sildenafil treatment was 1696 days (excluding the 5 subjects who received placebo in double-blind and were not treated in the long-term extension study).Kaplan-Meier estimates of survival at 3 years in patients > 20 kg in weight at baseline were 94 %, 93 % and 85 % in the low, medium and high dose groups, respectively; for patients ≤ 20 kg in weight at baseline, the survival estimates were 94 % and 93 % for subjects in the medium and high dose groups respectively (see sections 4.4 and 4.8). During the conduct of the study, there were a total of 42 deaths reported, whether on treatment or reported as part of the survival follow-up. 37 deaths occurred prior to a decision taken by the Data Monitoring Committee to down titrate subjects to a lower dosage, based on an observed mortality imbalance with increasing sildenafil doses. Among these 37 deaths, the number (%) of deaths was 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. An additional 5 deaths were reported subsequently.The causes of deaths were related to PAH. Higher than recommended doses should not be used in paediatric patients with PAH (see sections 4.2 and 4.4).Peak VO2 was assessed 1 year after the start of the placebo-controlled study. Of those sildenafil treated subjects developmentally able to perform the CPET 59/114 subjects (52 %) had not shown any deterioration in Peak VO2 from start of sildenafil. Similarly 191 of 229 subjects (83 %) who had received sildenafil had either maintained or improved their WHO Functional Class at 1 year assessment. The European Medicines Agency has deferred the obligation to submit the results of studies with Revatio in newborns with pulmonary arterial hypertension (see section 4.2 for information on paediatric use).