Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction
ATC code: G04BE03
Sildenafil 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.
Studies 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 oral dosing of 80mg 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 mmHg respectively. After chronic oral dosing of 80mg 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 oral dose of 20mg three times a day no reductions in systolic or diastolic pressure were seen.
Single oral doses of sildenafil up to 100mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80mg 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 100mg 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 100mg 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, 100mg) demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, colour discrimination simulated traffic light, Humphrey perimeter and photostress).
A 10mg dose of Revatio solution for injection is predicted to provide total exposure of free sildenafil and its N-desmethyl metabolite and their combined pharmacological effects comparable to those of a 20mg oral dose. This is based on Pharmacokinetic data only (see section 5.2. Pharmacokinetic Properties). The consequences of the subsequent lower exposure to the active N-desmethyl metabolite observed after repeated IV administration of Revatio have not been documented. No clinical studies have been performed to demonstrate that these formulations have comparable efficacy
Study A1481262 was a single centre, single dose, open label study to assess the safety, tolerability and pharmacokinetics of a single intravenous dose of sildenafil (10mg) administered as a bolus injection to patients with PAH who were already receiving and stable on oral Revatio 20mg TID.
A total of 10 PAH subjects enrolled and completed the study. Eight subjects were taking bosentan and one subject was taking treprostinil in addition to bosentan and Revatio. After dosing, sitting and standing blood pressure and heart rate were recorded at 30, 60, 120, 180 and 360 minute post dose. The mean changes from baseline in sitting blood pressure were greatest at 1 hour, -9.1 mmHg (SD ± 12.5) and -3.0 (SD ± 4.9) mmHg for systolic and diastolic pressure respectively. The mean postural changes in systolic and diastolic blood pressure over time were small (<10 mmHg) and returned towards baseline beyond 2 hours.
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 20mg, sildenafil 40mg or sildenafil 80mg, 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 20mg, 40mg and 80mg TID respectively. There was no significant difference in effect between sildenafil doses. For patients with a low baseline 6 MWD < 325 m improved efficacy was observed with higher doses (placebo-corrected improvements of 58 metres, 65 metres and 87 metres for 20mg, 40mg and 80mg doses TID, respectively).
When analysed by WHO functional class, a statistically significant increase in 6MWD was observed in the 20mg 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 mmHg (p=0.01) and -5.1 mmHg (p<0.0001) for sildenafil 20mg, 40mg and 80mg TID, respectively. Placebo-corrected treatment effects with PVR were -178 dyne.sec/cm 5 (p=0.0051), -195 dyne.sec/cm 5 (p=0.0017) and -320 dyne.sec/cm 5 (p<0.0001) for sildenafil 20mg, 40mg and 80mg TID, respectively. The percent reduction at 12 weeks for sildenafil 20mg, 40mg and 80mg TID in PVR (11.2%, 12.9%, 23.3%) was proportionally greater than the reduction in systemic vascular resistance (SVR) (7.2%, 5.9%, and 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 20mg, 40mg and 80mg 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) .
Patients enrolled into the pivotal oral route study were eligible to enter a long term open label extension study. At 3 years 87% of the patients were receiving a dose of 80mg 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.
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 20mg, to 40mg and then 80mg, 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%).
Patients 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 80mg 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.
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 (20mg three times a day) in combination with bosentan (62.5-125mg 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 (20mg 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).
The mean absolute oral bioavailability for sildenafil is 41% (range 25-63%). In study A1481262 Cmax, CL and AUC(0-8) of 248 ng/ml, 30.3 l/h and 330 ng h/ml, were observed respectively. The Cmax and AUC(0-8) of the N-desmethyl metabolite were 30.8 ng/ml and 147 ng h/ml, respectively.
The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into the tissues. After oral doses of 20mg three times a day, the mean maximum total plasma concentration of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.
Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% that of the parent drug. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 h. In patients with pulmonary arterial hypertension, plasma concentrations of N-desmethyl metabolite are approximately 72% those of sildenafil after 20mg three times a day oral dosing (translating into a 36% contribution to sildenafil’s pharmacological effects). The subsequent effect on efficacy is unknown. In healthy volunteers, the plasma levels of the N-desmethyl metabolite following intravenous dosing are significantly lower than those observed following oral dosing. At steady state plasma concentrations of N-desmethyl metabolite are approximately 16% versus 61% those of sildenafil after IV and oral dosing, respectively.
The total body clearance of sildenafil is 41 l/h with a resultant terminal phase half-life of 3-5 h. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose).
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.
In volunteers with mild to moderate renal impairment (creatinine clearance =30-80 ml/min), the pharmacokinetics of sildenafil were not altered after receiving a 50mg single oral dose. In volunteers with severe renal impairment (creatinine clearance <30 ml/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax of 100% and 88% respectively compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased by 200% and 79% respectively in subjects with severe renal impairment compared to subjects with normal renal function.
In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) sildenafil clearance was reduced, resulting in increases in AUC (85%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased by 154% and 87%, respectively in cirrhotic subjects compared to subjects with normal hepatic function. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function have not been studied.
In patients with pulmonary arterial hypertension, the average steady state concentrations were 20-50% higher over the investigated oral dose range of 20–80mg three times a day compared to healthy volunteers. There was a doubling of the Cmin compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary arterial hypertension compared to healthy volunteers.
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential, toxicity to reproduction and development.
In pups of rats which were pre- and postnatally treated with 60mg/kg sildenafil, a decreased litter size, a lower pup weight on day 1 and a decreased 4-day survival were seen at exposures which were approximately fifty times the expected human intravenous exposure at 10mg three times a day. Effects in non-clinical studies were observed at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
There were no adverse reactions, with possible relevance to clinical use, seen in animals at clinically relevant exposure levels which were not also observed in clinical studies.
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