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Pharmacology: Pharmacodynamics: 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 PAH 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 dosing of 80 mg three times a day to healthy male volunteers, the largest average change from baseline of supine systolic blood pressure was a decrease of 9.0 mmHg. The corresponding change in supine diastolic blood pressure was a decrease of 8.4 mmHg.
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 mmHg 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 oral 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 PAH 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 color 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 color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity, contrast sensitivity, electroretinograms, intraocular pressure, or pupillometry. 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, color discrimination simulated traffic light, Humphrey perimeter and photostress).
Efficacy in adult patients with PAH: A randomized, double-blind, placebo-controlled study was conducted in 278 patients with primary PAH, PAH associated with connective tissue disease (CTD), and PAH following surgical repair of congenital heart lesions. Patients were randomized 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 randomized, 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 (6MWD) between 100 and 450 meters (mean: 344 meters). 175 patients (63%) included were diagnosed with primary pulmonary hypertension, 84 (30%) were diagnosed with PAH associated with CTD 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 anticoagulants, digoxin, calcium channel blockers, diuretics and/or oxygen. The use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted 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 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 meters (p < 0.0001), 46 meters (p < 0.0001) and 50 meters (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg 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 20 mg, 40 mg and 80 mg doses TID, respectively).
The improvement in walk distance was apparent after 4 weeks of treatment and this effect was maintained at Weeks 8 and 12. Mean treatment effects consistently showed improvement in 6MWD in all sildenafil groups compared to placebo in all pre-defined subpopulations based on demographics, geographical regions, disease characteristics (in particular effects were similar among WHO functional class groups and etiologies) and baseline parameters (walk test and hemodynamics).
When analyzed 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 meters (p = 0.0007) and 45 meters (p = 0.0031) were observed respectively.
Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo. Placebo-corrected treatment effects were -2.7 mmHg (p = 0.04), -3.0 mmHg (p = 0.01) and -5.1 mmHg (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 (28%, 36% and 42% of subjects in sildenafil 20 mg, 40 mg and 80 mg, respectively) showed an improvement in at least 1 WHO functional class over the 12-week period 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: Patients 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.
Effects on mortality in adults with PAH: A study to assess the effects of different dose levels 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 three times a day, based on body weight, compared to those taking a lower dose 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 mg three times a day (4 times lower than the recommended dose), 20 mg three times a day (recommended dose) and 80 mg three times a day (4 times the maximum recommended dose). In total, the majority of patients were PAH treatment naïve (83.4%). For most patients the etiology of PAH was idiopathic (71.7%). The most common WHO Functional Class was Class III (57.7% of patients). All three 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 mortality rates were 26.4% (n=34) for the 5 mg TID dose, 19.5% (n=25) for the 20 mg TID dose and 14.8% (n=19) with the 80 mg TID dose.
Pharmacokinetics: Absorption: Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 41% (range 25-63%). After oral three times a day dosing of sildenafil, AUC and Cmax increase in proportion with dose over the dose range of 20-40 mg. After oral doses of 80 mg three times a day a more than dose proportional increase in sildenafil plasma levels has been observed. In pulmonary arterial hypertension patients, the oral bioavailability of sildenafil after 80 mg three times a day was on average 43% (90% CI: 27% - 60%) higher compared to the lower doses.
When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29% however, the extent of absorption was not significantly affected (AUC decreased by 11%).
Distribution: The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into the tissues. After oral doses of 20 mg 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.
Biotransformation: 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 20 mg three times a day dosing (translating into a 36% contribution to sildenafil's pharmacological effects). The subsequent effect on efficacy is unknown.
Elimination: 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).
Pharmacokinetics in special patient groups: Elderly: 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%.
Renal insufficiency: In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 ml/min), the pharmacokinetics of sildenafil were not altered after receiving a 50 mg 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.
Hepatic insufficiency: 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.
Population pharmacokinetics: In patients with pulmonary arterial hypertension, the average steady state concentrations were 20-50% higher over the investigated dose range of 20-80 mg 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.
Toxicology: Preclinical safety data: Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity potential, toxicity to reproduction and development. In pups of rats which were pre- and post-natally treated with 60 mg/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 exposure at 20 mg 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.
