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One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%).

The primary objective of the study was to assess the effect of sildenafil citrate on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil citrate did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil citrate remained on his/her dose of sildenafil citrate or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil citrate. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6: During the study, there were 42 reported deaths with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil citrate doses.

For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Use of sildenafil citrate, particularly chronic use, is not recommended in children.

Clinical studies of sildenafil citrate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical suhagra online experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

There is no FDA guidance on the use of Sildenafil with respect to specific gender populations.

There is no FDA guidance on the use of Sildenafil with respect to specific racial populations.

No dose adjustment is required (including severe impairment CLcr Hepatic Impairment. No dose adjustment for mild to moderate impairment is required.

There is no FDA guidance on the use of Sildenafil in women of reproductive potentials and males. There is no FDA guidance one the use of Sildenafil in patients who are immunocompromised. FDA Package Insert for Sildenafil contains no information regarding drug monitoring.

There is limited information about the IV Compatibility. In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is sildenafil citrate tablets buy online not eliminated in the urine.

Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP.

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 PDE-5.

Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11).

The approximately 4,000-fold selectivity for PDE-5 versus suhagra online PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina.

This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.

Sildenafil citrate, USP, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as Sildenafil citrate® for erectile dysfunction.

Sildenafil citrate, USP is designated chemically as 1-[ [3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Pharmacodynamics. Effects of Sildenafil citrate on Hemodynamic Measures. Patients on all Sildenafil citrate doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)].

Data on other hemodynamic measures for the Sildenafil citrate 20 mg three times a day and placebo dosing regimens is displayed in Table suhagra online 3.

The relationship between these effects and improvements in 6minute walk distance is unknown.

mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; non prescription viagra online CO = cardiac output; HR = heart rate *The number of patients per treatment group varied slightly for each parameter due to missing assessments.

In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg, there were no significant differences in the effects on hemodynamic variables between doses. Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg).

The decrease in blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range.

Larger effects were recorded among patients receiving concomitant nitrates.

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 TID to patients with PAH, no clinically relevant effects on ECG were reported.

After chronic dosing of 80 mg TID sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively.

After chronic dosing of 80 mg TID sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg TID sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).

At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels.

This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina.

An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry.

Sildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25% to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%.

The mean steady-state volume of distribution (Vss) for sildenafil is 105 L,

indicating

Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate).

Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes.

The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug.

In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. 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). Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH.

The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20% to 50% higher when compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to healthy volunteers.

Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years).

Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. In volunteers with mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered.

In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased 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 (84%) and Cmax(47%) compared to age-matched volunteers with no hepatic impairment.

Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 ?M). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations.

The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively. 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

Sildenafil exposure without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day.

This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil.

Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers.

The mean reduction of sildenafil (80 mg three times a day) bioavailability when administered with epoprostenol was 28%, resulting in about 22% lower mean average steady-state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. Studies of Adults with Pulmonary Arterial Hypertension. Study 1 Sildenafil Citrate monotherapy (20 mg, 40 mg, and 80 mg three times a day) A randomized, double-blind, placebo-controlled study of sildenafil citrate (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World Health Organization (WHO) functional classes II-III.

Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen.

The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted.

Subjects who had failed to respond to bosentan were also excluded.

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 citrate 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) TID for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%).

The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343).

The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute sildenafil citrate 100mg online walk distance. Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil citrate.

These increases were significantly different from placebo, but the sildenafil citrate dose groups were not different from each other (see Figure 9), indicating no additional clinical benefit from doses higher than 20 mg TID. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12.

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. 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.

At suhagra online the end of 1 year, 94% of these patients were still alive.

Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil citrate.

Without a control group, these data must be interpreted cautiously.

Study 2 (Sildenafil Citrate 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 had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days 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 349 meters).