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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 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 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; 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 distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. 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

The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory

parameters

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

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

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% reductions in sildenafil clearance when co-administered with beta-blockers. 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 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 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).

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 citrate 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 citrate (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). Table 4 displays the number of patients with clinical worsening events in Study 2. 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 11. Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil citrate 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 3 (Sildenafil Citrate monotherapy (1 mg, 5 mg, and 20 mg three times a day) A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This study was prematurely terminated with 129 subjects enrolled.

Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart catheterization within 12 weeks 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 345 meters).

Patients were randomized to 1 of 3 doses of sildenafil citrate: 1 mg, 5 mg, and 20 mg, three times a day. At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian.

The primary efficacy endpoint was the change from baseline at Week 12 (at. least 4 hours after the last dose) in the 6-minute walk distance.

Similar increases in walk distance (mean increase of 38 to 41 meters) were observed in the 5 and 20 mg dose groups. These increases were significantly better than those observed in the 1 mg dose group (Figure 12). Study 4 (Sildenafil Citrate added to bosentan therapy – lack of effect on exercise capacity) A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months.

The PAH patients included those with primary PAH, and PAH associated with CTD.

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 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 plus bosentan and bosentan alone.

Sildenafil tablets, 20 mg, are supplied as white to off-white, round shaped film-coated tablets with debossing ‘AN 351’ on one side and plain on the other side, containing sildenafil citrate, USP equivalent to the nominally indicated amount of sildenafil. They are available as follows: Bottles of 90: NDC 68001-176-05. Recommended Storage for Sildenafil Tablets: Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Drug Name : Sildenafil 20 MG (as sildenafil citrate) Oral Tablet Ingredient(s) : croscarmellose sodium, calcium phosphate, dibasic, anhydrous, hypromelloses, magnesium stearate, cellulose, microcrystalline, polyethylene glycols, polyvinyl alcohol, talc, titanium dioxide Imprint : AN;351 Dosage : 20 mg Color(s) : White Shape : Round Size (mm) : 7 Score : 1 NDC :68001-176.

Read this Patient Information before you start taking sildenafil citrate and each time you get a refill. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about sildenafil citrate, ask your doctor or pharmacist. What is the most important information I should know about sildenafil citrate?

Never take sildenafil citrate with any nitrate medicines.

Your blood pressure could drop quickly to an unsafe level. Nitrate medicines include: Medicines that treat chest pain (angina) Nitroglycerin in any form including tablets, patches, sprays, and ointments Isosorbide mononitrate or dinitrate Street drugs called “poppers” (amyl nitrate or nitrite) Ask your doctor or pharmacist if you are not sure if you are taking a nitrate medicine.

Sildenafil citrate is a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your brand viagra without prescription lungs. Sildenafil citrate improves the ability to exercise and can slow down worsening changes in your physical condition. Sildenafil citrate is not for use in children Adding sildenafil citrate to another medication used to treat PAH, bosentan (Tracleer®), does not result in improvement in your ability to exercise.

Sildenafil citrate contains the same medicine as Sildenafil citrate® (sildenafil), which is used to treat erectile dysfunction (impotence).

Do not take sildenafil citrate with Sildenafil citrate or other PDE-5 inhibitors.

Do not take sildenafil citrate if you: Take nitrate medicines. See “What is the most important information I should know about sildenafil citrate?” Are allergic to sildenafil or any other ingredient in sildenafil tablets. See “What are the ingredients in sildenafil tablets?” at the end of this leaflet.

What should I tell my doctor before taking sildenafil citrate? Tell your doctor about all of your medical conditions, including if you Have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a heart attack Have a disease called pulmonary veno-occlusive disease (PVOD) Have high or low blood pressure or blood circulation problems Have an eye problem called retinitis pigmentosa Have or had loss of sight in one or both eyes Have any problem with the shape of your penis or Peyronie’s disease Have any blood cell problems such sickle cell anemia Have a stomach ulcer or any bleeding problems Are pregnant or planning to become pregnant.