PRS7 Efficacy and Safety of Sildenafil Above 60 mg Daily in Pulmonary Arterial Hypertension Treatment - a Systematic Literature Review

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Disease-Associated Maternal And/Or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.

• The medication should be used only as prescribed.
• The tablet should be swallowed whole with water.
• Do not crush or chew the tablet.
• Take it approximately one hour before intimacy.

No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m² basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day.

• Sildenafil 60mg is one of several doses available.
• Your doctor may adjust the dose based on response.
• Use only the dose prescribed to you.
• Do not self-adjust the medication without medical advice.

In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m² basis). Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of REVATIO to an infant during lactation. The safety and efficacy of REVATIO have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underlie improvements in exercise. Use of REVATIO for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see ADVERSE REACTIONS, Clinical Studies]. The safety and effectiveness of REVATIO have not been established in pediatric patients younger than 1 year of age. During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324). Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients > 45 kg up to a maximum of 40 mg three times a day. Clinical studies of REVATIO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Form	Description	Suitable for
Tablets	Standard oral tablets	Most common form
Orally disintegrating tablets	Dissolves on tongue	For easier administration
Liquid suspension	Less common, for special cases	Difficult swallowing 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 [see CLINICAL PHARMACOLOGY]. No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see CLINICAL PHARMACOLOGY]. No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see CLINICAL PHARMACOLOGY].

Further information

Larger effects were recorded among patients receiving concomitant nitrates [see CONTRAINDICATIONS]. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (ECG). After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively.

Organic Nitrates, Nitrites, and Nitric Oxide Donors

After chronic dosing of 80 mg three times a day 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. An evaluation of visual function at doses up to 200 mg revealed no effects of REVATIO on visual acuity, intraocular pressure, or pupillometry. REVATIO is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). When REVATIO 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%.

Less common

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 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. Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see WARNINGS AND PRECAUTIONS]. Phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat.

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Known hypersensitivity to sildenafil or any component of the tablet, injection, or oral suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP.

Dosage for Revatio

In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal halflives 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). Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle sildenafil citrate tablets 50 mg 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. Its effect is more potent on PDE5 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 times as potent for PDE5 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 [see CLINICAL PHARMACOLOGY]. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets.

Reviews for Sildenafil

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Disease-Associated Maternal And/Or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m² basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day.

Patient resources

In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m² basis). Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of REVATIO to an infant during lactation. The safety and efficacy of REVATIO have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underlie improvements in exercise.

Usual Adult Dose for:

Use of REVATIO for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see ADVERSE REACTIONS, Clinical Studies]. The safety and effectiveness of REVATIO have not been established in pediatric patients younger than 1 year of age. During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324). The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo. Patients on all REVATIO doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies]. Data on other hemodynamic measures for the REVATIO 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 2: Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the REVATIO 20 mg Three Times a Day and Placebo Group Patients on REVATIO medium and high dose groups achieved dose related improvements in pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies]. Improvements were observed with cardiac index in all three REVATIO dose groups over placebo.

What side effects can this medication cause?

Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients > 45 kg up to a maximum of 40 mg three times a day. Clinical studies of REVATIO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical 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 [see CLINICAL PHARMACOLOGY]. No dose adjustment for mild to moderate impairment is required.

Drug Interactions

Severe impairment has not been studied [see CLINICAL PHARMACOLOGY]. No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see CLINICAL PHARMACOLOGY]. 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. Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see WARNINGS AND PRECAUTIONS]. Phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat.

Viagra form

Known hypersensitivity to sildenafil or any component of the tablet, injection, or oral suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. Sildenafil is an inhibitor of cGMP specific 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 sildenafil citrate tablets 50 mg 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. Data on other hemodynamic measures for the REVATIO low, medium and high dose groups compared to placebo is displayed in Table 3. Table 3: Placebo Corrected Changes in Hemodynamic Parameters by Dose Group 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 1-2 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 [see CONTRAINDICATIONS]. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (ECG).

What is Erectile Dysfunction?

After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively.

Advice To Patients

Its effect is more potent on PDE5 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 times as potent for PDE5 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 [see CLINICAL PHARMACOLOGY]. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets.

Special Populations

The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo. Patients on all REVATIO doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies]. Data on other hemodynamic measures for the REVATIO 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 2: Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the REVATIO 20 mg Three Times a Day and Placebo Group Patients on REVATIO medium and high dose groups achieved dose related improvements in pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies].

Platelet-aggregation Inhibitors

Improvements were observed with cardiac index in all three REVATIO dose groups over placebo. Data on other hemodynamic measures for the REVATIO low, medium and high dose groups compared to placebo is displayed in Table 3. Table 3: Placebo Corrected Changes in Hemodynamic Parameters by Dose Group 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 1-2 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. After chronic dosing of 80 mg three times a day 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. An evaluation of visual function at doses up to 200 mg revealed no effects of REVATIO on visual acuity, intraocular pressure, or pupillometry.

• Consult your healthcare provider before starting sildenafil.
• Monitor blood pressure regularly if prescribed anticoagulants.
• Be cautious with activities requiring alertness post-dose.
• Treatment should be part of a broader health plan.

REVATIO is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). When REVATIO 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%.

• Sildenafil has been shown to improve erectile function.
• It was originally developed for pulmonary hypertension.
• Unexpected side effects should be reported to a doctor.
• Avoid using other ED medications simultaneously.

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 halflives 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).