Sildenafil Oral Suspension (SILDENAFIL SUSPENSION (LUNGS) - ORAL)

For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007.

• The shelf life of sildenafil syrup depends on formulation and storage.
• Expiry dates should always be checked before use.
• Improper storage can lead to degradation of active ingredients.
• The liquid form allows for precise dose adjustments.
• Careful titration is essential to avoid overdose risks.

Causes of death were typical of patients with PAH. Use of Sildenafil for Oral Suspension, particularly chronic use, is not recommended in children.8.5 Geriatric UseClinical studies of Sildenafil for Oral Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8 USE IN SPECIFIC POPULATIONS

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).Population PharmacokineticsAge, 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. 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 20–50% higher when compared to those of healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.Geriatric PatientsHealthy 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 (18–45 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.Renal ImpairmentIn volunteers with mild (CLcr = 50–80 mL/min) and moderate (CLcr = 30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. 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.Hepatic ImpairmentIn 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.

12.3 Pharmacokinetics

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 (12.3)].8.6 Patients with Hepatic ImpairmentNo dose adjustment for mild to moderate impairment is required.

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Severe impairment has not been studied [see Clinical Pharmacology (12.3)].8.7 Patients with Renal ImpairmentNo dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)]. Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively [See Data].

Pregnancy & Lactation

In the U.S.

8.6 Patients with Hepatic Impairment

For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of Sildenafil for Oral Suspension, particularly chronic use, is not recommended in children.8.5 Geriatric UseClinical studies of Sildenafil for Oral Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 (12.3)].8.6 Patients with Hepatic ImpairmentNo dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3)].8.7 Patients with Renal ImpairmentNo dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)].

5.3 Epistaxis

Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively [See Data]. 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. In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of Sildenafil, or placebo, for 16 weeks of treatment. Drug or placebo was administered three times a day. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of Sildenafil, or placebo, for 16 weeks of treatment. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of Sildenafil on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to Sildenafil remained on his/her dose of Sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose Sildenafil. 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 for Oral Suspension doses. Use of Sildenafil for Oral Suspension, particularly chronic use, is not recommended in children. Clinical studies of Sildenafil for Oral Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Sildenafil is also marketed as VIAGRA® for erectile dysfunction.Sildenafil citrate 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:Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.Sildenafil for Oral Suspension is supplied as white to off-white powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g sildenafil) in an amber glass bottle intended for reconstitution. 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 sildenafil white 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).

13. Nonclinical Toxicology

The primary objective of the study was to assess the effect of Sildenafil on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to Sildenafil remained on his/her dose of Sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose Sildenafil. 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 for Oral Suspension doses. Use of Sildenafil for Oral Suspension, particularly chronic use, is not recommended in children.

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Clinical studies of Sildenafil for Oral Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Sildenafil is also marketed as VIAGRA® for erectile dysfunction.Sildenafil citrate 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:Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.Sildenafil for Oral Suspension is supplied as white to off-white powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g sildenafil) in an amber glass bottle intended for reconstitution. 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 sildenafil white 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). 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. 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 [see Clinical Pharmacology (12.2)].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.

5. Warnings and Precautions

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 (12.2)].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.12.2 PharmacodynamicsEffects of Sildenafil for Oral Suspension on Hemodynamic Measures Patients on all Sildenafil for Oral Suspension 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 for Oral Suspension 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown.mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance;SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiacoutput; HR = heart rateIn another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [Study 3 in Clinical Studies (14)], there were no significant differences in the effects on hemodynamic variables between doses.Effects of Sildenafil for Oral Suspension on Blood PressureSingle 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.

What is sildenafil used for?

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 (4)].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 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 mmHg and 9.1 mmHg, respectively.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).Effects of Sildenafil for Oral Suspension on VisionAt 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 Sildenafil for Oral Suspension on visual acuity, intraocular pressure, or pupillometry.12.3 PharmacokineticsAbsorption and DistributionSildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25–63%). 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. 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.12.2 PharmacodynamicsEffects of Sildenafil for Oral Suspension on Hemodynamic Measures Patients on all Sildenafil for Oral Suspension 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)].

Condition	Patient Age Group	Dosage Recommendations	Notes
Erectile Dysfunction	Adults (18-65)	20 mg, 1 hour before	用于改善勃起功能
Pulmonary Hypertension	Adults	10–20 mg, 3 times daily	用于降低肺动脉压力
Off-label Performance Enhancement	Adults	Under medical supervision	未经批准，需医生指导
Children with Pulmonary Hypertension (Rare)	1–17 years	10 mg as prescribed	特殊病例，严格监控

Data on other hemodynamic measures for the Sildenafil for Oral Suspension 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown.mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance;SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiacoutput; HR = heart rateIn another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [Study 3 in Clinical Studies (14)], there were no significant differences in the effects on hemodynamic variables between doses.Effects of Sildenafil for Oral Suspension on Blood PressureSingle 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).

• Sildenafil syrup is sometimes used in pediatric cases, off-label.
• Off-label use in children requires careful dosage adjustment.
• Lack of standardization makes typical dosing guidelines difficult.
• Pharmacokinetics in syrup form are less well-studied.
• Always seek professional medical advice before use.

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 (4)].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 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 mmHg and 9.1 mmHg, respectively.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).Effects of Sildenafil for Oral Suspension on VisionAt 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 Sildenafil for Oral Suspension on visual acuity, intraocular pressure, or pupillometry.12.3 PharmacokineticsAbsorption and DistributionSildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25–63%). 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. 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).Population PharmacokineticsAge, 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. 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 20–50% higher when compared to those of healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.Geriatric PatientsHealthy 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 (18–45 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.Renal ImpairmentIn volunteers with mild (CLcr = 50–80 mL/min) and moderate (CLcr = 30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. 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.Hepatic ImpairmentIn 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.