2.4 Dosage Adjustments Due to Drug Interactions

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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.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.DataAnimal DataNo 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. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation.8.4 Pediatric UseIn 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.

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Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. 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). Administration of sildenafil 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 remained on his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil.

8.1 Pregnancy

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, particularly chronic use, is not recommended in children.8.5 Geriatric UseClinical studies of sildenafil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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)]. In the U.S.

How does sildenafil work (mechanism of action)?

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. 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 doses. Use of sildenafil, particularly chronic use, is not recommended in children.

Effectiveness by condition:

Clinical studies of sildenafil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Severe impairment has not been studied [see Clinical Pharmacology 12.3)]. Sildenafil is also marketed as VIAGRA® 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 :Sildenafil citrate, USP 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 Tablets USP, 20 mg: Sildenafil tablets are formulated as white, film-coated round tablets for oral administration. Sildenafil Tablets USP, 20 mg: Sildenafil tablets are formulated as white, film-coated round tablets for oral administration. 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. 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 oral strips 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:Figure 6: Kaplan-Meier Plot of Mortality by Sildenafil Dose.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 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.

Sildenafil tablets are not intended for recreational use or performance enhancement.
Always follow a healthcare provider’s instructions for safe use.
Sildenafil’s effects last for a few hours, depending on individual factors.
The medication is taken as needed, not as a daily supplement.
Only use sildenafil under medical supervision if you have heart disease.
Do not take sildenafil if you are allergic to sildenafil citrate.
The drug helps improve quality of life for men with ED.
Sildenafil may cause temporary visual disturbances, like a blue tint.
Proper hydration can help minimize side effects.
Certain genetic conditions may affect sildenafil's effectiveness.
Regular medical reviews ensure safe long-term use of sildenafil.

Causes of death were typical of patients with PAH.

10. What else does sildenafil treat?

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 sildenafil oral jelly 100mg lovegra 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 on Hemodynamic MeasuresPatients on all sildenafil 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 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.Table 3.

How it works for PAH

Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo GroupmPAP = 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 [Study 3 in Clinical Studies (14)], there were no significant differences in the effects on hemodynamic variables between doses.Effects of Sildenafil 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. 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 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.

What are the most common side effects of sildenafil?

An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil 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%). 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. Use of sildenafil, particularly chronic use, is not recommended in children.8.5 Geriatric UseClinical studies of sildenafil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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)]. 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. 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 doses. Use of sildenafil, particularly chronic use, is not recommended in children. Clinical studies of sildenafil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Severe impairment has not been studied [see Clinical Pharmacology 12.3)]. Sildenafil is also marketed as VIAGRA® 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 :Sildenafil citrate, USP 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 Tablets USP, 20 mg: Sildenafil tablets are formulated as white, film-coated round tablets for oral administration. Sildenafil Tablets USP, 20 mg: Sildenafil tablets are formulated as white, film-coated round tablets for oral administration. 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.

Quiz: Is it erectile dysfunction?

There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope.Amlodipine. When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil [see Warnings and Precautions (5.2)]. 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.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.DataAnimal DataNo 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.

Teva sildenafil pills are white, not blue

Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation.8.4 Pediatric UseIn 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. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. 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).

What does Teva sildenafil do?

Administration of sildenafil 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 remained on his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil. 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 oral strips 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:Figure 6: Kaplan-Meier Plot of Mortality by Sildenafil Dose.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 doses. 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.

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This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical sildenafil oral jelly 100mg lovegra 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.

Ingredient	Quantity per Tablet	Function	Notes
Sildenafil Citrate	50 mg	Active ingredient	Main component
Microcrystalline Cellulose	20 mg	Filler and binder	Increases tablet stability
Magnesium Stearate	2 mg	Lubricant	Ensures smooth manufacturing
Starch	10 mg	Diluent	Helps with disintegration

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 on Hemodynamic MeasuresPatients on all sildenafil 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 20 mg three times a day and placebo dosing regimens is displayed in Table 3.

Some sildenafil tablets are coated to improve taste and ease swallowing.
Sildenafil should not be used if allergic to citrate compounds.
Cost savings on generic sildenafil make it accessible to more users.
The medication requires no special diet, but avoid fatty foods close to ingestion.
Sildenafil may cause a modest drop in blood pressure temporarily.
Do not share prescribed sildenafil with others; it is tailored to individual health.
Inform your doctor of all medications and health conditions before use.
Sildenafil may have different effects based on age and health status.
The medication has been available in various formulations for convenience.
The effectiveness may vary, and some users might need dose adjustments.
Always keep sildenafil tablets out of reach of children and pets.

The relationship between these effects and improvements in 6-minute walk distance is unknown.Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo GroupmPAP = 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 [Study 3 in Clinical Studies (14)], there were no significant differences in the effects on hemodynamic variables between doses.Effects of Sildenafil 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).

Precaution/Contraindication	Description	Notes
Nitrate use	Do not take with nitrates for chest pain	Risk of severe hypotension
Heart conditions	Consult a doctor if you have cardiovascular issues	Risk of adverse cardiovascular events
Liver or kidney impairment	Reduced dosing may be necessary	Altered drug metabolism
Drug interactions	Combine with caution; may interact with other meds	Always consult a healthcare provider

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 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 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%). 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.

Sildenafil tablets are often stored in their original packaging to avoid contamination.
Use only the amount prescribed; more does not mean better results.
Sildenafil helps improve erectile function but doesn’t increase libido.
The tablets are designed for rapid and effective absorption.
Always inform your doctor about existing health conditions before use.
Some brands of sildenafil are marketed as "white tablets" for easy recognition.
The medication can cause a mild increase in blood flow to other body parts.
Avoid caffeine or heavy meals before taking sildenafil for better results.
The safety and efficacy of sildenafil are supported by numerous clinical trials.
Never take expired sildenafil tablets, as their safety can’t be guaranteed.
Regular blood pressure checks are recommended when using sildenafil long-term.