14 CLINICAL STUDIES

The average age of these men was 55 years and they had ED for an average of 5 years before entering the study. Sildenafil was effective in roughly 70% of subjects. Response rates of 90% have been achieved in trials of male patients with psychogenic ED. Sildenafil may also be effective in male patients with ED related to diabetes mellitus or due to pelvic fracture urethral disruption.

10. Overdosage

The average age of these men was 55 years and they had ED for an average of 5 years before entering the study. Sildenafil was effective in roughly 70% of subjects. Response rates of 90% have been achieved in trials of male patients with psychogenic ED. Sildenafil may also be effective in male patients with ED related to diabetes mellitus or due to pelvic fracture urethral disruption. [1][2] Sildenafil has been shown to be effective and well tolerated in patients on multidrug antihypertensive regimens and not associated with additional safety risks in these patients.

2.2 Recommended Dosage in Pediatric Patients

[3] According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy. [4] Final FDA approval for sildenafil for the treatment of ED was granted in March 1998. Shortly after approval for ED, studies showed sildenafil was effective in treating patients with pulmonary arterial hypertension (PAH). [5][6][7] Sildenafil improved exercise capacity as well as mean pulmonary artery pressure and other measures of cardiac function in patients with PAH. Sildenafil is the first oral therapy approved for treating early stages of PAH.

What should I do if I miss a dose of sildenafil?

Although preliminary data from 12 patients with sickle cell anemia showed a decrease in PAH, a larger clinical trial (n = 134) investigating the use of sildenafil for pulmonary hypertension in adults with sickle cell anemia was stopped early due to an increased risk of severe adverse effects, especially sickle cell pain crises, compared to placebo (38% vs. 8%, respectively). The reason for the increased risk of pain is unknown; however, in the initial trial, patients were aggressively treated with transfusions and hydroxyurea to control crises; the larger trial offered no intervention for crises. Sildenafil has also shown efficacy in treating altitude sickness. [5][6][8] The oral formulation of sildenafil (Revatio) was approved by the FDA for treatment of pulmonary arterial hypertension (PAH) in June 2005; the injectable formulation was approved in November 2009. [1][2] Sildenafil has been shown to be effective and well tolerated in patients on multidrug antihypertensive regimens and not associated with additional safety risks in these patients. [3] According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy. [4] Final FDA approval for sildenafil for the treatment of ED was granted in March 1998. Shortly after approval for ED, studies showed sildenafil was effective in treating patients with pulmonary arterial hypertension (PAH). [5][6][7] Sildenafil improved exercise capacity as well as mean pulmonary artery pressure and other measures of cardiac function in patients with PAH.

Sildenafil is the first oral therapy approved for treating early stages of PAH. Although preliminary data from 12 patients with sickle cell anemia showed a decrease in PAH, a larger clinical trial (n = 134) investigating the use of sildenafil for pulmonary hypertension in adults with sickle cell anemia was stopped early due to an increased risk of severe adverse effects, especially sickle cell pain crises, compared to placebo (38% vs. 8%, respectively). The reason for the increased risk of pain is unknown; however, in the initial trial, patients were aggressively treated with transfusions and hydroxyurea to control crises; the larger trial offered no intervention for crises. Sildenafil has also shown efficacy in treating altitude sickness. [5][6][8] The oral formulation of sildenafil (Revatio) was approved by the FDA for treatment of pulmonary arterial hypertension (PAH) in June 2005; the injectable formulation was approved in November 2009.

5.9 Counseling Patients About Sexually Transmitted Diseases

Systolic blood pressure was reduced an average of 7 mmHg compared to baseline. [10] Another study showed that sildenafil inhibited beta-adrenergic-stimulated systolic function. Using dobutamine in healthy volunteers, investigators reported that sildenafil suppressed the cardiac response to dobutamine but had minimal effect under resting conditions. It was also reported that the effects of sildenafil were independent of cardiac afterload or preload changes. [11] Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined.

Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. In vitro studies show that sildenafil is selective for PDE5 and its effect is more potent on PDE5 than on other known phosphodiesterases (>80-fold for PDE1, >1,000-fold for PDE2, PDE3, and PDE4). Sildenafil is one-tenth as potent for PDE6, an enzyme found in the retina, as it is for PDE5; this lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of the drug. As reported by the manufacturer, the pharmacodynamic response to sildenafil was assessed in eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction. In these studies sexual stimulation resulted in improved erections, as assessed by penile plethysmography, after sildenafil administration compared with placebo. Most studies evaluated the efficacy of sildenafil approximately 60 minutes post dose. The erectile response, as determined by penile plethysmography, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study.

Related/similar drugs

Inhibition of PDE5 present in esophageal smooth muscle can cause a marked inhibition of esophageal motility as well as a reduction in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). [9] Sildenafil has been shown to cross the blood-brain barrier and inhibit PDE5 sildenafil 100 mg tab in cerebral blood vessels. The areas of the brain that have the highest activity of PDE5 are the hippocampus, cerebral cortex, and basal ganglia.

Risk Summary

Although clinical studies have not proven this effect, inhibition of PDE5 by sildenafil in the brain may result in emotional, neurological, and psychological effects (see Adverse Reactions). Do not take this medicine with any of the following medications: cisapride; methscopolamine nitrate; nitrates like amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin; nitroprusside; other medicines for erectile dysfunction like tadalafil, vardenafil; other sildenafil products. Your health care provider needs to know if you have any of these conditions: bleeding disorders; eye or vision problems, including retinitis pigmentosa; Peyronie’s disease, or history of priapism; heart disease, angina, a history of heart attack, irregular heartbeats, or other heart problems; high or low blood pressure; history of blood diseases; history of stomach bleeding; kidney disease; liver disease; stroke; an unusual or allergic reaction to sildenafil or other products. If you notice any changes in your vision while taking this drug, call your healthcare provider immediately. If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medicine, you should refrain from further activity and call your healthcare provider immediately.

What Are the Available Sildenafil Dosages?

Do not use alcohol while using this medicine. Using this medicine does not protect you or your partner against HIV infection or other sexually transmitted infections. Sildenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet or injection. The safety and efficacy of combinations of sildenafil with other treatments for erectile dysfunction have not been studied. The use of sildenafil is not recommended in patients with pulmonary veno-occlusive disease (PVOD). The effects of sildenafil were evident for up to 4 hours but the response was diminished compared to 2 hours. Sildenafil can inhibit PDE5 present in esophageal smooth muscle, lung tissue, and brain tissue. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequently pulmonary vasodilation, thereby making sildenafil an effective agent in treating pulmonary hypertension. Inhibition of PDE5 present in esophageal smooth muscle can cause a marked inhibition of esophageal motility as well as a reduction in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD).

2.1 Dosage Information

Administration of sildenafil in this population may significantly worsen cardiovascular status. In addition, if signs of pulmonary edema occur during sildenafil administration, the possibility of associated PVOD should be considered. Sildenafil is contraindicated in patients who are currently on nitrate/nitrite therapy (see Drug Interactions). Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive sildenafil.

Recreational use

This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once sildenafil has been administered. The following factors are associated with up to an eight time increase in plasma concentrations of sildenafil compared with healthy subjects: geriatric patients (40% increase in sildenafil AUC), hepatic disease (e.g., cirrhosis, 80% increase), severe renal impairment (i.e., CrCl < 30 ml/min, 100% increase), concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin (182% increase), itraconazole, ketoconazole, saquinavir (210% increase)). Because higher plasma concentrations may increase the incidence of adverse reactions, the sildenafil starting dose should be 25 mg in these patients. Additionally, ritonavir greatly increased the systemic concentrations of sildenafil in a study of healthy, non-HIV infected volunteers (11-fold increase in AUC).

Erectile dysfunction

Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg sildenafil in a 48 hour period. There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Over 75 deaths due to cardiovascular events have been reported in association with sildenafil use. In a study conducted at the Mayo Clinic, sildenafil was shown to have limited cardiovascular effects during exercise in men with known or probable coronary artery disease. The study reported that sildenafil had no effect on exercise capacity or the hemodynamic response to exercise. [9] Sildenafil has been shown to cross the blood-brain barrier and inhibit PDE5 sildenafil 100 mg tab in cerebral blood vessels. The areas of the brain that have the highest activity of PDE5 are the hippocampus, cerebral cortex, and basal ganglia. Although clinical studies have not proven this effect, inhibition of PDE5 by sildenafil in the brain may result in emotional, neurological, and psychological effects (see Adverse Reactions).

Publication types

In particular, caution should be used if sildenafil is prescribed in the following patient groups: patients who have suffered a myocardial infarction, stroke, or life-threatening cardiac arrhythmias in the last 6 months; patients with resting hypotension (BP < 90/50) or resting hypertension (BP > 170/100); patients with fluid depletion; patients with cardiac disease, heart failure or coronary artery disease which causes unstable angina. The American College of Cardiology recommends that sildenafil be used with caution in the following: patients with active coronary ischemia who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of sildenafil (see Drug Interactions). Do not take this medicine with any of the following medications: cisapride; methscopolamine nitrate; nitrates like amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin; nitroprusside; other medicines for erectile dysfunction like tadalafil, vardenafil; other sildenafil products. Your health care provider needs to know if you have any of these conditions: bleeding disorders; eye or vision problems, including retinitis pigmentosa; Peyronie’s disease, or history of priapism; heart disease, angina, a history of heart attack, irregular heartbeats, or other heart problems; high or low blood pressure; history of blood diseases; history of stomach bleeding; kidney disease; liver disease; stroke; an unusual or allergic reaction to sildenafil or other products. If you notice any changes in your vision while taking this drug, call your healthcare provider immediately. If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medicine, you should refrain from further activity and call your healthcare provider immediately. Do not use alcohol while using this medicine. Using this medicine does not protect you or your partner against HIV infection or other sexually transmitted infections.

• Sildenafil is sometimes used off-label for other health issues.
• Its interaction with blood thinners should be monitored.
• Men with retinitis pigmentosa should avoid sildenafil.
• Always inform healthcare providers about all treatments.
• Use sildenafil in conjunction with a healthy lifestyle.
• Avoid unnecessary medication to prevent side effects.
• Be aware of potential drug interactions with sildenafil.
• Proper storage maintains medication efficacy over time.

Sildenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet or injection.

The safety and efficacy of combinations of sildenafil with other treatments for erectile dysfunction have not been studied. The use of sildenafil is not recommended in patients with pulmonary veno-occlusive disease (PVOD). Administration of sildenafil in this population may significantly worsen cardiovascular status. In addition, if signs of pulmonary edema occur during sildenafil administration, the possibility of associated PVOD should be considered. Sildenafil is contraindicated in patients who are currently on nitrate/nitrite therapy (see Drug Interactions). Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive sildenafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once sildenafil has been administered. The following factors are associated with up to an eight time increase in plasma concentrations of sildenafil compared with healthy subjects: geriatric patients (40% increase in sildenafil AUC), hepatic disease (e.g., cirrhosis, 80% increase), severe renal impairment (i.e., CrCl < 30 ml/min, 100% increase), concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin (182% increase), itraconazole, ketoconazole, saquinavir (210% increase)). Because higher plasma concentrations may increase the incidence of adverse reactions, the sildenafil starting dose should be 25 mg in these patients. Additionally, ritonavir greatly increased the systemic concentrations of sildenafil in a study of healthy, non-HIV infected volunteers (11-fold increase in AUC). Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg sildenafil in a 48 hour period.

11. Sildenafil Oral Suspension Description

Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation.

12.3 Pharmacokinetics

In vitro studies show that sildenafil is selective for PDE5 and its effect is more potent on PDE5 than on other known phosphodiesterases (>80-fold for PDE1, >1,000-fold for PDE2, PDE3, and PDE4). Sildenafil is one-tenth as potent for PDE6, an enzyme found in the retina, as it is for PDE5; this lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of the drug. As reported by the manufacturer, the pharmacodynamic response to sildenafil was assessed in eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction. In these studies sexual stimulation resulted in improved erections, as assessed by penile plethysmography, after sildenafil administration compared with placebo. Most studies evaluated the efficacy of sildenafil approximately 60 minutes post dose.

Allergy warning

The erectile response, as determined by penile plethysmography, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study. The effects of sildenafil were evident for up to 4 hours but the response was diminished compared to 2 hours. Sildenafil can inhibit PDE5 present in esophageal smooth muscle, lung tissue, and brain tissue. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequently pulmonary vasodilation, thereby making sildenafil an effective agent in treating pulmonary hypertension. There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Over 75 deaths due to cardiovascular events have been reported in association with sildenafil use. In a study conducted at the Mayo Clinic, sildenafil was shown to have limited cardiovascular effects during exercise in men with known or probable coronary artery disease. The study reported that sildenafil had no effect on exercise capacity or the hemodynamic response to exercise. Systolic blood pressure was reduced an average of 7 mmHg compared to baseline. [10] Another study showed that sildenafil inhibited beta-adrenergic-stimulated systolic function. Using dobutamine in healthy volunteers, investigators reported that sildenafil suppressed the cardiac response to dobutamine but had minimal effect under resting conditions.

• Sildenafil tablets 125 mg are often prescribed for pulmonary hypertension.
• The dosage can vary depending on the condition.
• It’s important to maintain open communication with your doctor.
• Alcohol consumption can impair sildenafil’s effectiveness.
• Avoid driving if you experience dizziness or vision problems.
• Use sildenafil exactly as prescribed to avoid complications.
• Do not share medication with others.
• Regular medical check-ups are recommended during use.

It was also reported that the effects of sildenafil were independent of cardiac afterload or preload changes. [11] Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. In particular, caution should be used if sildenafil is prescribed in the following patient groups: patients who have suffered a myocardial infarction, stroke, or life-threatening cardiac arrhythmias in the last 6 months; patients with resting hypotension (BP < 90/50) or resting hypertension (BP > 170/100); patients with fluid depletion; patients with cardiac disease, heart failure or coronary artery disease which causes unstable angina. The American College of Cardiology recommends that sildenafil be used with caution in the following: patients with active coronary ischemia who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of sildenafil (see Drug Interactions).