WARNINGS AND PRECAUTIONS

Sildenafil tablets have systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), [see Clinical Pharmacology (12.2)].While this normally would be expected to be of little consequence in most patients, prior to prescribing sildenafil tablets, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. Use with caution in patients with the following underlying conditions which can be particularly sensitive to the actions of vasodilators including sildenafil tablets – those with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure. There are no controlled clinical data on the safety or efficacy of sildenafil tablets in the following groups; if prescribed, this should be done with caution.

6. Adverse Reactions/Side Effects

Theresults suggestan approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). Other risk factors for NAION,such as the presence of ''crowded'' optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare post-marketing reports, nor the association of PDE5 inhibitor use and NAION in theobservationalstudies, substantiate a causal relationship between PDE5 inhibitor use and NAION [see Adverse Reactions(6.2)]. Therefore, PDE5 inhibitors, including sildenafil tablets, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with ''crowded'' optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including sildenafil tablets, for this uncommon condition.

2.3 Dosage Adjustments in Specific Situations

There are no controlled clinical data on the safety or efficacy of sildenafil tablets in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); if prescribed, this should be done with caution. Physicians should advise patients to stop taking PDE5 inhibitors, including sildenafil tablets, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including sildenafil tablets. Alpha-blockers Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including sildenafil tablets, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. •Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months; •Patients with resting hypotension (BP <90/50 mmHg) or hypertension (BP >170/110 mmHg); •Patients with cardiac failure or coronary artery disease causing unstable angina.

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of sildenafil tablets. Sildenafil tablets should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). However, there are no controlled clinical data on the safety or efficacy of sildenafil tablets in patients with sickle cell or related anemias.

• Sildenafil helps facilitate natural arousal, not cause an instant erection.
• It is important to hydrate well when taking sildenafil.
• The medication can interact with certain herbal supplements.
• Avoid sharing medication with others due to potential health risks.
• Regular check-ups can help monitor the effects of sildenafil on health.

Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil tablets, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a signof non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal associationwith theuse of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 in males aged ≥ 50.An observationalcase-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period.

• Sildenafil is available in various dosage forms beyond oral tablets.
• Revatio is available as an injectable solution for intravenous use in PAH.
• The IV dose is 10mg administered three times a day as a bolus injection.
• There is also an oral suspension formulation of Revatio for pediatric use.
• A topical gel formulation of sildenafil has been investigated for ED.
• Orally disintegrating tablets and fast-dissolving films are also in development.
• Different formulations aim to improve onset of action or patient convenience.
• The bioavailability and pharmacokinetics differ between formulations.
• Only the oral tablet and IV solution are currently widely approved and available.
• Patients should never switch formulations without consulting their doctor.
• The dose and dosing frequency are specific to each formulation and indication.

Theresults suggestan approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). Other risk factors for NAION,such as the presence of ''crowded'' optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare post-marketing reports, nor the association of PDE5 inhibitor use and NAION in theobservationalstudies, substantiate a causal relationship between PDE5 inhibitor use and NAION [see Adverse Reactions(6.2)]. Therefore, PDE5 inhibitors, including sildenafil tablets, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with ''crowded'' optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including sildenafil tablets, for this uncommon condition.

There are no controlled clinical data on the safety or efficacy of sildenafil tablets in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); if prescribed, this should be done with caution. Physicians should advise patients to stop taking PDE5 inhibitors, including sildenafil tablets, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including sildenafil tablets.

What special precautions should I follow?

There have been postmarketing reports of bleeding events in patients who have taken sildenafil tablets. A causal relationship between sildenafil tablets and these events has not been established. In humans, sildenafil tablets have no effect on bleeding time when taken alone or with aspirin. However, in vitrostudies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). In addition, the combination of heparin and sildenafil tablets had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.

Dosage Forms and Strengths

The safety of sildenafil tablets is unknown in patients with bleeding disorders and patients with active peptic ulceration. The use of sildenafil tablets offers no protection against sexually transmitted diseases. The following are discussed in more detail in other sections of the labeling: •Cardiovascular [see Warnings and Precautions(5.1)] •Prolonged Erection and Priapism [see Warnings and Precautions (5.2)] •Effects on the Eye [see Warnings and Precautions(5.3)] •Hearing Loss [ see Warnings and Precautions (5.4)] •Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [see Warnings and Precautions(5.5)] •Adverse Reactions with the Concomitant Use of Ritonavir [see Warnings and Precautions(5.6)] •Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies [see Warnings and Precautions (5.7)] •Effects on Bleeding [see Warnings and Precautions(5.8)] •Counseling Patients About Sexually Transmitted Diseases [see Warnings and Precautions (5.9)] The most common adverse reactions reported in clinical trials (≥ 2%) are headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. Sildenafil tablets were administered to over 3700 patients (aged 19 to 87 years) during pre-marketing clinical trials worldwide. In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for sildenafil tablets (2.5%) was not significantly different from placebo (2.3%). Alpha-blockers Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including sildenafil tablets, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see Drug Interactions (7.2)and Clinical Pharmacology (12.2)]leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting). Consideration should be given to the following: •Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. •In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose.

How to take liquid

Table 1: Adverse Reactions Reported by ≥2% of Patients with Sildenafil Tablets and More Frequently than Placebo in Fixed-Dose Phase II/III Studies †Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision. When sildenafil tablets were taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took sildenafil tablets at least once weekly, and the following adverse reactions were reported: Table 2. Adverse Reactions Reported by ≥2% of Patients Treated with Sildenafil Tablets and More Frequent than Placebo in Flexible-Dose Phase II/III Studies † Abnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision. The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to sildenafil tablets is uncertain. •Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs. Anti-hypertensives Sildenafil tablets have systemic vasodilatory properties and may further lower blood pressure in patients taking anti-hypertensive medications. In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and sildenafil tablets, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg sildenafil citrate sublingual tablets 100mg systolic and 7 mmHg diastolic were noted [see Drug Interactions (7.3)and Clinical Pharmacology (12.2)]. If sildenafil tablets are prescribed to patients taking ritonavir, caution should be used.

12. Sildenafil Tablets - Clinical Pharmacology

Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful: Body as a Whole:face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200 to 800 mg). To decrease the chance of adverse reactions in patients taking ritonavir, a decrease in sildenafil dosage is recommended [see Dosage and Administration (2.4),Drug Interactions (7.4),and Clinical Pharmacology (12.3)]. The safety and efficacy of combinations of sildenafil tablets with other PDE5 Inhibitors, including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil, or other treatments for erectile dysfunction have not been studied. There have been postmarketing reports of bleeding events in patients who have taken sildenafil tablets. A causal relationship between sildenafil tablets and these events has not been established. In humans, sildenafil tablets have no effect on bleeding time when taken alone or with aspirin. However, in vitrostudies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). In addition, the combination of heparin and sildenafil tablets had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.

14. Clinical Studies

In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see Drug Interactions (7.2)and Clinical Pharmacology (12.2)]leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting). Consideration should be given to the following: •Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. •In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. •Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs. Anti-hypertensives Sildenafil tablets have systemic vasodilatory properties and may further lower blood pressure in patients taking anti-hypertensive medications.

12.3 Pharmacokinetics

In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and sildenafil tablets, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg sildenafil citrate sublingual tablets 100mg systolic and 7 mmHg diastolic were noted [see Drug Interactions (7.3)and Clinical Pharmacology (12.2)]. If sildenafil tablets are prescribed to patients taking ritonavir, caution should be used. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200 to 800 mg). To decrease the chance of adverse reactions in patients taking ritonavir, a decrease in sildenafil dosage is recommended [see Dosage and Administration (2.4),Drug Interactions (7.4),and Clinical Pharmacology (12.3)]. The safety and efficacy of combinations of sildenafil tablets with other PDE5 Inhibitors, including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil, or other treatments for erectile dysfunction have not been studied. The safety of sildenafil tablets is unknown in patients with bleeding disorders and patients with active peptic ulceration. The use of sildenafil tablets offers no protection against sexually transmitted diseases. The following are discussed in more detail in other sections of the labeling: •Cardiovascular [see Warnings and Precautions(5.1)] •Prolonged Erection and Priapism [see Warnings and Precautions (5.2)] •Effects on the Eye [see Warnings and Precautions(5.3)] •Hearing Loss [ see Warnings and Precautions (5.4)] •Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [see Warnings and Precautions(5.5)] •Adverse Reactions with the Concomitant Use of Ritonavir [see Warnings and Precautions(5.6)] •Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies [see Warnings and Precautions (5.7)] •Effects on Bleeding [see Warnings and Precautions(5.8)] •Counseling Patients About Sexually Transmitted Diseases [see Warnings and Precautions (5.9)] The most common adverse reactions reported in clinical trials (≥ 2%) are headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. Sildenafil tablets were administered to over 3700 patients (aged 19 to 87 years) during pre-marketing clinical trials worldwide. In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for sildenafil tablets (2.5%) was not significantly different from placebo (2.3%). Table 1: Adverse Reactions Reported by ≥2% of Patients with Sildenafil Tablets and More Frequently than Placebo in Fixed-Dose Phase II/III Studies †Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision. When sildenafil tablets were taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took sildenafil tablets at least once weekly, and the following adverse reactions were reported: Table 2.

What should I know about storage and disposal of this medication?

Sildenafil tablets have systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), [see Clinical Pharmacology (12.2)].While this normally would be expected to be of little consequence in most patients, prior to prescribing sildenafil tablets, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. Use with caution in patients with the following underlying conditions which can be particularly sensitive to the actions of vasodilators including sildenafil tablets – those with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure. There are no controlled clinical data on the safety or efficacy of sildenafil tablets in the following groups; if prescribed, this should be done with caution. •Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months; •Patients with resting hypotension (BP <90/50 mmHg) or hypertension (BP >170/110 mmHg); •Patients with cardiac failure or coronary artery disease causing unstable angina. Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of sildenafil tablets.

6.1 Clinical Trials Experience

Sildenafil tablets should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). However, there are no controlled clinical data on the safety or efficacy of sildenafil tablets in patients with sickle cell or related anemias. Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil tablets, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a signof non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal associationwith theuse of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 in males aged ≥ 50.An observationalcase-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. Adverse Reactions Reported by ≥2% of Patients Treated with Sildenafil Tablets and More Frequent than Placebo in Flexible-Dose Phase II/III Studies † Abnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision.

• Numerous drug interaction studies have been conducted with sildenafil.
• Co-administration with nitrates causes synergistic blood pressure lowering.
• This interaction can lead to life-threatening hypotension and cardiovascular collapse.
• Alpha-blockers (e.g., tamsulosin) can enhance the blood pressure-lowering effect.
• A separation of at least 4 hours between alpha-blocker and sildenafil dose is advised.
• HIV protease inhibitors significantly increase sildenafil AUC (up to 11-fold).
• A maximum sildenafil dose of 25mg in a 48-hour period is recommended with ritonavir.
• Other CYP3A4 inhibitors require similar dose reductions and cautious use.
• No significant interaction was observed with tolbutamide, warfarin, or alcohol.
• Alcohol can increase the potential for orthostatic hypotension and dizziness.
• Always assume a potential interaction exists with any new medication.

The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to sildenafil tablets is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful: Body as a Whole:face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury.