DRUG INTERACTIONS

Sildenafil citrate has 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)].

Country	Approved Use	Prescription Required	Maximum Allowed Dose	Notes
United States	Erectile Dysfunction	Yes	100mg tablet max	200mg often not approved OTC
European Union	Erectile Dysfunction	Yes	100mg per dose	200mg used only under medical supervision
Australia	Pulmonary Hypertension	Yes	Up to 200mg daily	Under special prescription
India	Both Uses	Yes	200mg dose	Commonly available in pharmacies

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.

5.1 Cardiovascular

How does sildenafil work (mechanism of action)?

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Use with caution in patients with the following underlying conditions which can be particularly sensitive to the actions of vasodilators including sildenafil citrate - those with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure.

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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.

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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. The safety of sildenafil citrate 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. 6 ADVERSE REACTIONS 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.6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Sildenafil tablets were administered to over 3700 patients (aged 19-87 years) during pre-marketing clinical trials worldwide. Over 550 patients were treated for longer than one year.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%).In fixed-dose studies, the incidence of some adverse reactions increased with dose.

CAUTION & WARNING:

The type of adverse reactions in flexible-dose studies, which reflect the recommended dosage regimen, was similar to that for fixed-dose studies. At doses above the recommended dose range, adverse reactions were similar to those detailed in Table 1 below but generally were reported more frequently.†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 sildenafil otc 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:†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. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions.6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of sildenafil tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.Cardiovascular and cerebrovascularSerious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of sildenafil tablets. Most, but not all, of these patients had preexisting cardiovascular risk factors. 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. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result. 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. Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies.

• Overdose of 200mg sildenafil can cause severe hypotension and priapism.
• Taking multiple 200mg tablets (e.g., 400mg) greatly increases danger.
• Symptoms: prolonged erection, chest pain, nausea, dizziness, fainting.
• Emergency treatment includes supportive care and possibly vasopressors.
• Priapism lasting >4 hours may require intracavernosal aspiration or surgery.
• Activated charcoal may be given if ingestion is recent.
• No specific antidote for sildenafil overdose exists.
• Dialysis is ineffective due to high protein binding of the drug.
• Always call poison control or go to ER if overdose is suspected.

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors.

8.6 Renal Impairment

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 sildenafil citrate tablets 200mg 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. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions (6.1, 6.2)]. Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers.

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It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions (6.1, 6.2)]. Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. 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. Patients sildenafil oral jelly 100 mg should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor.

1. Regulatory Documentation Provided

In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose [see Dosage and Administration (2.3)]. In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor. 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. Sildenafil citrate has systemic vasodilatory properties and may further lower blood pressure in patients taking anti-hypertensive medications.

Other Interactions

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 systolic and 7 mmHg diastolic were noted [see Drug Interactions (7.3) and Clinical Pharmacology (12.2)]. 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. Therefore, the use of such combinations is not recommended. There have been postmarketing reports of bleeding events in patients who have taken sildenafil tablets. 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. Patients sildenafil oral jelly 100 mg should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose [see Dosage and Administration (2.3)]. In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor. 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. Sildenafil citrate has systemic vasodilatory properties and may further lower blood pressure in patients taking anti-hypertensive medications.

• Sildenafil 200mg should be taken exactly as prescribed; never double dose.
• If a dose is missed, do not take two tablets at once.
• Spacing doses 24 hours apart is mandatory to avoid accumulation.
• Monitor your blood pressure regularly if you have hypertension.
• Watch for signs of allergic reaction: hives, difficulty breathing, swelling.
• Stop use and contact a doctor if you experience sudden vision/hearing loss.
• Keep a log of side effects to discuss with your physician.
• Do not drive if you feel dizzy or have visual disturbances.
• Inform all healthcare providers, including dentists, that you take 200mg.

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 systolic and 7 mmHg diastolic were noted [see Drug Interactions (7.3) and Clinical Pharmacology (12.2)]. 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)].

12.3 Pharmacokinetics

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. Therefore, the use of such combinations is not recommended.

In-Depth Details for Importers / Exporters / Buyers

Sildenafil citrate has 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 citrate - 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.

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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. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result. 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.

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Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies. Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. 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 sildenafil citrate tablets 200mg 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. There have been postmarketing reports of bleeding events in patients who have taken sildenafil tablets. 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. The safety of sildenafil citrate 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. 6 ADVERSE REACTIONS 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.6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Sildenafil tablets were administered to over 3700 patients (aged 19-87 years) during pre-marketing clinical trials worldwide. Over 550 patients were treated for longer than one year.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%).In fixed-dose studies, the incidence of some adverse reactions increased with dose. The type of adverse reactions in flexible-dose studies, which reflect the recommended dosage regimen, was similar to that for fixed-dose studies. At doses above the recommended dose range, adverse reactions were similar to those detailed in Table 1 below but generally were reported more frequently.†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 sildenafil otc 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:†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. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions.6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of sildenafil tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.Cardiovascular and cerebrovascularSerious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of sildenafil tablets.

Contraindication	Explanation	Alternative Action
Use with Nitrates	Risk of severe hypotension	Avoid combined use
Severe Liver Impairment	Reduced metabolism, increased side effects	Consult healthcare provider
Hypotension (<90/60 mm Hg)	Sildenafil can lower blood pressure further	Monitor blood pressure before use
Recent Stroke or Heart Attack	Increased cardiovascular risk	Medical consultation prior to use
Allergic Reaction to Sildenafil	Risk of anaphylaxis	Discontinue use, seek medical advice

Most, but not all, of these patients had preexisting cardiovascular risk factors.