7 DRUG INTERACTIONS

A maximum dose in pediatric patients has not been identified. Based on the experience in adults, dose may be titrated to a maximum of 40 mg three times a day for pediatric patients >45 kg, if required, based on symptoms and tolerability [see Clinical Studies (14)]. Sildenafil tablets, USP are supplied as white to off-white, round, biconvex, film-coated tablets debossed with '85' on one side and plain on other side containing sildenafil citrate equivalent to 20 mg of sildenafil. Sildenafil citrate is contraindicated in patients with: Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions ( 5.1)] . Phosphodiesterase-5 (PDE5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. Sildenafil citrate has vasodilatory properties, resulting in mild and transient decreases in blood pressure.

8.4 Pediatric Use

A maximum dose in pediatric patients has not been identified. Based on the experience in adults, dose may be titrated to a maximum of 40 mg three times a day for pediatric patients >45 kg, if required, based on symptoms and tolerability [see Clinical Studies (14)]. Sildenafil tablets, USP are supplied as white to off-white, round, biconvex, film-coated tablets debossed with '85' on one side and plain on other side containing sildenafil citrate equivalent to 20 mg of sildenafil. Sildenafil citrate is contraindicated in patients with: Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions ( 5.1)] . Phosphodiesterase-5 (PDE5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat.

What’s the difference between sildenafil 50 mg and 100 mg?

Sildenafil citrate has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil tablets, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [blood pressure less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil citrate. 5.2 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil citrate to patients with veno-occlusive disease, administration of sildenafil citrate to such patients is not recommended. Before prescribing sildenafil tablets, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [blood pressure less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction).

• 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.

Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil citrate.

5.2 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil citrate to patients with veno-occlusive disease, administration of sildenafil citrate to such patients is not recommended.

5.4 Visual Loss

There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations). 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 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.

Missed Dose

Data Animal Data No 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. In a rat pre-and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis). Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil citrate to an infant during lactation. The safety and efficacy of Sildenafil citrate have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underly improvements in exercise Use of sildenafil citrate for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)]. Should signs of pulmonary edema occur when sildenafil citrate is administered, sildenafil 130mg consider the possibility of associated PVOD. The incidence of epistaxis was 13% in patients taking sildenafil citrate with PAH secondary to CTD. The safety of sildenafil citrate is unknown in patients with bleeding disorders or active peptic ulceration. When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of PDE-5 inhibitors, including sildenafil. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking sildenafil citrate. There are no controlled clinical data on the safety or efficacy of sildenafil citrate in patients with retinitis pigmentosa, a minority of whom have genetic disorders of retinal phosphodiesterases. Therefore, use of sildenafil citrate in patients with retinitis pigmentosa is not recommended. Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil citrate. It is not possible to determine whether these reported events are related directly to the use of sildenafil citrate, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil tablets. 5.6 Combination with Other PDE-5 inhibitors The safety and efficacy of combinations of sildenafil tablets with VIAGRA or other PDE-5 inhibitors have not been studied.

• The societal impact of sildenafil has been profound since its introduction.
• It helped destigmatize the discussion and treatment of erectile dysfunction.
• It spawned a multi-billion dollar market for sexual health pharmaceuticals.
• The "Viagra" brand name became one of the most recognized in the world.
• It led to increased research and development in urology and sexual medicine.
• It also raised important questions about medicalization and lifestyle drugs.
• Direct-to-consumer advertising for ED treatments became widespread.
• It prompted debates about insurance coverage for quality-of-life medications.
• The success of sildenafil accelerated research into other PDE5 inhibitors.
• It highlighted the importance of serendipity in drug discovery.
• Its impact extends beyond medicine into cultural and social spheres.

5.8 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil citrate than by those randomized to placebo. The effectiveness and safety of sildenafil citrate in the treatment of PH secondary to sickle cell disease has not been established.

2. Sildenafil Tablets Dosage and Administration

5.6 Combination with Other PDE-5 inhibitors The safety and efficacy of combinations of sildenafil tablets with VIAGRA or other PDE-5 inhibitors have not been studied. 5.8 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil citrate than by those randomized to placebo. The effectiveness and safety of sildenafil citrate in the treatment of PH secondary to sickle cell disease has not been established. The following serious adverse events are discussed elsewhere in the labeling: Hypotension [see Warnings and Precautions (5.1)] Vision Loss [see Warnings and Precautions (5.4)] Hearing Loss [see Warnings and Precautions (5.5)] Priapism [see Warnings and Precautions (5.7)] Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease [see Warnings and Precautions (5.8) ] Because 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 practice. In a sildenafil 100mg hexal 12-week, placebo-controlled clinical study and an open-label extension study (SUPER-1) in 277 sildenafil citrate-treated adults with PAH (WHO Group I) [see Clinical Studies (14)] the adverse reactions that were reported by at least 10% of sildenafil citrate-treated patients in any dosing group, and were more frequent in sildenafil citrate-treated patients than in placebo-treated patients are shown in Table 1.

2.4 Dosage Adjustments Due to Drug Interactions

The overall frequency of discontinuation in sildenafil citrate-treated patients was 3% (20 mg and 40 mg three times a day) and 8% (80 mg three times a day). Most Common Adverse Reactions in Patients Treated with sildenafil tablets 20 mg, 40 mg, 80 mg and Placebo three times per day in SUPER-1 (More Frequent in sildenafil-Treated Patients than Placebo-Treated Patients) In a placebo-controlled fixed dose titration study (PACES-1) of sildenafil citrate (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined sildenafil citrate + epoprostenol group compared with 13% of subjects in the epoprostenol group [see Clinical Studies (14)]. In a study to assess the effects of multiple doses of sildenafil citrate on mortality in adults with PAH (StudyA1481324), the lower dose 5 mg TID group showed a higher observed number of deaths (all related to underlying disease/disease under study), serious adverse events, and severe adverse events than the 20 mg and 80 mg TID groups [see Clinical Studies (14)]. Overall, the safety data for sildenafil 80 mg TID dose in Study A1481324 was consistent with the established safety profile of sildenafil in previous adult PAH studies. Sildenafil citrate was studied in a total of 234 PAH pediatric patients 1 to 17 years of age in a 16-week, double-blind placebo-controlled study (STARTS-1); 220 patients continued in a longterm extension study (STARTS-2). The following serious adverse events are discussed elsewhere in the labeling: Hypotension [see Warnings and Precautions (5.1)] Vision Loss [see Warnings and Precautions (5.4)] Hearing Loss [see Warnings and Precautions (5.5)] Priapism [see Warnings and Precautions (5.7)] Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease [see Warnings and Precautions (5.8) ] Because 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 practice. In a sildenafil 100mg hexal 12-week, placebo-controlled clinical study and an open-label extension study (SUPER-1) in 277 sildenafil citrate-treated adults with PAH (WHO Group I) [see Clinical Studies (14)] the adverse reactions that were reported by at least 10% of sildenafil citrate-treated patients in any dosing group, and were more frequent in sildenafil citrate-treated patients than in placebo-treated patients are shown in Table 1. The overall frequency of discontinuation in sildenafil citrate-treated patients was 3% (20 mg and 40 mg three times a day) and 8% (80 mg three times a day). Most Common Adverse Reactions in Patients Treated with sildenafil tablets 20 mg, 40 mg, 80 mg and Placebo three times per day in SUPER-1 (More Frequent in sildenafil-Treated Patients than Placebo-Treated Patients) In a placebo-controlled fixed dose titration study (PACES-1) of sildenafil citrate (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined sildenafil citrate + epoprostenol group compared with 13% of subjects in the epoprostenol group [see Clinical Studies (14)]. In a study to assess the effects of multiple doses of sildenafil citrate on mortality in adults with PAH (StudyA1481324), the lower dose 5 mg TID group showed a higher observed number of deaths (all related to underlying disease/disease under study), serious adverse events, and severe adverse events than the 20 mg and 80 mg TID groups [see Clinical Studies (14)]. Overall, the safety data for sildenafil 80 mg TID dose in Study A1481324 was consistent with the established safety profile of sildenafil in previous adult PAH studies. Sildenafil citrate was studied in a total of 234 PAH pediatric patients 1 to 17 years of age in a 16-week, double-blind placebo-controlled study (STARTS-1); 220 patients continued in a longterm extension study (STARTS-2). Erection increased was observed in 9% of patients treated with sildenafil in STARTS-1.

• 20mg sildenafil is a standard starting dose for many men.
• Its safety profile is well-established when used responsibly.
• The drug should be taken at least 30 minutes before sexual activity.
• Use caution if you experience dizziness or sudden vision loss.
• Always follow medical advice when using sildenafil for ED.

No other new adverse reactions were identified in pediatric patients [see Use in Specific Populations (8.4)]. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these or other factors. NAION [see Warnings and Precautions (5.4), Patient Counseling Information (17)]. Concomitant use of sildenafil citrate with liquid sildenafil citrate nitrates in any form is contraindicated [see Contraindications (4)] .

• Myths and misconceptions about sildenafil are common and should be addressed.
• It is not a "party drug" or aphrodisiac; it requires sexual stimulation to work.
• It does not cause spontaneous erections without sexual arousal.
• More is not always better; higher doses increase side effect risk, not pleasure.
• It is not addictive, but psychological dependence on its use can develop.
• It does not permanently cure erectile dysfunction; effects are temporary.
• It is not safe to use just because it is widely available or discussed.
• Herbal "natural Viagra" products are not regulated and can be dangerous.
• It does not protect against sexually transmitted infections or prevent pregnancy.
• It is not approved or proven to enhance sexual performance in men without ED.
• Accurate information from a healthcare provider is essential.

Strong CYP3A Inhibitors Concomitant use of sildenafil citrate with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)]. Moderate-to-Strong CYP3A Inducers Concomitant use of Sildenafil citrate with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of sildenafil citrate may be needed when initiating treatment with moderate-to-strong CYP3A inducers.

Reduce the dose of sildenafil tablets to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations). 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).

INFORMATION ABOUT SILDENAFIL

Should signs of pulmonary edema occur when sildenafil citrate is administered, sildenafil 130mg consider the possibility of associated PVOD. The incidence of epistaxis was 13% in patients taking sildenafil citrate with PAH secondary to CTD. The safety of sildenafil citrate is unknown in patients with bleeding disorders or active peptic ulceration. When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of PDE-5 inhibitors, including sildenafil. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking sildenafil citrate.

What happens if I take too much sildenafil?

There are no controlled clinical data on the safety or efficacy of sildenafil citrate in patients with retinitis pigmentosa, a minority of whom have genetic disorders of retinal phosphodiesterases. Therefore, use of sildenafil citrate in patients with retinitis pigmentosa is not recommended. Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil citrate. It is not possible to determine whether these reported events are related directly to the use of sildenafil citrate, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil tablets. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No 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. In a rat pre-and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis). Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk.

8.6 Patients with Hepatic Impairment

Erection increased was observed in 9% of patients treated with sildenafil in STARTS-1. No other new adverse reactions were identified in pediatric patients [see Use in Specific Populations (8.4)]. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these or other factors. NAION [see Warnings and Precautions (5.4), Patient Counseling Information (17)]. Concomitant use of sildenafil citrate with liquid sildenafil citrate nitrates in any form is contraindicated [see Contraindications (4)] .

Drugs you should not use with sildenafil

Strong CYP3A Inhibitors Concomitant use of sildenafil citrate with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)]. Moderate-to-Strong CYP3A Inducers Concomitant use of Sildenafil citrate with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of sildenafil citrate may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of sildenafil tablets to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil citrate to an infant during lactation. The safety and efficacy of Sildenafil citrate have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underly improvements in exercise Use of sildenafil citrate for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)].

Warnings & Precautions