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1 INDICATIONS AND USAGE Adults Sildenafil for oral suspension is indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening [see Clinical Studies (14) ] . Pediatric Patients (1 to 17 Years Old) Sildenafil for oral suspension is indicated in pediatric patients 1 to 17 years old for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise ability and, in pediatric patients too young to perform standardized exercise testing, pulmonary hemodynamics thought to underlie improvements in exercise [see Clinical Studies (14) ] . Adults Sildenafil for oral suspension is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening. ( 1 ) Pediatric Patients (1 to 17 years old) Sildenafil for oral suspension is indicated in pediatric patients 1 to 17 years old for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise ability and, in pediatric patients too young to perform standard exercise testing, pulmonary hemodynamics thought to underlie improvements in exercise ( 1 , 14 )

2 DOSAGE AND ADMINISTRATION Adults: 20 mg orally three times a day. Dose may be increased based on symptoms and tolerability. ( 2.1 ) Pediatric patients ( 2.2 ) ≤ 20 kg: 10 mg three times a day 20 kg to 45 kg: 20 mg three times a day 45 kg: 20 mg three times a day. Dose may be increased based on symptoms and tolerability. 2.1 Recommended Dosage in Adults Oral Dosage The recommended dosage of sildenafil for oral suspension is 20 mg three times a day. Dose may be titrated to a maximum of 80 mg three times a day, if required, based on symptoms and tolerability [see Clinical Studies (14) ] . Although dose-response improvement in exercise ability was not observed in short-term studies in adults with PAH, the delay in clinical worsening with long-term use of sildenafil in Study A1481324 supports dosing up to a maximum of 80 mg three times a day [see Clinical Studies (14) ] . 2.2 Recommended Dosage in Pediatric Patients Oral Dosage The recommended dosage in patients ≤ 20 kg is 10 mg three times a day. For pediatric patients 20 kg to 45 kg, the recommended dosage is 20 mg three times a day. For pediatric patients 45 kg and greater, the recommended dosage is 20 mg three times a day. 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) ] . 2.3 Reconstitution of the Powder for Oral Suspension Note: Reconstitute the contents of the bottle with a total volume of 90 mL (60 mL followed by 30 mL). Refer to the detailed instructions below. 1. Tap the bottle to loosen the powder. 2. Add 60 mL of water to the bottle. 3. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. 4. Add another 30 mL of water to the bottle. 5. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. 6. Remove cap and press the bottle adaptor into the neck of the bottle. Replace the cap on the bottle. 7. Write the expiration date of the reconstituted oral suspension on the bottle label (the expiration date of the reconstituted oral suspension is 60 days from the date of reconstitution). Incompatibilities Do not mix with any other medication or additional flavoring agent.

3 DOSAGE FORMS AND STRENGTHS Sildenafil for Oral Suspension White to off-white granular powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g of sildenafil) in a bottle for reconstitution to 10 mg/mL. Following reconstitution with 90 mL of water, the total volume of the oral suspension is 112 mL. A 2-mL oral dosing syringe (with 0.5 mL and 2 mL dose markings) and a press-in bottle adaptor are also provided. For oral suspension: 10 mg/mL (when reconstituted) ( 3 )

4 CONTRAINDICATIONS Sildenafil for oral suspension 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) ]. Concomitant use of riociguat, a guanylate cyclase stimulator. Phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. Known hypersensitivity to sildenafil or any component of the tablet, injection, or oral suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. Use with organic nitrates or riociguat. ( 4 ) History of hypersensitivity reaction to sildenafil or any component of the tablet, injection, or oral suspension. ( 4 )

5 WARNINGS AND PRECAUTIONS Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. ( 5.1 ) Use in pulmonary veno-occlusive disease (PVOD) may cause pulmonary edema and is not recommended. ( 5.2 ) Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. ( 5.4 , 5.5 ) Pulmonary hypertension (PH) secondary to sickle cell disease: Sildenafil for oral suspension may cause serious vaso-occlusive crises. ( 5.8 ) 5.1 Hypotension Sildenafil has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil for oral suspension, 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 presuure 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 for oral suspension. 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 for oral suspension to patients with veno-occlusive disease, administration of sildenafil for oral suspension to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil for oral suspension is administered, consider the possibility of associated PVOD. 5.3 Epistaxis The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to CTD. This effect was not seen in idiopathic PAH (Sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil for oral suspension-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil for oral suspension is unknown in patients with bleeding disorders or active peptic ulceration. 5.4 Visual Loss 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. Most patients had underlying anatomic or vascular risk factors for developing NAION, including low cup to disc ratio ("crowded disc"). Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking sildenafil. There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis pigmentosa, a minority of whom have genetic disorders of retinal phosphodiesterases. Therefore, use of sildenafil in patients with retinitis pigmentosa is not recommended. 5.5 Hearing Loss 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. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up in formation was limited.

hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up in formation was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil for oral suspension, 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 for oral suspension. 5.6 Combination with Other PDE-5 Inhibitors Sildenafil is also marketed as VIAGRA ® . The safety and efficacy of combinations of sildenafil for oral suspension with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil for oral suspension not to take VIAGRA or other PDE-5 inhibitors. 5.7 Priapism Use sildenafil for oral suspension with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie's disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. 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 for oral suspension than by those randomized to placebo. The effectiveness and safety of sildenafil for oral suspension in the treatment of PH secondary to sickle cell disease has not been established.

6 ADVERSE REACTIONS 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) ] Adults: Headache, dyspepsia, flushing, pain in limb, myalgia, back pain and diarrhea. ( 6.1 , 6.2 ) Children: Priapism. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 12-week, placebo-controlled clinical study and an open-label extension study (SUPER-1) in 277 sildenafil-treated adults with PAH (WHO Group I) [see Clinical Studies (14) ] the adverse reactions that were reported by at least 10% of sildenafil-treated patients in any dosing group, and were more frequent in sildenafil-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. The overall frequency of discontinuation in sildenafil-treated patients was 3% (20 mg and 40 mg three times a day) and 8% (80 mg three times a day). The overall frequency of discontinuation for placebo was 3%. Table 1. Most Common Adverse Reactions in Patients Treated with Sildenafil 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) Sildenafil 20 mg (n = 69) Sildenafil 40 mg (n = 67) Sildenafil 80 mg (n = 71) Placebo (n = 70) Headache 46% 42% 49% 39% Flushing 10% 9% 16% 4% Pain in Limb 7% 15% 9% 6% Myalgia 7% 6% 14% 4% Back Pain 13% 13% 9% 11% Dyspepsia 13% 8% 13% 7% Diarrhea 9% 12% 10% 6% In a placebo-controlled fixed dose titration study (PACES-1) of sildenafil (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 + 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 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. Pediatric Patients Sildenafil 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 long-term extension study (STARTS-2). Erection increased was observed in 9% of patients treated with sildenafil in STARTS-1.

Pediatric Patients Sildenafil 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 long-term extension study (STARTS-2). 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) ]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). 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. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. 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. Nervous System Seizure, seizure recurrence Ophthalmologic NAION [see Warnings and Precautions (5.4) and Patient Counseling Information (17) ] .

<table ID="ID62" width="89%" styleCode="Noautorules"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td colspan="5" valign="top" styleCode=" Botrule" align="center"><content styleCode="bold"> Table 1.

<table ID="ID62" width="89%" styleCode="Noautorules"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td colspan="5" valign="top" styleCode=" Botrule" align="center"><content styleCode="bold"> Table 1. Most Common Adverse Reactions in Patients Treated with Sildenafil 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)</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule"/><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil</content> <content styleCode="bold"> 20 mg</content> <content styleCode="bold"> (n = 69)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil</content> <content styleCode="bold"> 40 mg</content> <content styleCode="bold"> (n = 67)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil</content> <content styleCode="bold"> 80 mg</content> <content styleCode="bold"> (n = 71)</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Placebo</content> <content styleCode="bold"> (n = 70)</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="center"> Headache </td><td styleCode=" Botrule Rrule" align="center"> 46% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 42% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 49% </td><td styleCode=" Botrule Rrule" align="center"> 39% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="center"> Flushing </td><td styleCode=" Botrule Rrule" align="center"> 10% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 16% </td><td styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="center"> Pain in Limb </td><td styleCode=" Botrule Rrule" align="center"> 7% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 15% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td><td styleCode=" Botrule Rrule" align="center"> 6% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="center"> Myalgia </td><td styleCode=" Botrule Rrule" align="center"> 7% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14% </td><td styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="center"> Back Pain </td><td styleCode=" Botrule Rrule" align="center"> 13% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td><td styleCode=" Botrule Rrule" align="center"> 11% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="center"> Dyspepsia </td><td styleCode=" Botrule Rrule" align="center"> 13% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13% </td><td styleCode=" Botrule Rrule" align="center"> 7% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="center"> Diarrhea </td><td styleCode=" Botrule Rrule" align="center"> 9% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 12% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10% </td><td styleCode=" Botrule Rrule" align="center"> 6% </td></tr></tbody></table>

7 DRUG INTERACTIONS Nitrates Concomitant use of sildenafil with nitrates in any form is contraindicated [see Contraindications (4) ]. Strong CYP3A Inhibitors Concomitant use of sildenafil with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3) ]. Moderate-to-Strong CYP3A Inducers Concomitant use of sildenafil with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of sildenafil may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of sildenafil 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) ]. Use with strong CYP3A inhibitors: Not recommended. ( 7 , 12.3 ) Concomitant PDE-5 inhibitors: Avoid use with Viagra ® or other PDE-5 inhibitors. ( 5.6 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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, embryo toxicity, 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/m 2 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/m 2 basis). 8.2 Lactation Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation. 8.4 Pediatric Use The safety and efficacy of sildenafil 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 underlie improvements in exercise. Use of sildenafil 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) and Clinical Studies (14) ] . The safety and effectiveness of sildenafil have not been established in pediatric patients younger than 1 year of age. During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies (14) ] , an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324).

s was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324). Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients > 45 kg up to a maximum of 40 mg three times a day. 8.5 Geriatric Use Clinical studies of sildenafil did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ]. 8.6 Patients with Hepatic Impairment No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3) ]. 8.7 Patients with Renal Impairment No dose adjustment is required (including severe impairment CLcr <30 mL/min) [see Clinical Pharmacology (12.3) ].

8.1 Pregnancy 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). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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, embryo toxicity, 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/m 2 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/m 2 basis).

8.4 Pediatric Use The safety and efficacy of sildenafil 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 underlie improvements in exercise. Use of sildenafil 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) and Clinical Studies (14) ] . The safety and effectiveness of sildenafil have not been established in pediatric patients younger than 1 year of age. During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies (14) ] , an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324). Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients > 45 kg up to a maximum of 40 mg three times a day.

8.5 Geriatric Use Clinical studies of sildenafil did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

11 DESCRIPTION Sildenafil for oral suspension, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). 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 or almost white crystalline powder with a solubility of 10mg/100ml in water and a molecular weight of 666.7. Sildenafil for oral suspension is supplied as white to off-white granular powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g sildenafil) in an amber glass bottle and in HDPE bottle intended for reconstitution. Following reconstitution with 90 mL water, the volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil. The inactive ingredients include sorbitol, citric acid anhydrous, sucralose, tri-sodium citrate dihydrate, xanthan gum, titanium dioxide, sodium benzoate, colloidal silicon dioxide, carbomer homopolymer and grape flavor. In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (with 0.5 mL and 2 mL dose markings) are provided. Image

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. 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 PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10 times 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 Pharmacology (12.2) ]. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 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 Pharmacodynamics Effects of sildenafil on Hemodynamic Measures Adults Patients 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 [ see SUPER-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 2. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65) The number of patients per treatment group varied slightly for each parameter due to missing assessments. Sildenafil 20 mg (n = 65) mPAP (mmHg) 0.6 (-0.8, 2) -2.1 (-4.3, 0) PVR (dyn∙s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn∙s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate. Pediatric Patients Patients on sildenafil medium and high dose groups achieved dose related improvements in pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies (14) ] . Improvements were observed with cardiac index in all three sildenafil dose groups over placebo. Data on other hemodynamic measures for the sildenafil low, medium and high dose groups compared to placebo is displayed in Table 3. Table 3.

sure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies (14) ] . Improvements were observed with cardiac index in all three sildenafil dose groups over placebo. Data on other hemodynamic measures for the sildenafil low, medium and high dose groups compared to placebo is displayed in Table 3. Table 3. Placebo Corrected Changes in Hemodynamic Parameters by Dose Group Parameter [Estimate (95% CI)] Low Dose Medium Dose High Dose PVRI (%) -2% (-20%, 20%) n = 37 -18% (-32%, -2%) n = 51 -27% (-39%, -14%) n = 68 mPAP (mmHg) 1.6 (-4.5, 7.6) n = 39 -3.5 (-8.9, 1.9) n = 55 -7.3 (-12.4, -2.1) n = 71 CI (%) 10% (-4%, 26%) n = 37 4% (-7%, 18%) n = 51 15% (3%, 29%) n = 69 SVRI (%) -9% (-22%, 7%) n = 37 -5% (-17%, 10%) n = 50 -16% (-26%, -4%) n = 68 RAP (mmHg) -0.17 (-1.91, 1.57) n = 39 -0.19 (-1.73, 1.36) n = 55 -1.14 (-2.61, 0.33) n = 71 HR (%) 3% (-5%, 12%) n = 39 2% (-5%, 9%) n = 55 -2% (-9%, 5%) n = 71 Abbreviations: CI = cardiac index; HR = heart rate; mPAP = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; RAP = right atrial pressure; SVRI = systemic vascular resistance index. Note: n = 52, 56, 55, 54, 56, and 56 placebo patients for PVRI, mPAP, CI, SVRI, RAP and HR, respectively. Effects of Sildenafil on Blood Pressure Single 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 to 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 electrocardiogram (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 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 Vision At 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. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. 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 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%.

ability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. 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 to 50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Pediatric Patients Body weight was shown to be a good predictor of drug exposure in children. Sildenafil plasma concentration half-life values were estimated to range from 2.9 to 4.4 hours for a range of 10 kg to 70 kg of body weight. T max was estimated at approximately 1 hour. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered.

crease in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in patients with severe renal impairment compared to patients with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 µM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 1 and Figure 2, respectively. Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 2 Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reduction in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 Inducers Including Bosentan Concomitant administration of strong CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. figure 7 figure 8

12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. 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 PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10 times 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 Pharmacology (12.2) ]. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 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 Pharmacodynamics Effects of sildenafil on Hemodynamic Measures Adults Patients 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 [ see SUPER-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 2. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65) The number of patients per treatment group varied slightly for each parameter due to missing assessments. Sildenafil 20 mg (n = 65) mPAP (mmHg) 0.6 (-0.8, 2) -2.1 (-4.3, 0) PVR (dyn∙s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn∙s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate. Pediatric Patients Patients on sildenafil medium and high dose groups achieved dose related improvements in pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies (14) ] . Improvements were observed with cardiac index in all three sildenafil dose groups over placebo. Data on other hemodynamic measures for the sildenafil low, medium and high dose groups compared to placebo is displayed in Table 3. Table 3. Placebo Corrected Changes in Hemodynamic Parameters by Dose Group Parameter [Estimate (95% CI)] Low Dose Medium Dose High Dose PVRI (%) -2% (-20%, 20%) n = 37 -18% (-32%, -2%) n = 51 -27% (-39%, -14%) n = 68 mPAP (mmHg) 1.6 (-4.5, 7.6) n = 39 -3.5 (-8.9, 1.9) n = 55 -7.3 (-12.4, -2.1) n = 71 CI (%) 10% (-4%, 26%) n = 37 4% (-7%, 18%) n = 51 15% (3%, 29%) n = 69 SVRI (%) -9% (-22%, 7%) n = 37 -5% (-17%, 10%) n = 50 -16% (-26%, -4%) n = 68 RAP (mmHg) -0.17 (-1.91, 1.57) n = 39 -0.19 (-1.73, 1.36) n = 55 -1.14 (-2.61, 0.33) n = 71 HR (%) 3% (-5%, 12%) n = 39 2% (-5%, 9%) n = 55 -2% (-9%, 5%) n = 71 Abbreviations: CI = cardiac index; HR = heart rate; mPAP = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; RAP = right atrial pressure; SVRI = systemic vascular resistance index. Note: n = 52, 56, 55, 54, 56, and 56 placebo patients for PVRI, mPAP, CI, SVRI, RAP and HR, respectively. Effects of Sildenafil on Blood Pressure Single 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 to 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) ].

erent 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 electrocardiogram (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 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 Vision At 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. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry.

<table ID="ID96" width="100%" styleCode="Noautorules"><col width="37%"/><col width="31%"/><col width="31%"/><tbody><tr><td colspan="3" valign="top" styleCode=" Botrule" align="center"><content styleCode="bold"> Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the sildenafil 20 mg Three Times a Day and Placebo Group</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (n = 65)<footnote ID="ID96_0">The number of patients per treatment group varied slightly for each parameter due to missing assessments.</footnote></content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil 20 mg</content> <content styleCode="bold"> (n = 65)<footnoteRef IDREF="ID96_0"/></content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> mPAP (mmHg) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.6 (-0.8, 2) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -2.1 (-4.3, 0) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> PVR (dyn&#x2219;s/cm⁵) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 49 (-54, 153) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -122 (-217, -27) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> SVR (dyn&#x2219;s/cm⁵) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -78 (-197, 41) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -167 (-307, -26) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> RAP (mmHg) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.3 (-0.9, 1.5) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -0.8 (-1.9, 0.3) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> CO (L/min) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -0.1 (-0.4, 0.2) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.4 (0.1, 0.7) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> HR (beats/min) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -1.3 (-4.1, 1.4) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -3.7 (-5.9, -1.4) </td></tr><tr><td colspan="3" valign="top" align="left"> mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate. </td></tr></tbody></table>

Code=" Botrule Rrule" align="center"> -3.7 (-5.9, -1.4) </td></tr><tr><td colspan="3" valign="top" align="left"> mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate. </td></tr></tbody></table> <table ID="ID183" width="690" styleCode="Noautorules"><caption> Table 3. Placebo Corrected Changes in Hemodynamic Parameters by Dose Group </caption><col width="151"/><col width="151"/><col width="158"/><col width="230"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Parameter</content> <content styleCode="bold"> [Estimate (95% CI)]</content> </td><td valign="bottom" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Low Dose</content> </td><td valign="bottom" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Medium Dose</content> </td><td valign="bottom" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> High Dose</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> PVRI (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -2% (-20%, 20%) n = 37 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -18% (-32%, -2%) n = 51 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -27% (-39%, -14%) n = 68 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> mPAP (mmHg) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.6 (-4.5, 7.6) n = 39 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -3.5 (-8.9, 1.9) n = 55 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -7.3 (-12.4, -2.1) n = 71 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> CI (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10% (-4%, 26%) n = 37 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% (-7%, 18%) n = 51 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 15% (3%, 29%) n = 69 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> SVRI (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -9% (-22%, 7%) n = 37 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -5% (-17%, 10%) n = 50 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -16% (-26%, -4%) n = 68 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> RAP (mmHg) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -0.17 (-1.91, 1.57) n = 39 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -0.19 (-1.73, 1.36) n = 55 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -1.14 (-2.61, 0.33) n = 71 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> HR (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% (-5%, 12%) n = 39 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% (-5%, 9%) n = 55 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -2% (-9%, 5%) n = 71 </td></tr><tr><td colspan="4" valign="top" align="left"> Abbreviations: CI = cardiac index; HR = heart rate; mPAP = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; RAP = right atrial pressure; SVRI = systemic vascular resistance index. Note: n = 52, 56, 55, 54, 56, and 56 placebo patients for PVRI, mPAP, CI, SVRI, RAP and HR, respectively. </td></tr></tbody></table>

12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. 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 to 50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Pediatric Patients Body weight was shown to be a good predictor of drug exposure in children. Sildenafil plasma concentration half-life values were estimated to range from 2.9 to 4.4 hours for a range of 10 kg to 70 kg of body weight. T max was estimated at approximately 1 hour. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years).

y 1 hour. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in patients with severe renal impairment compared to patients with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 µM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 1 and Figure 2, respectively. Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 2 Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reduction in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 Inducers Including Bosentan Concomitant administration of strong CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant.

l The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38-times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38-times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day.

14 CLINICAL STUDIES SUPER-1 (NCT00644605) - Sildenafil for oral suspension monotherapy [20 mg, 40 mg, and 80 mg three times a day] A randomized, double-blind, placebo-controlled study of sildenafil for oral suspension (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure ≥25 mmHg at rest with a pulmonary capillary wedge pressure <15 mmHg). Patients were predominantly WHO Functional Classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Patients who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied. Patients were randomized to receive placebo (n = 70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45-50 meters were observed with all doses of sildenafil for oral suspension. These increases were significantly different from placebo, but the sildenafil for oral suspension dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12. Figure 3. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval) Figure 4 displays subgroup efficacy analyses in SUPER-1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters. Figure 4. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-1: Mean (95% Confidence Interval) Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily. SUPER-2 (NCT00159887) Long-term Treatment of PAH In a long-term follow-up of patients who were treated with sildenafil (n=277), K-M estimates of survival at 1, 2, and 3 years were 94%, 88%, and 79%, respectively. These uncontrolled observations do not allow comparison with a group not given sildenafil and cannot be used to determine the long term-effect of sildenafil on mortality. PACES-1 (NCT00159861) - Sildenafil for oral suspension Co-administered with Epoprostenol A randomized, double-blind, placebo-controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol.

t be used to determine the long term-effect of sildenafil on mortality. PACES-1 (NCT00159861) - Sildenafil for oral suspension Co-administered with Epoprostenol A randomized, double-blind, placebo-controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil for oral suspension (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO Functional Class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil for oral suspension group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil for oral suspension group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil for oral suspension achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil for oral suspension (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in PACES-1. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil for oral suspension-treated patients and that sildenafil for oral suspension-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 5. Table 4. Clinical Worsening Events in PACES 1 Placebo (N = 131) Sildenafil for oral suspension (N = 134) Number of patients with clinical worsening first event 23 8 First Event All Events First Event All Events Death, n 3 4 0 0 Lung transplantation, n 1 1 0 0 Hospitalization due to PAH, n 9 11 8 8 Clinical deterioration resulting in: Change of Epoprostenol Dose, n Initiation of Bosentan, n 9 1 16 1 0 0 2 0 Proportion worsened 95% Confidence Interval 0.187 (0.12 to 0.26) 0.062 (0.02 to 0.1) Figure 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES 1 Improvements in WHO Functional Class for PAH were also demonstrated in patients on sildenafil for oral suspension compared to placebo. More than twice as many sildenafil for oral suspension-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.

tional Class for PAH were also demonstrated in patients on sildenafil for oral suspension compared to placebo. More than twice as many sildenafil for oral suspension-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study A1481243 (NCT00323297) - Sildenafil Added to Bosentan Therapy – Lack of Effect on Exercise Capacity A randomized, double-blind, placebo-controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of 3 months. The PAH patients included those with primary PAH and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6-minute walk distance (6MWD). The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone. STARTS-1 (NCT00159913) - Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, with Pulmonary Arterial Hypertension A total of 234 patients with PAH aged 1 to 17 years were treated in a randomized, double-blind, multi-center, placebo-controlled parallel group, dose-ranging study. Patients (38% male and 62% female) had body weight ≥ 8 kg and had idiopathic pulmonary arterial hypertension (33%), or PAH associated with congenital heart disease (systemic-to-pulmonary shunt 37%, surgical repair 30%). In this trial, 27% of patients were < 7 years old. Patients were WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists were not permitted in the study, and neither were arginine supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors. The primary objective of the study was to assess the effect of sildenafil on percent change from baseline in PVO 2 , normalized to body weight, from baseline to week 16 as measured by the Cardiopulmonary Exercise Test (CPET) (patients who were developmentally able to perform the test, n = 115). Secondary endpoints included hemodynamic monitoring, symptom assessment, WHO Functional Class, change in background treatment, and quality of life measurements (n = 234). Patients were allocated to one of three sildenafil treatment groups (low, medium, or high) or placebo. Actual doses administered were dependent on body weight (see Table 5). Table 5. Treatment Allocation by Dose and Body Weight in Pediatric Study Placebo Low Dose Medium Dose High Dose Body Weight (kg) N Dose N Dose N Dose N ≥ 8 to 20 18 na 10 mg 15 20 mg 35 > 20 to 45 32 10 mg 31 20 mg 30 40 mg 31 > 45 10 10 mg 11 40 mg 10 80 mg 11 The proportion of patients receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (48%) and the placebo treatment group (42%). The primary endpoint was a percentage change in VO 2peak from baseline to week 16 assessed by CPET. Mean baseline peak volume of oxygen consumed (VO 2 ) values were similar across the sildenafil treatment groups (17 mL/kg/min to 18 mL/kg/min), and slightly higher for the placebo treatment group (20 mL/kg/min). See Figure 6. A total of 45% of patients were evaluable for CPET, which comprised those children ≥ 7 years old and developmentally able to perform the test. Children < 7 years were evaluable only for the secondary endpoints.

mL/kg/min to 18 mL/kg/min), and slightly higher for the placebo treatment group (20 mL/kg/min). See Figure 6. A total of 45% of patients were evaluable for CPET, which comprised those children ≥ 7 years old and developmentally able to perform the test. Children < 7 years were evaluable only for the secondary endpoints. Mean increases in VO 2peak percentage change from baseline at Week 16, were observed with all 3 sildenafil doses (range of 6% to 13%, Figure 6), with little change with placebo (0.5%). Figure 6. Percentage Change from Baseline in VO2Peak: Mean (95% Confidence Intervals) The estimated difference between the combined sildenafil doses and placebo was 8% (95% CI: - 0.2 to 16). The results of the main analysis (combined dose groups versus placebo) were not statistically significant (p = 0.056). The estimated difference between the sildenafil medium dose group and placebo was 11 ± 5% (95% CI: 2 to 21). Impact on Hemodynamic Parameters Dose related improvements were observed with PVRI and mPAP. Statistically significant PVRI reductions compared to placebo were seen with the sildenafil medium and high dose groups (18% [95% CI: -32% to -2%] and 27% [95% CI: -39% to -14%], respectively) but not the low dose group (2% (95% CI: -20%, 20%). The sildenafil medium and high dose groups displayed mPAP changes from baseline compared to placebo, of -3.5 mmHg (95% CI: -8.9, 1.9) and -7.3 mmHg (95% CI: -12.4, -2.1), respectively; while the low dose group showed little difference from placebo (difference of 1.6 mmHg [95% CI: -4.5, 7.6]). Improvements were observed with cardiac index with all three sildenafil groups over placebo, 10%, 4%, and 15% for the low, medium, and high dose groups, respectively [see Clinical Pharmacology (12.2) ] . STARTS-2 (NCT00159874) - Long-Term Survival with Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension Of the 234 pediatric patients treated in the short-term, placebo-controlled study, 220 patients entered the long-term extension study. Patients who had been in the placebo group in the shortterm study were randomly reassigned to sildenafil treatment; patients weighing ≤ 20 kg entered the medium or high dose groups (1:2), while patients weighing > 20 kg entered the low, medium, or high dose groups (1:1:1). Of the total 229 patients who received sildenafil, there were 55, 74, and 100 patients in the low, medium, and high dose groups, respectively. Across the short-term and long-term studies, the overall duration of treatment from start of double-blind for individual patients ranged from 3 to 3,129 days. By sildenafil treatment group, median duration of sildenafil treatment was 1,696 days (excluding the 5 patients who received placebo in double-blind and were not treated in the long-term extension study). Peak VO 2 was assessed 1 year after the start of the placebo-controlled study. Of sildenafil-treated patients developmentally able to perform the CPET 59/114 patients (52%) had not shown any deterioration in PVO 2 from start of sildenafil. Similarly, 191 of 229 patients (83%) who had received sildenafil had either maintained or improved their WHO Functional Class at 1 year assessment. Kaplan-Meier estimates of survival at 3 years in patients > 20 kg in weight at baseline were 94%, 93%, and 85% in the low, medium, and high dose groups, respectively; for patients ≤ 20 kg in weight at baseline, the survival estimates were 94% and 93% for patients in the medium and high dose groups, respectively [see Use in Specific Populations (8.4) and Adverse Reactions (6.1) ].

kg in weight at baseline were 94%, 93%, and 85% in the low, medium, and high dose groups, respectively; for patients ≤ 20 kg in weight at baseline, the survival estimates were 94% and 93% for patients in the medium and high dose groups, respectively [see Use in Specific Populations (8.4) and Adverse Reactions (6.1) ]. Study A1481324 (NCT02060487) - Study to Assess the Effects of Sildenafil on Mortality in Adults with PAH A study to assess the effects of multiple doses of sildenafil on mortality in adults with PAH was conducted following the observation of a higher risk of mortality in pediatric patients taking a high dose of sildenafil TID, based on body weight, compared to those taking a lower dose of sildenafil in the long-term extension of the pediatric clinical trial. The study was a randomized, double-blind, parallel-group study in 385 adults with PAH. Patients were randomly assigned 1:1:1 to one of three treatment groups (5, 20, and 80 mg TID). Most patients were PAH treatment naïve (83%). For most patients the etiology of PAH was idiopathic (72%). The most common WHO Functional Class was Class III (58% of patients). Treatment groups were well balanced with respect to baseline demographics of strata history of PAH treatment and etiology of PAH, as well as the WHO Functional Class categories. The primary objective of the study was to compare sildenafil 80 mg TID versus 5 mg TID for mortality, with success defined by ruling out twice the mortality at 80 mg. The key secondary efficacy endpoint was time to first event of clinical worsening, defined as a composite endpoint of all-cause mortality, hospitalization for worsening PAH or disease progression. An additional secondary endpoint was 6MWD at Months 6 and 12. Overall Survival At the time of a planned interim analysis (50% deaths) it was identified that the primary efficacy objective of this protocol was met and therefore the study was stopped. Based on the primary efficacy endpoint (mortality), the non-inferiority of sildenafil 80 mg TID arm versus 5 mg TID arm was met using a 2-sided significance level of 0.003 for the interim analysis. Primary comparison of the 80 mg TID group to the 5 mg TID group yielded the HR (99.7% CI) = 0.51 (0.22, 1.21); i.e., non-inferiority was established. Table 6. Hazard Ratios for Overall Survival, Assessed in the Proportional Hazards Model – Intent To Treat Population Sildenafil 5 mg N = 129 Sildenafil 20 mg N = 128 Sildenafil 80 mg N = 128 Patient-years of follow-up 329.8 340.5 356.7 Number of deaths (%) 34 (26) 25 (20) 19 (15) On treatment deaths a (%) 22 (17) 13 (10) 15 (12) Off treatment deaths (%) 12 (9) 12 (9) 4 (3) Hazard ratio relative to sildenafil 5 mg Hazard ratio estimate b 99.7% CI 0.68 0.31, 1.49 0.51 0.22, 1.21 Hazard ratio relative to sildenafil 20 mg Hazard ratio estimate 99.7% CI 0.74 0.30, 1.84 a. On treatment deaths: Any death within 7 days of last dose was regarded as "On treatment", thus might include deaths occurred after discontinuation from study treatment. b. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. Kaplan-Meier estimates of survival at 3 years were 66%, 79%, and 85% in the 5-, 20-, and 80- mg TID dose groups, respectively. Clinical Worsening Sildenafil 80 mg was also superior to 5 mg for time to first event of clinical worsening with HR (99.7% CI) = 0.44 (0.22, 0.89). Table 7.

s PAH treatment and etiology of PAH. Kaplan-Meier estimates of survival at 3 years were 66%, 79%, and 85% in the 5-, 20-, and 80- mg TID dose groups, respectively. Clinical Worsening Sildenafil 80 mg was also superior to 5 mg for time to first event of clinical worsening with HR (99.7% CI) = 0.44 (0.22, 0.89). Table 7. Hazard Ratios for Time to First Event of Clinical Worsening – Intent to Treat Population Sildenafil 5 mg N = 129 Sildenafil 20 mg N = 128 Sildenafil 80 mg N = 128 Patient-years of follow-up 249.6 276.4 306.5 Number of patients with clinical worsening 52 36 28 First Event of clinical worsening a n (%) Disease progression b 8 (6) 2 (2) 6 (5) Hospitalization for PAH c 28 (22) 23 (18) 11 (9) Death d 16 (12) 11 (9) 11 (9) Hazard ratio relative to sildenafil 5 mg Hazard ratio estimate e 0.63 0.44 99.7% CI 0.33, 1.21 0.22, 0.89 p-value 0.035 < 0.001 Hazard ratio relative to sildenafil 20 mg Hazard ratio estimate e 0.72 99.7% CI 0.34, 1.52 p-value 0.195 Note: Sildenafil 5 mg is not an approved dosage. Abbreviations: 6MWD = 6-minute walk distance; CI = confidence interval; PAH = pulmonary arterial hypertension. a. Clinical worsening events were defined as reduction from baseline in the 6MWD test by at least 15% and worsening functional class from baseline, both confirmed by a second test/evaluation within 2 weeks. b. Count of cases of disease progression as the first event of clinical worsening. c. Count of non-elective hospital stays for worsening PAH as the first event of clinical worsening. d. Count of deaths as the first event of clinical worsening. e. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. P-value from the Wald test. 6MWD at Months 6 and 12 At baseline, the median of 6MWD for the intent-to-treat (ITT) population was 332 m to 352 m. At Month 6, the median change from baseline was highest for sildenafil 80 mg TID with 28 m compared to 18 m and 19 m for sildenafil 5 mg TID and sildenafil 20 mg TID groups, respectively. The same was seen at Month 12, the median change from baseline for sildenafil 80 mg TID group was 33 m compared to 17 m for sildenafil 5 mg TID and 31 m in sildenafil 20 mg TID groups. Overall, the safety data for sildenafil 20 mg TID and for the higher sildenafil 80 mg TID dose were consistent with the established safety profile of sildenafil in previous adult PAH studies [see Adverse Reactions (6.1) ] . figure 9 figure 10 Image image

<table ID="ID107" width="100%" styleCode="Noautorules"><caption> Table 4. Clinical Worsening Events in PACES 1 </caption><col width="39%"/><col width="18%"/><col width="13%"/><col width="14%"/><col width="14%"/><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule"/><td colspan="2" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo</content> <content styleCode="bold"> (N = 131)</content> </td><td colspan="2" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil for oral suspension </content> <content styleCode="bold"> (N = 134)</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Number of patients with clinical worsening first event </td><td colspan="2" styleCode=" Botrule Rrule" align="center"> 23 </td><td colspan="2" styleCode=" Botrule Rrule" align="center"> 8 </td></tr><tr><td styleCode="Lrule Botrule Rrule"/><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> First Event</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> All Events</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> First Event</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> All Events</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Death, n </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 0 </td><td styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Lung transplantation, n </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> 0 </td><td styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Hospitalization due to PAH, n </td><td styleCode=" Botrule Rrule" align="center"> 9 </td><td styleCode=" Botrule Rrule" align="center"> 11 </td><td styleCode=" Botrule Rrule" align="center"> 8 </td><td styleCode=" Botrule Rrule" align="center"> 8 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Clinical deterioration resulting in: Change of Epoprostenol Dose, n Initiation of Bosentan, n </td><td styleCode=" Botrule Rrule" align="center"> 9 1 </td><td styleCode=" Botrule Rrule" align="center"> 16 1 </td><td styleCode=" Botrule Rrule" align="center"> 0 0 </td><td styleCode=" Botrule Rrule" align="center"> 2 0 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Proportion worsened 95% Confidence Interval </td><td colspan="2" styleCode=" Botrule Rrule" align="center"> 0.187 (0.12 to 0.26) </td><td colspan="2" styleCode=" Botrule Rrule" align="center"> 0.062 (0.02 to 0.1) </td></tr></tbody></table>

gn="center"> 2 0 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Proportion worsened 95% Confidence Interval </td><td colspan="2" styleCode=" Botrule Rrule" align="center"> 0.187 (0.12 to 0.26) </td><td colspan="2" styleCode=" Botrule Rrule" align="center"> 0.062 (0.02 to 0.1) </td></tr></tbody></table> <table ID="ID185" width="640" styleCode="Noautorules"><caption> Table 5. Treatment Allocation by Dose and Body Weight in Pediatric Study </caption><col width="140"/><col width="94"/><col width="85"/><col width="57"/><col width="76"/><col width="57"/><col width="76"/><col width="55"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule RruleLrule Toprule Botrule Rrule"/><td valign="top" styleCode=" Toprule Botrule Rrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Placebo</content> </td><td colspan="2" valign="top" styleCode=" Toprule Botrule Rrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Low Dose</content> </td><td colspan="2" valign="top" styleCode=" Toprule Botrule Rrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Medium Dose</content> </td><td colspan="2" valign="top" styleCode=" Toprule Botrule Rrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> High Dose</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Body Weight (kg)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> N</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> Dose</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> N</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> Dose</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> N</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> Dose</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> N</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> &#x2265; 8 to 20 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 18 </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="left"> na </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 10 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 15 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 20 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 35 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> &gt; 20 to 45 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 32 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 10 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 31 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 20 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 30 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 40 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 31 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> &gt; 45 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 10 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 10 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 11 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 40 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 10 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 80 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 11 </td></tr></tbody></table>

Rrule" align="left"> 11 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 40 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 10 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 80 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 11 </td></tr></tbody></table> <table ID="ID189" width="689" styleCode="Noautorules"><caption> Table 6. Hazard Ratios for Overall Survival, Assessed in the Proportional Hazards Model &#x2013; Intent To Treat Population </caption><col width="232"/><col width="153"/><col width="153"/><col width="151"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule"/><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil 5 mg</content> <content styleCode="bold"> N = 129</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil 20 mg</content> <content styleCode="bold"> N = 128</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil 80 mg</content> <content styleCode="bold"> N = 128</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Patient-years of follow-up </td><td styleCode=" Botrule Rrule" align="center"> 329.8 </td><td styleCode=" Botrule Rrule" align="center"> 340.5 </td><td styleCode=" Botrule Rrule" align="center"> 356.7 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Number of deaths (%) </td><td styleCode=" Botrule Rrule" align="center"> 34 (26) </td><td styleCode=" Botrule Rrule" align="center"> 25 (20) </td><td styleCode=" Botrule Rrule" align="center"> 19 (15) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> On treatment deaths^a (%) </td><td styleCode=" Botrule Rrule" align="center"> 22 (17) </td><td styleCode=" Botrule Rrule" align="center"> 13 (10) </td><td styleCode=" Botrule Rrule" align="center"> 15 (12) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Off treatment deaths (%) </td><td styleCode=" Botrule Rrule" align="center"> 12 (9) </td><td styleCode=" Botrule Rrule" align="center"> 12 (9) </td><td styleCode=" Botrule Rrule" align="center"> 4 (3) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hazard ratio relative to sildenafil 5 mg Hazard ratio estimate^b 99.7% CI </td><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule" align="center"> 0.68 0.31, 1.49 </td><td styleCode=" Botrule Rrule" align="center"> 0.51 0.22, 1.21 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hazard ratio relative to sildenafil 20 mg Hazard ratio estimate 99.7% CI </td><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule" align="center"> 0.74 0.30, 1.84 </td></tr><tr><td colspan="4" valign="top" align="left"> a. On treatment deaths: Any death within 7 days of last dose was regarded as &quot;On treatment&quot;, thus might include deaths occurred after discontinuation from study treatment. b. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. </td></tr></tbody></table>

deaths: Any death within 7 days of last dose was regarded as &quot;On treatment&quot;, thus might include deaths occurred after discontinuation from study treatment. b. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. </td></tr></tbody></table> <table ID="ID191" width="639" styleCode="Noautorules"><caption> Table 7.

deaths: Any death within 7 days of last dose was regarded as &quot;On treatment&quot;, thus might include deaths occurred after discontinuation from study treatment. b. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. </td></tr></tbody></table> <table ID="ID191" width="639" styleCode="Noautorules"><caption> Table 7. Hazard Ratios for Time to First Event of Clinical Worsening &#x2013; Intent to Treat Population </caption><col width="215"/><col width="142"/><col width="142"/><col width="140"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule"/><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil 5 mg</content> <content styleCode="bold"> N = 129</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil 20 mg</content> <content styleCode="bold"> N = 128</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Sildenafil 80 mg</content> <content styleCode="bold"> N = 128</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Patient-years of follow-up </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 249.6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 276.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 306.5 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Number of patients with clinical worsening </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 52 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 36 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> First Event of clinical worsening^an (%) </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Disease progression^b </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 (6) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (2) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 (5) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hospitalization for PAH^c </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 (22) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 23 (18) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11 (9) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Death^d </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 16 (12) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11 (9) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11 (9) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hazard ratio relative to sildenafil 5 mg </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hazard ratio estimate^e </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.63 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.44 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 99.7% CI </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.33, 1.21 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.22, 0.89 </td></tr><tr><td valign="top" styleCode="Lr

tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 99.7% CI </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.33, 1.21 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.22, 0.89 </td></tr><tr><td valign="top" styleCode="Lr ule Botrule Rrule" align="left"> p-value </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.035 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt; 0.001 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hazard ratio relative to sildenafil 20 mg </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hazard ratio estimate^e </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.72 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 99.7% CI </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.34, 1.52 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> p-value </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.195 </td></tr><tr><td colspan="4" valign="top" align="left"> Note: Sildenafil 5 mg is not an approved dosage.

styleCode="Lrule Botrule Rrule" align="left"> p-value </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.195 </td></tr><tr><td colspan="4" valign="top" align="left"> Note: Sildenafil 5 mg is not an approved dosage. Abbreviations: 6MWD = 6-minute walk distance; CI = confidence interval; PAH = pulmonary arterial hypertension. a. Clinical worsening events were defined as reduction from baseline in the 6MWD test by at least 15% and worsening functional class from baseline, both confirmed by a second test/evaluation within 2 weeks. b. Count of cases of disease progression as the first event of clinical worsening. c. Count of non-elective hospital stays for worsening PAH as the first event of clinical worsening. d. Count of deaths as the first event of clinical worsening. e. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. P-value from the Wald test. </td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Sildenafil for oral suspension is supplied in amber glass bottles and in HDPE bottles. Each bottle contains white to off-white granular powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g sildenafil). Following reconstitution, the volume of the oral suspension is 112 mL (10 mg sildenafil/mL). A 2 mL oral dosing syringe (with 0.5 mL and 2 mL dose markings) and a press-in bottle adaptor are also provided. Sildenafil for Oral Suspension Package Configuration Strength NDC Powder for oral suspension - Amber glass bottle 10 mg/mL (when reconstituted) 70771-1668-4 Powder for oral suspension - HDPE bottle 10 mg/mL (when reconstituted) 70771-1668-5 Recommended storage for sildenafil for oral suspension: Store below 30°C (86°F) in the original package in order to protect from moisture. Reconstituted Oral Suspension Store below 30°C (86°F) or in refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze. The shelf-life of the reconstituted oral suspension is 60 days. Any remaining oral suspension should be discarded 60 days after reconstitution.

<table ID="ID113" width="100%" styleCode="Noautorules"><col width="33%"/><col width="36%"/><col width="30%"/><tbody><tr><td colspan="3" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"> Sildenafil for Oral Suspension </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Package Configuration </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Strength </td><td valign="top" styleCode=" Botrule Rrule" align="left"> NDC </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Powder for oral suspension - Amber glass bottle </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 10 mg/mL (when reconstituted) </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 70771-1668-4 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Powder for oral suspension - HDPE bottle </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 10 mg/mL (when reconstituted) </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 70771-1668-5 </td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Inform patients of contraindication of sildenafil for oral suspension with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil for oral suspension not to take VIAGRA or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil for oral suspension. Such an event may be a sign of NAION. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil for oral suspension. These events may be accompanied by tinnitus and dizziness. Manufactured by: Zydus Lifesciences Ltd., Baddi, India. Rev.: 02/2026

PATIENT INFORMATION Sildenafil (sil den ' a fil) for oral suspension What is the most important information I should know about sildenafil for oral suspension? Never take sildenafil for oral suspension with any nitrate or guanylate cyclase stimulator medicines. • Your blood pressure could drop quickly to an unsafe level. Nitrates include: • Medicines that treat chest pain (angina) • Nitroglycerin in any form including tablets, patches, sprays, and ointments • Isosorbide mononitrate or dinitrate • Street drugs called "poppers" (amyl nitrate, butyl nitrate or nitrite) Guanylate cyclase stimulators include: • Riociguat, a medicine that treats pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Ask your healthcare provider or pharmacist if you are not sure if you or your child are taking a nitrate or a guanylate cyclase stimulator medicine. See "What are the possible side effects of sildenafil for oral suspension?" for more information about side effects. What is sildenafil for oral suspension? Sildenafil for oral suspension is a prescription medicine used to treat pulmonary arterial hypertension (PAH). PAH is a type of high blood pressure in the arteries of your lungs. Sildenafil for oral suspension may be used in: • adults to improve your ability to exercise and help slow down the worsening of your physical condition. • children 1 to 17 years old to improve their ability to exercise, and in children too young to do certain exercise and lung testing. It is not known if sildenafil for oral suspension is safe and effective in children younger than 1 year of age. Do not take sildenafil for oral suspension if you or your child: • take medicines called nitrates. • take riociguat, a guanylate cyclase stimulator medicine. • are allergic to sildenafil or any of the ingredients in sildenafil for oral suspension. See the end of this leaflet for a complete list of ingredients in sildenafil for oral suspension. Before taking sildenafil for oral suspension, tell your healthcare provider about all of your medical conditions, including if you or your child: • have low blood pressure • have heart problems • have pulmonary veno-occlusive disease (PVOD) • have bleeding problems or a stomach (peptic) ulcer. It is not known if sildenafil for oral suspension is safe in people with bleeding problems or who have a stomach ulcer • have an eye problem called retinitis pigmentosa • have ever had sudden loss of vision in one or both eyes, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION) • have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearing • have a deformed penis shape or Peyronie's disease • have any blood cell problems such as sickle cell anemia • are pregnant or plan to become pregnant. It is not known if sildenafil for oral suspension will harm your unborn baby • are breastfeeding or plan to breastfeed. Sildenafil for oral suspension passes into your breast milk. It is not known if it can harm your baby. Talk with your healthcare provider about the best way to feed your baby during treatment with sildenafil for oral suspension Tell your healthcare provider about all of the medicines you or your child take , including prescription and over- the-counter medicines, vitamins, and herbal supplements. Sildenafil for oral suspension and certain other medicines may affect each other and can cause side effects.

ent with sildenafil for oral suspension Tell your healthcare provider about all of the medicines you or your child take , including prescription and over- the-counter medicines, vitamins, and herbal supplements. Sildenafil for oral suspension and certain other medicines may affect each other and can cause side effects. Especially tell your healthcare provider if you or your child take: • nitrates or guanylate cyclase stimulators. See " What is the most important information I should know about sildenafil for oral suspension? " • medicines to treat high blood pressure • medicines for erectile dysfunction (impotence). Sildenafil for oral suspension contains sildenafil, which is the same medicine found in another medicine called VIAGRA ® . VIAGRA is used for the treatment of erectile dysfunction. Do not take VIAGRA or other PDE-5 inhibitors during treatment with sildenafil for oral suspension. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you or your child take. Keep a list of your or your child's medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take sildenafil for oral suspension? • Take or give sildenafil for oral suspension exactly as your healthcare provider tells you. • Your healthcare provider may change your or your child's dose of sildenafil for oral suspension as needed. Do not change your dose or stop taking sildenafil for oral suspension without talking to your healthcare provider. • Sildenafil for oral suspension may be prescribed to you as sildenafil tablets or sildenafil for oral suspension. • Take your prescribed dose of sildenafil tablets or oral suspension 3 times a day. • See the detailed Instructions for Use that comes with sildenafil for oral suspension for information on how to take or give sildenafil for oral suspension. Sildenafil for oral suspension will be mixed for you by your pharmacist. Do not mix sildenafil for oral suspension with other medicine or flavoring. • If you or your child take too much sildenafil for oral suspension, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of sildenafil for oral suspension? Sildenafil for oral suspension may cause serious side effects, including: • See "What is the most important information I should know about sildenafil for oral suspension?" • Decreased blood pressure. sildenafil for oral suspension may cause low blood pressure that last for a short time. If you take medicines to treat high blood pressure, your healthcare provider should monitor your blood pressure during treatment with sildenafil for oral suspension. • Decreased eyesight or permanent loss of vision in one or both eyes can be a sign of non-arteritic anterior ischemic optic neuropathy (NAION). Most people who develop NAION have certain risk factors. You can ask your healthcare provider if you have questions about risk factors for NAION. If you notice a sudden decrease or loss of vision in one or both eyes during treatment with sildenafil for oral suspension, contact your healthcare provider right away. • Sudden decrease or loss of hearing , sometimes with ringing in the ears and dizziness . If you notice a sudden decrease or loss of hearing during treatment with sildenafil for oral suspension, contact your healthcare provider right away. • In men, an erection that lasts for more than 4 hours (priapism). If you have an erection, with or without pain, that lasts more than 4 hours, contact your healthcare provider or get emergency medical help right away. A painful erection that lasts more than 6 hours must be treated right away or you can have lasting damage to your penis, including the inability to have erections.

sm). If you have an erection, with or without pain, that lasts more than 4 hours, contact your healthcare provider or get emergency medical help right away. A painful erection that lasts more than 6 hours must be treated right away or you can have lasting damage to your penis, including the inability to have erections. The most common side effects of sildenafil for oral suspension in adults include: • Nosebleeds • headache • upset stomach • getting red or hot in the face (flushing) • arm or leg pain • muscle aches and pain • back pain • diarrhea The most common side effect of sildenafil for oral suspension in children is an erection that lasts for more than 4 hours (priapism). These are not all the possible side effects of sildenafil for oral suspension. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store sildenafil for oral suspension? • Store mixed (reconstituted) sildenafil for oral suspension below 30°C (86°F) or in a refrigerator between 2°C to 8°C (36°F to 46°F). • Do not freeze sildenafil for oral suspension. • Throw away (discard) any remaining sildenafil for oral suspension 60 days after mixed by the pharmacist. See the "Discard after" date written on the bottle label. Keep sildenafil for oral suspension and all drugs out of the reach of children. General information about the safe and effective use of sildenafil for oral suspension Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use sildenafil for oral suspension for a condition for which it was not prescribed. Do not give sildenafil for oral suspension to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about sildenafil for oral suspension that is written for health professionals. What are the ingredients in sildenafil for oral suspension? Active ingredients: sildenafil citrate Inactive ingredients: sorbitol, citric acid anhydrous, sucralose, tri-sodium citrate dihydrate, xanthan gum, titanium dioxide, sodium benzoate, colloidal silicon dioxide, carbomer homopolymer and grape flavor. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured by: Zydus Lifesciences Ltd ., Baddi, India. Rev.: 02/2026

Instructions for Use Sildenafil (sil den ' a fil) for oral suspension Read this Instructions for Use before you start taking sildenafil for oral suspension or giving sildenafil oral suspension to your child and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child's medical condition or treatment. Important information: • Ask your healthcare provider or pharmacist to show you how to measure and take or give your child's prescribed dose of sildenafil for oral suspension. • Your pharmacist will mix (reconstitute) sildenafil for oral suspension before it is given to you. Do not take or give sildenafil for oral suspension and contact your pharmacist if the medicine in the bottle is still a powder. • Always use the oral dosing syringe that comes with sildenafil for oral suspension. If your carton does not come with an oral dosing syringe, contact your pharmacist. • Do not take or give sildenafil for oral suspension if the bottle adaptor is not in the bottle. If the bottle adaptor is not in the bottle, contact your pharmacist. • Sildenafil for oral suspension should not be mixed with any other medicine or flavoring. Supplies you will need to take or give a dose of sildenafil for oral suspension (See Figure A): • 1 bottle of sildenafil for oral suspension with pre-inserted bottle adaptor • 1 oral dosing syringe (provided in the carton) Step 1. Shake the bottle of sildenafil for oral suspension for 10 seconds before each use. (See Figure B) Step 2. Remove the cap. Open the bottle by pushing down on the cap and twisting it in the direction of the arrow (counter-clockwise). (See Figure C) Step 3. Fully push down (depress) the plunger of the oral dosing syringe. Then insert the tip of the oral dosing syringe into the bottle adaptor while holding the bottle upright, on a flat surface. (See Figure D) Step 4. Turn the bottle upside down while holding the oral dosing syringe in place. Slowly pull back the plunger of the oral dosing syringe until the bottom of the plunger is even with the mL marking on the syringe for your or your child's prescribed dose. (See Figure E) If your or your child's dose of sildenafil for oral suspension is more than 2 mL (20 mg), you will need to divide the dose. Follow the instructions given to you by your healthcare provider or pharmacist about how to prepare the divided dose. If you see air bubbles in the oral dosing syringe, slowly push the plunger all the way up so that sildenafil for oral suspension flows back into the bottle and repeat Step 4. Step 5. Turn the bottle back upright with the oral dosing syringe still in place. Place the bottle on a flat surface. Remove the oral dosing syringe from the bottle adaptor by pulling straight up on the barrel of the oral dosing syringe. (See Figure F) Do not press on the plunger of the oral dosing syringe at this time. Step 6. Put the tip of the oral dosing syringe into your or your child's mouth and point it towards the inside of the cheek. Slowly push the plunger of the oral dosing syringe all the way down to give the entire dose. Do not squirt the medicine out quickly. (See Figure G) If you are giving sildenafil for oral suspension to a child, make sure they are in an upright position before giving the medicine. Step 7. Replace the cap on the bottle, leaving the bottle adaptor in place. Turn the cap in the direction of the arrow (clockwise) to close the bottle.

medicine out quickly. (See Figure G) If you are giving sildenafil for oral suspension to a child, make sure they are in an upright position before giving the medicine. Step 7. Replace the cap on the bottle, leaving the bottle adaptor in place. Turn the cap in the direction of the arrow (clockwise) to close the bottle. (See Figure H) Step 8. Wash the oral dosing syringe after each use. Pull the plunger out of the barrel and rinse both parts with water. (See Figure I) Step 9. Dry all parts with a clean paper towel. Push the plunger back into the barrel. Store the oral dosing syringe with the sildenafil for oral suspension bottle. How should I store sildenafil for oral suspension? • Store mixed (reconstituted) sildenafil for oral suspension below 30°C (86°F) or in a refrigerator between 2°C to 8°C (36°F to 46°F). • Do not freeze mixed sildenafil for oral suspension • Throw away (discard) any remaining sildenafil for oral suspension 60 days after mixed by the pharmacist. See the "Discard after" date written on the bottle label. Keep sildenafil for oral suspension and all drugs out of the reach of children. This Instruction for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Zydus Lifesciences Ltd., Baddi, India. Rev.: 02/2026 Image Image image Image Image Image image f f

<table width="100%"><col width="80%"/><col width="20%"/><tbody><tr><td styleCode="Botrule Toprule " valign="top"><paragraph>Warnings and Precautions, Effects on the Eye (<linkHtml href="#S5.3">5.3</linkHtml>)</paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph>08/2017</paragraph></td></tr></tbody></table>

2 DOSAGE AND ADMINISTRATION • For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, VIAGRA may be taken anywhere from 30 minutes to 4 hours before sexual activity ( 2.1 ) • Based on effectiveness and toleration, may increase to a maximum of 100 mg or decrease to 25 mg ( 2.1 ) • Maximum recommended dosing frequency is once per day ( 2.1 ) 2.1 Dosage Information For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, VIAGRA may be taken anywhere from 30 minutes to 4 hours before sexual activity. The maximum recommended dosing frequency is once per day. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. 2.2 Use with Food VIAGRA may be taken with or without food. 2.3 Dosage Adjustments in Specific Situations VIAGRA was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors such as organic nitrates or organic nitrites in any form is therefore contraindicated [ see Contraindications (4.1) , Drug Interactions (7.1) , and Clinical Pharmacology (12.2) ] . When VIAGRA is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at 25 mg [ see Warnings and Precautions (5.5) , Drug Interactions (7.2) , and Clinical Pharmacology (12.2) ]. 2.4 Dosage Adjustments Due to Drug Interactions Ritonavir The recommended dose for ritonavir-treated patients is 25 mg prior to sexual activity and the recommended maximum dose is 25 mg within a 48 hour period because concomitant administration increased the blood levels of sildenafil by 11-fold [ see Warnings and Precautions (5.6) , Drug Interactions (7.4) , and Clinical Pharmacology (12.3) ]. CYP3A4 Inhibitors Consider a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin. Clinical data have shown that co-administration with saquinavir or erythromycin increased plasma levels of sildenafil by about 3 fold [ see Drug Interactions (7.4) and Clinical Pharmacology (12.3) ]. 2.5 Dosage Adjustments in Special Populations Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e.g., cirrhosis), and patients with severe renal impairment (creatinine clearance <30 mL/minute) because administration of VIAGRA in these patients resulted in higher plasma levels of sildenafil [ see Use in Specific Populations (8.5 , 8.6 , 8.7) and Clinical Pharmacology (12.3) ] .

3 DOSAGE FORMS AND STRENGTHS VIAGRA is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to 25 mg, 50 mg, or 100 mg of sildenafil. Tablets are debossed with PFIZER on one side and VGR25, VGR50 or VGR100 on the other to indicate the dosage strengths. Tablets: 25 mg, 50 mg, 100 mg ( 3 )

4 CONTRAINDICATIONS • Administration of VIAGRA to patients using nitric oxide donors, such as organic nitrates or organic nitrites in any form. VIAGRA was shown to potentiate the hypotensive effect of nitrates ( 4.1 , 7.1 , 12.2 ) • Known hypersensitivity to sildenafil or any component of tablet ( 4.2 ) • Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 4.3 ) 4.1 Nitrates Consistent with its known effects on the nitric oxide/cGMP pathway [ see Clinical Pharmacology (12.1 , 12.2) ], VIAGRA was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using nitric oxide donors such as organic nitrates or organic nitrites in any form either regularly and/or intermittently is therefore contraindicated. After patients have taken VIAGRA, it is unknown when nitrates, if necessary, can be safely administered. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Dosage and Administration (2.3) , Drug Interactions (7.1) , and Clinical Pharmacology (12.2) ]. 4.2 Hypersensitivity Reactions VIAGRA is contraindicated in patients with a known hypersensitivity to sildenafil, as contained in VIAGRA and REVATIO, or any component of the tablet. Hypersensitivity reactions have been reported, including rash and urticaria [ see Adverse Reactions (6.1) ] . 4.3 Concomitant Guanylate Cyclase (GC) Stimulators Do not use VIAGRA in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including VIAGRA, may potentiate the hypotensive effects of GC stimulators.

5 WARNINGS AND PRECAUTIONS • Patients should not use VIAGRA if sexual activity is inadvisable due to cardiovascular status ( 5.1 ) • Patients should seek emergency treatment if an erection lasts >4 hours. Use VIAGRA with caution in patients predisposed to priapism ( 5.2 ) • Patients should stop VIAGRA and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of non arteritic anterior ischemic optic neuropathy (NAION). VIAGRA should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a "crowded" optic disc may also be at an increased risk of NAION. ( 5.3 ) • Patients should stop VIAGRA and seek prompt medical attention in the event of sudden decrease or loss of hearing ( 5.4 ) • Caution is advised when VIAGRA is co-administered with alpha-blockers or anti-hypertensives. Concomitant use may lead to hypotension ( 5.5 ) • Decreased blood pressure, syncope, and prolonged erection may occur at higher sildenafil exposures. In patients taking strong CYP inhibitors, such as ritonavir, sildenafil exposure is increased. Decrease in VIAGRA dosage is recommended ( 2.4 , 5.6 ) 5.1 Cardiovascular There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including VIAGRA, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment. VIAGRA 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 VIAGRA, 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 VIAGRA – 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 VIAGRA 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. 5.2 Prolonged Erection and Priapism Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result. VIAGRA 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 VIAGRA in patients with sickle cell or related anemias. 5.3 Effects on the Eye Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of 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 association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males aged ≥ 50. An observational case-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. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). 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 the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [ see Adverse Reactions (6.2) ]. Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including VIAGRA, 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 VIAGRA, for this uncommon condition. There are no controlled clinical data on the safety or efficacy of VIAGRA in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); if prescribed, this should be done with caution. 5.4 Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including VIAGRA, 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 VIAGRA. 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) ]. 5.5 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives Alpha-blockers Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers.

e 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) ]. 5.5 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives Alpha-blockers Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including VIAGRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may occur. 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 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. Anti-hypertensives VIAGRA has 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 VIAGRA, 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) ]. 5.6 Adverse Reactions with the Concomitant Use of Ritonavir The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC). If VIAGRA is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of sildenafil are limited. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200–800 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) ]. 5.7 Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies The safety and efficacy of combinations of VIAGRA 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. Such combinations may further lower blood pressure. Therefore, the use of such combinations is not recommended. 5.8 Effects on Bleeding There have been postmarketing reports of bleeding events in patients who have taken VIAGRA. A causal relationship between VIAGRA and these events has not been established. In humans, VIAGRA has no effect on bleeding time when taken alone or with aspirin. However, in vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor).

causal relationship between VIAGRA and these events has not been established. In humans, VIAGRA has no effect on bleeding time when taken alone or with aspirin. However, in vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). In addition, the combination of heparin and VIAGRA had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans. The safety of VIAGRA is unknown in patients with bleeding disorders and patients with active peptic ulceration. 5.9 Counseling Patients About Sexually Transmitted Diseases The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.

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. Most common adverse reactions (≥ 2%) include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness and rash ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 clinical practice. VIAGRA was 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 VIAGRA (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. Table 1: Adverse Reactions Reported by ≥2% of Patients Treated with VIAGRA and More Frequent than Placebo in Fixed-Dose Phase II/III Studies Adverse Reaction 25 mg (n=312) 50 mg (n=511) 100 mg (n=506) Placebo (n=607) Headache 16% 21% 28% 7% Flushing 10% 19% 18% 2% Dyspepsia 3% 9% 17% 2% Abnormal vision Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision. 1% 2% 11% 1% Nasal congestion 4% 4% 9% 2% Back pain 3% 4% 4% 2% Myalgia 2% 2% 4% 1% Nausea 2% 3% 3% 1% Dizziness 3% 4% 3% 2% Rash 1% 2% 3% 1% When VIAGRA was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took VIAGRA at least once weekly, and the following adverse reactions were reported: Table 2.

2% 4% 1% Nausea 2% 3% 3% 1% Dizziness 3% 4% 3% 2% Rash 1% 2% 3% 1% When VIAGRA was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took VIAGRA at least once weekly, and the following adverse reactions were reported: Table 2. Adverse Reactions Reported by ≥2% of Patients Treated with VIAGRA and More Frequent than Placebo in Flexible-Dose Phase II/III Studies Adverse Reaction VIAGRA PLACEBO N=734 N=725 Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal Congestion 4% 2% Abnormal Vision 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. 3% 0% Back pain 2% 2% Dizziness 2% 1% Rash 2% 1% The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to VIAGRA 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. Cardiovascular: angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy. Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis. Hemic and Lymphatic: anemia and leukopenia. Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia. Musculoskeletal : arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis. Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia. Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased. Skin and Appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis. Special Senses: sudden decrease or loss of hearing, mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, ear pain, eye hemorrhage, cataract, dry eyes. Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia. Analysis of the safety database from controlled clinical trials showed no apparent difference in adverse reactions in patients taking VIAGRA with and without anti-hypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of VIAGRA. 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.

om 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 cerebrovascular Serious 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 VIAGRA. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of VIAGRA without sexual activity. Others were reported to have occurred hours to days after the use of VIAGRA and sexual activity. It is not possible to determine whether these events are related directly to VIAGRA, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors [ see Warnings and Precautions (5.1) and Patient Counseling Information (17) ]. Hemic and Lymphatic: vaso-occlusive crisis: In a small, prematurely terminated study of REVATIO (sildenafil) in patients with pulmonary arterial hypertension (PAH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported in patients who received sildenafil than in those randomized to placebo. The clinical relevance of this finding to men treated with VIAGRA for ED is not known. Nervous: seizure, seizure recurrence, anxiety, and transient global amnesia. Respiratory: epistaxis Special senses: Hearing: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including VIAGRA. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of VIAGRA, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors [ see Warnings and Precautions (5.4) and Patient Counseling Information (17) ]. Ocular : diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal edema, retinal vascular disease or bleeding, and vitreous traction/detachment. Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including VIAGRA. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking [ see Warnings and Precautions (5.3) and Patient Counseling Information (17) ]. Urogenital: prolonged erection, priapism [ see Warnings and Precautions (5.2) and Patient Counseling Information (17) ], and hematuria.

<table ID="_RefID0ERFAG" width="75%"><caption>Table 1: Adverse Reactions Reported by &#x2265;2% of Patients Treated with VIAGRA and More Frequent than Placebo in Fixed-Dose Phase II/III Studies</caption><col width="18%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><thead><tr><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Adverse Reaction</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">25 mg</content> <content styleCode="bold">(n=312)</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">50 mg</content> <content styleCode="bold">(n=511)</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">100 mg</content> <content styleCode="bold">(n=506)</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">(n=607)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Headache</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>16%</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>21%</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>28%</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Flushing</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>10%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>19%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>18%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspepsia</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>9%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>17%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abnormal vision<footnote ID="_Reffoot11">Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision.</footnote></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>11%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nasal congestion</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>9%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Back pain</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><

><paragraph>9%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Back pain</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top">< paragraph>4%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Myalgia</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Rash</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr></tbody></table>

td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr></tbody></table> <table ID="_RefID0E4KAG" width="60%"><caption>Table 2. Adverse Reactions Reported by &#x2265;2% of Patients Treated with VIAGRA and More Frequent than Placebo in Flexible-Dose Phase II/III Studies</caption><col width="32%"/><col width="18%"/><col width="19%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Adverse Reaction</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">VIAGRA</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">PLACEBO</content></th></tr><tr><th align="left" styleCode="Rrule Lrule Botrule " valign="top"/><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">N=734</content></th><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">N=725</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Headache</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>16%</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Flushing</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>10%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspepsia</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>7%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nasal Congestion</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abnormal Vision<footnote ID="_Reffoot21">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.</footnote></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>0%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Back pain</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Rash</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS • VIAGRA can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives ( 4.1 , 5.5 , 7.1 , 7.2 , 7.3 , 12.2 ) • With concomitant use of alpha blockers, initiate VIAGRA at 25 mg dose ( 2.3 ) • CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin): Increase VIAGRA exposure ( 2.4 , 7.4 , 12.3 ) • Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period ( 2.4 , 5.6 ) • Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg ( 2.4 , 7.4 ) 7.1 Nitrates Administration of VIAGRA with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, VIAGRA was shown to potentiate the hypotensive effects of nitrates [ see Dosage and Administration (2.3) , Contraindications (4.1) , Clinical Pharmacology (12.2) ] . 7.2 Alpha-blockers Use caution when co-administering alpha-blockers with VIAGRA because of potential additive blood pressure-lowering effects. When VIAGRA is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose [ see Dosage and Administration (2.3) , Warnings and Precautions (5.5) , Clinical Pharmacology (12.2) ] . 7.3 Amlodipine When VIAGRA 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic [ see Warnings and Precautions (5.5) , Clinical Pharmacology (12.2) ]. 7.4 Ritonavir and other CYP3A4 inhibitors Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC). It is therefore recommended not to exceed a maximum single dose of 25 mg of VIAGRA in a 48 hour period [ see Dosage and Administration (2.4) , Warnings and Precautions (5.6) , Clinical Pharmacology (12.3) ]. Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil C max and AUC, respectively. Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil C max and AUC, respectively. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. A starting dose of 25 mg of VIAGRA should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole) [ see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] . 7.5 Alcohol In a drug-drug interaction study sildenafil 50 mg given with alcohol 0.5 g/kg in which mean maximum blood alcohol levels of 0.08% was achieved, sildenafil did not potentiate the hypotensive effect of alcohol in healthy volunteers [ see Clinical Pharmacology (12.2) ].

8 USE IN SPECIFIC POPULATIONS • Geriatric use: Consider a starting dose of 25 mg ( 2.5 , 8.5 ) • Severe renal impairment: Consider a starting dose of 25 mg ( 2.5 , 8.6 ) • Hepatic impairment: Consider a starting dose of 25 mg ( 2.5 , 8.7 ) 8.1 Pregnancy Risk Summary VIAGRA is not indicated for use in females. There are no data with the use of VIAGRA in pregnant women to inform any drug-associated risks for adverse developmental outcomes. Animal reproduction studies conducted with sildenafil did not show adverse developmental outcomes when administered during organogenesis in rats and rabbits at oral doses up to 16 and 32 times, respectively, the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m 2 basis ( see Error! Hyperlink reference not valid. ). Data Animal Data No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received oral doses up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 16 and 32 times the MRHD on a mg/m 2 basis in a 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days, about 2 times the MRHD on a mg/m 2 basis in a 50 kg subject. 8.2 Lactation Risk Summary VIAGRA is not indicated for use in females. Limited data indicate that sildenafil and its active metabolite are present in human milk. There is no information on the effects on the breastfed child, or the effects on milk production. 8.4 Pediatric Use VIAGRA is not indicated for use in pediatric patients. Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18–45 years) [ see Clinical Pharmacology (12.3) ]. Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [ see Clinical Pharmacology (12.3) ]. Of the total number of subjects in clinical studies of Viagra, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older (≥ 65 years of age) and younger (< 65 years of age) subjects. However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure [ see Dosage and Administration (2.5) ]. 8.6 Renal Impairment No dose adjustment is required for mild (CLcr=50–80 mL/min) and moderate (CLcr=30–49 mL/min) renal impairment. In volunteers with severe renal impairment (Clcr<30 mL/min), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (~2 fold), approximately doubling of C max and AUC. A starting dose of 25 mg should be considered in patients with severe renal impairment [ see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C max and 85% for AUC).

n patients with severe renal impairment [ see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C max and 85% for AUC). The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied. A starting dose of 25 mg should be considered in patients with any degree of hepatic impairment [ see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary VIAGRA is not indicated for use in females. There are no data with the use of VIAGRA in pregnant women to inform any drug-associated risks for adverse developmental outcomes. Animal reproduction studies conducted with sildenafil did not show adverse developmental outcomes when administered during organogenesis in rats and rabbits at oral doses up to 16 and 32 times, respectively, the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m 2 basis ( see Error! Hyperlink reference not valid. ). Data Animal Data No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received oral doses up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 16 and 32 times the MRHD on a mg/m 2 basis in a 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days, about 2 times the MRHD on a mg/m 2 basis in a 50 kg subject.

8.5 Geriatric Use Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18–45 years) [ see Clinical Pharmacology (12.3) ]. Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [ see Clinical Pharmacology (12.3) ]. Of the total number of subjects in clinical studies of Viagra, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older (≥ 65 years of age) and younger (< 65 years of age) subjects. However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure [ see Dosage and Administration (2.5) ].

10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

11 DESCRIPTION VIAGRA (sildenafil citrate), an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H -pyrazolo[4,3- d ]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate 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. VIAGRA is formulated as blue, film-coated rounded-diamond-shaped tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. Binding Characteristics Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [ see Clinical Pharmacology (12.2) ]. In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro , an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo . 12.2 Pharmacodynamics Effects of VIAGRA on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan ® ), after VIAGRA administration compared with placebo. Most studies assessed the efficacy of VIAGRA approximately 60 minutes post dose. The erectile response, as assessed by RigiScan ® , generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Effects of VIAGRA on Blood Pressure: Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1–2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA, therefore the effects are not related to dose or plasma levels within this dosage range.

mHg). The decrease in sitting blood pressure was most notable approximately 1–2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA, 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 (4.1) ]. Figure 1: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers. Figure 1 Effects of VIAGRA on Blood Pressure When Nitroglycerin is Subsequently Administered: Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Contraindications (4.1) ]. Effects of VIAGRA on Blood Pressure When Co-administered with Alpha-Blockers: Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of VIAGRA with doxazosin, an alpha-adrenergic blocking agent. Study 1: VIAGRA with Doxazosin In the first study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the VIAGRA dose was reduced to 25 mg. Thereafter, 17 subjects were treated with VIAGRA 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). The mean subject age was 66.5 years. For the 17 subjects who received VIAGRA 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg Supine 7.4 (-0.9 , 15.7) Standing 6.0 (-0.8, 12.8) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg VIAGRA or matching placebo are shown in Figure 2. Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after VIAGRA or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of <85 mmHg or a decrease from baseline in standing systolic blood pressure of >30 mmHg at one or more timepoints. There were no subjects treated with VIAGRA 25 mg who had a standing SBP < 85mmHg. There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following VIAGRA 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.

GRA 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group. Of the four subjects who received VIAGRA 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with VIAGRA with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). There were no reports of syncope among these patients. For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively. Two of these subjects had a standing SBP < 85mmHg. Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension. Figure 2 Study 2: VIAGRA with Doxazosin In the second study, a single oral dose of VIAGRA 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, VIAGRA 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63.9 years. Twenty subjects received VIAGRA 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with VIAGRA 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study. For the 19 subjects who received both VIAGRA and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI) Supine 9.08 (5.48, 12.68) Standing 11.62 (7.34, 15.90) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg VIAGRA or matching placebo are shown in Figure 3. Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of VIAGRA at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of < 85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of VIAGRA 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP >30mmHg following VIAGRA 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study. Figure 3 Study 3: VIAGRA with Doxazosin In the third study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study.

ver design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study (using VIAGRA 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66.4 years. Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label VIAGRA 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using VIAGRA 50 mg). For the 20 subjects who received VIAGRA 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg Supine 7.9 (4.6, 11.1) Standing 4.3 (-1.8,10.3) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg VIAGRA or matching placebo are shown in Figure 4. Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of VIAGRA at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of < 85 mmHg. All three were taking VIAGRA 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following VIAGRA 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both VIAGRA 50 mg and 100 mg. There were no episodes of syncope reported in this study. Figure 4 Effect of VIAGRA on Blood Pressure When Co-administered with Anti-hypertensives: When VIAGRA 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. Effect of VIAGRA on Blood Pressure When Co-administered with Alcohol: VIAGRA (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%. The maximum observed decrease in systolic blood pressure was -18.5 mmHg when sildenafil was co-administered with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum observed decrease in diastolic blood pressure was -17.2 mmHg when sildenafil was co-administered with alcohol versus -11.1 mmHg when alcohol was administered alone. There were no reports of postural dizziness or orthostatic hypotension.

red with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum observed decrease in diastolic blood pressure was -17.2 mmHg when sildenafil was co-administered with alcohol versus -11.1 mmHg when alcohol was administered alone. There were no reports of postural dizziness or orthostatic hypotension. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [ see Drug Interactions (7.5) ]. Effects of VIAGRA on Cardiac Parameters: Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of VIAGRA on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. A total dose of 40 mg sildenafil was administered by four intravenous infusions. The results from this pilot study are shown in Table 3; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients. Mean resting values for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressure and cardiac output decreased by 28%, 28%, 20% and 7% respectively. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients. Table 3. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil Means ± SD At rest After 4 minutes of exercise N Baseline (B2) n Sildenafil (D1) n Baseline n Sildenafil PAOP (mmHg) 8 8.1 ± 5.1 8 6.5 ± 4.3 8 36.0 ± 13.7 8 27.8 ± 15.3 Mean PAP (mmHg) 8 16.7 ± 4 8 12.1 ± 3.9 8 39.4 ± 12.9 8 31.7 ± 13.2 Mean RAP (mmHg) 7 5.7 ± 3.7 8 4.1 ± 3.7 - - - - Systolic SAP (mmHg) 8 150.4 ± 12.4 8 140.6 ± 16.5 8 199.5 ± 37.4 8 187.8 ± 30.0 Diastolic SAP (mmHg) 8 73.6 ± 7.8 8 65.9 ± 10 8 84.6 ± 9.7 8 79.5 ± 9.4 Cardiac output (L/min) 8 5.6 ± 0.9 8 5.2 ± 1.1 8 11.5 ± 2.4 8 10.2 ± 3.5 Heart rate (bpm) 8 67 ± 11.1 8 66.9 ± 12 8 101.9 ± 11.6 8 99.0 ± 20.4 In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or VIAGRA 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (N=70) and placebo, respectively. These results demonstrated that the effect of VIAGRA on the primary endpoint was statistically non-inferior to placebo. Effects of VIAGRA on Vision: At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. Subjects in the study reported this finding as difficulties in discriminating blue/green. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry. Effects of VIAGRA on Sperm : There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRA in healthy volunteers. 12.3 Pharmacokinetics VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25–63%).

intraocular pressure, or pupillometry. Effects of VIAGRA on Sperm : There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRA in healthy volunteers. 12.3 Pharmacokinetics VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25–63%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 hours. Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below: Figure 5: Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers. Absorption and Distribution: VIAGRA is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When VIAGRA is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients. Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach. Pharmacokinetics in Special Populations Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18–45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [ see Dosage and Administration (2.5) , and Use in Specific Populations (8.5) ] Renal Impairment: In volunteers with mild (CLcr=50–80 mL/min) and moderate (CLcr=30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment [ see Dosage and Administration (2.5) , and Use in Specific Populations (8.6) ].

AGRA (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment [ see Dosage and Administration (2.5) , and Use in Specific Populations (8.6) ]. In addition, N-desmethyl metabolite AUC and C max values significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment: In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [ see Dosage and Administration (2.5) , and Use in Specific Populations (8.7) ]. Therefore, age >65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. A starting oral dose of 25 mg should be considered in those patients [ see Dosage and Administration (2.5) ] . Drug Interaction Studies Effects of Other Drugs on VIAGRA Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. The concomitant use of erythromycin or strong CYP3A4 inhibitors (e.g., saquinavir, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil [ see Dosage and Administration (2.4) ]. In vivo studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with VIAGRA (50 mg) to healthy volunteers. When a single 100 mg dose of VIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C max and a 182% increase in sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Viagra (100 mg single dose) resulted in a 140% increase in sildenafil C max and a 210% increase in sildenafil AUC. Viagra had no effect on saquinavir pharmacokinetics. A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect than that seen with saquinavir. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [ see Dosage and Administration (2.4) and Drug Interactions (7.4) ]. In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with VIAGRA (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C max and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. VIAGRA had no effect on ritonavir pharmacokinetics [ see Dosage and Administration (2.4) and Drug Interactions (7.4) ]. Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels.

ts on a broad range of P450 substrates. VIAGRA had no effect on ritonavir pharmacokinetics [ see Dosage and Administration (2.4) and Drug Interactions (7.4) ]. Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels. In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil C max . Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of VIAGRA. In healthy male volunteers, there was no evidence of a clinically significant effect of azithromycin (500 mg daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite. Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence. Effects of VIAGRA on Other Drugs In vitro studies: Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µM). Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that VIAGRA will alter the clearance of substrates of these isoenzymes. In vivo studies: No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates. VIAGRA (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg). Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in C max of bosentan (125 mg b.i.d.). Figure 5

12.1 Mechanism of Action The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. Binding Characteristics Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [ see Clinical Pharmacology (12.2) ]. In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro , an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo .

12.2 Pharmacodynamics Effects of VIAGRA on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan ® ), after VIAGRA administration compared with placebo. Most studies assessed the efficacy of VIAGRA approximately 60 minutes post dose. The erectile response, as assessed by RigiScan ® , generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Effects of VIAGRA on Blood Pressure: Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1–2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA, 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 (4.1) ]. Figure 1: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers. Figure 1 Effects of VIAGRA on Blood Pressure When Nitroglycerin is Subsequently Administered: Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Contraindications (4.1) ]. Effects of VIAGRA on Blood Pressure When Co-administered with Alpha-Blockers: Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of VIAGRA with doxazosin, an alpha-adrenergic blocking agent. Study 1: VIAGRA with Doxazosin In the first study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the VIAGRA dose was reduced to 25 mg. Thereafter, 17 subjects were treated with VIAGRA 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). The mean subject age was 66.5 years.

sin. Following a review of the data from these first 4 subjects (details provided below), the VIAGRA dose was reduced to 25 mg. Thereafter, 17 subjects were treated with VIAGRA 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). The mean subject age was 66.5 years. For the 17 subjects who received VIAGRA 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 25 mg Supine 7.4 (-0.9 , 15.7) Standing 6.0 (-0.8, 12.8) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg VIAGRA or matching placebo are shown in Figure 2. Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after VIAGRA or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of <85 mmHg or a decrease from baseline in standing systolic blood pressure of >30 mmHg at one or more timepoints. There were no subjects treated with VIAGRA 25 mg who had a standing SBP < 85mmHg. There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following VIAGRA 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group. Of the four subjects who received VIAGRA 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with VIAGRA with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). There were no reports of syncope among these patients. For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively. Two of these subjects had a standing SBP < 85mmHg. Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension. Figure 2 Study 2: VIAGRA with Doxazosin In the second study, a single oral dose of VIAGRA 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, VIAGRA 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63.9 years. Twenty subjects received VIAGRA 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with VIAGRA 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study.

e in this study was 63.9 years. Twenty subjects received VIAGRA 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with VIAGRA 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study. For the 19 subjects who received both VIAGRA and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI) Supine 9.08 (5.48, 12.68) Standing 11.62 (7.34, 15.90) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg VIAGRA or matching placebo are shown in Figure 3. Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of VIAGRA at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of < 85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of VIAGRA 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP >30mmHg following VIAGRA 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study. Figure 3 Study 3: VIAGRA with Doxazosin In the third study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study (using VIAGRA 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66.4 years. Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label VIAGRA 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using VIAGRA 50 mg). For the 20 subjects who received VIAGRA 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg Supine 7.9 (4.6, 11.1) Standing 4.3 (-1.8,10.3) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg VIAGRA or matching placebo are shown in Figure 4.

tracted mean maximum decrease in systolic blood pressure (mm Hg) VIAGRA 100 mg Supine 7.9 (4.6, 11.1) Standing 4.3 (-1.8,10.3) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg VIAGRA or matching placebo are shown in Figure 4. Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of VIAGRA at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of < 85 mmHg. All three were taking VIAGRA 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following VIAGRA 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both VIAGRA 50 mg and 100 mg. There were no episodes of syncope reported in this study. Figure 4 Effect of VIAGRA on Blood Pressure When Co-administered with Anti-hypertensives: When VIAGRA 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. Effect of VIAGRA on Blood Pressure When Co-administered with Alcohol: VIAGRA (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%. The maximum observed decrease in systolic blood pressure was -18.5 mmHg when sildenafil was co-administered with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum observed decrease in diastolic blood pressure was -17.2 mmHg when sildenafil was co-administered with alcohol versus -11.1 mmHg when alcohol was administered alone. There were no reports of postural dizziness or orthostatic hypotension. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [ see Drug Interactions (7.5) ]. Effects of VIAGRA on Cardiac Parameters: Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of VIAGRA on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. A total dose of 40 mg sildenafil was administered by four intravenous infusions. The results from this pilot study are shown in Table 3; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients. Mean resting values for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressure and cardiac output decreased by 28%, 28%, 20% and 7% respectively. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients. Table 3.

respectively. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients. Table 3. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil Means ± SD At rest After 4 minutes of exercise N Baseline (B2) n Sildenafil (D1) n Baseline n Sildenafil PAOP (mmHg) 8 8.1 ± 5.1 8 6.5 ± 4.3 8 36.0 ± 13.7 8 27.8 ± 15.3 Mean PAP (mmHg) 8 16.7 ± 4 8 12.1 ± 3.9 8 39.4 ± 12.9 8 31.7 ± 13.2 Mean RAP (mmHg) 7 5.7 ± 3.7 8 4.1 ± 3.7 - - - - Systolic SAP (mmHg) 8 150.4 ± 12.4 8 140.6 ± 16.5 8 199.5 ± 37.4 8 187.8 ± 30.0 Diastolic SAP (mmHg) 8 73.6 ± 7.8 8 65.9 ± 10 8 84.6 ± 9.7 8 79.5 ± 9.4 Cardiac output (L/min) 8 5.6 ± 0.9 8 5.2 ± 1.1 8 11.5 ± 2.4 8 10.2 ± 3.5 Heart rate (bpm) 8 67 ± 11.1 8 66.9 ± 12 8 101.9 ± 11.6 8 99.0 ± 20.4 In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or VIAGRA 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (N=70) and placebo, respectively. These results demonstrated that the effect of VIAGRA on the primary endpoint was statistically non-inferior to placebo. Effects of VIAGRA on Vision: At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. Subjects in the study reported this finding as difficulties in discriminating blue/green. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry. Effects of VIAGRA on Sperm : There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRA in healthy volunteers.

<table width="50%"><col width="31%"/><col width="26%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">VIAGRA 25 mg</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Supine</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>7.4 (-0.9<content styleCode="italics">,</content> 15.7)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Standing</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>6.0 (-0.8, 12.8)</paragraph></td></tr></tbody></table> <table width="50%"><col width="31%"/><col width="26%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">VIAGRA 50 mg (95% CI)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Supine</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>9.08 (5.48, 12.68)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Standing</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>11.62 (7.34, 15.90)</paragraph></td></tr></tbody></table>

paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>9.08 (5.48, 12.68)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Standing</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>11.62 (7.34, 15.90)</paragraph></td></tr></tbody></table> <table width="50%"><col width="31%"/><col width="26%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">VIAGRA 100 mg</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Supine</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>7.9 (4.6, 11.1)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Standing</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4.3 (-1.8,10.3)</paragraph></td></tr></tbody></table> <table ID="_RefID0E5QBG" width="75%"><caption>Table 3.

<table width="50%"><col width="31%"/><col width="26%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">VIAGRA 100 mg</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Supine</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>7.9 (4.6, 11.1)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Standing</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4.3 (-1.8,10.3)</paragraph></td></tr></tbody></table> <table ID="_RefID0E5QBG" width="75%"><caption>Table 3. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil</caption><col width="16%"/><col width="5%"/><col width="13%"/><col width="4%"/><col width="14%"/><col width="4%"/><col width="13%"/><col width="4%"/><col width="14%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Means &#xB1; SD</content></th><th align="center" colspan="4" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">At rest</content></th><th align="center" colspan="4" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">After 4 minutes of exercise</content></th></tr><tr><th align="left" styleCode="Rrule Lrule Botrule " valign="top"/><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">N</content></th><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Baseline</content> <content styleCode="bold">(B2)</content></th><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">n</content></th><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Sildenafil</content> <content styleCode="bold">(D1)</content></th><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">n</content></th><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Baseline</content></th><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">n</content></th><th align="left" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Sildenafil</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>PAOP (mmHg)</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>8.1 &#xB1; 5.1</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>6.5 &#xB1; 4.3</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>36.0 &#xB1; 13.7</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>27.8 &#xB1; 15.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mean PAP (mmHg)</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>16.7 &#xB1; 4</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>12.1 &#xB1; 3.9</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>39.4 &#xB1; 12.9</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>31.7 &#xB1; 13.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mean RAP (mmHg)</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>7</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>5.7 &#xB1; 3.7</paragraph

trule " valign="top"><paragraph>31.7 &#xB1; 13.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mean RAP (mmHg)</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>7</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>5.7 &#xB1; 3.7</paragraph ></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4.1 &#xB1; 3.7</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>-</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>-</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>-</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>-</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Systolic SAP (mmHg)</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>150.4 &#xB1; 12.4</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>140.6 &#xB1; 16.5</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>199.5 &#xB1; 37.4</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>187.8 &#xB1; 30.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diastolic SAP (mmHg)</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>73.6 &#xB1; 7.8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>65.9 &#xB1; 10</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>84.6 &#xB1; 9.7</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>79.5 &#xB1; 9.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cardiac output (L/min)</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>5.6 &#xB1; 0.9</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>5.2 &#xB1; 1.1</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>11.5 &#xB1; 2.4</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>10.2 &#xB1; 3.5</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Heart rate (bpm)</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>67 &#xB1; 11.1</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>66.9 &#xB1; 12</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>101.9 &#xB1; 11.6</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>99.0 &#xB1; 20.4</paragraph></td></tr></tbody></table>

12.3 Pharmacokinetics VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25–63%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 hours. Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below: Figure 5: Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers. Absorption and Distribution: VIAGRA is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When VIAGRA is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients. Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach. Pharmacokinetics in Special Populations Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18–45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [ see Dosage and Administration (2.5) , and Use in Specific Populations (8.5) ] Renal Impairment: In volunteers with mild (CLcr=50–80 mL/min) and moderate (CLcr=30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered.

methyl metabolite were 45% and 57%, respectively [ see Dosage and Administration (2.5) , and Use in Specific Populations (8.5) ] Renal Impairment: In volunteers with mild (CLcr=50–80 mL/min) and moderate (CLcr=30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment [ see Dosage and Administration (2.5) , and Use in Specific Populations (8.6) ]. In addition, N-desmethyl metabolite AUC and C max values significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment: In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [ see Dosage and Administration (2.5) , and Use in Specific Populations (8.7) ]. Therefore, age >65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. A starting oral dose of 25 mg should be considered in those patients [ see Dosage and Administration (2.5) ] . Drug Interaction Studies Effects of Other Drugs on VIAGRA Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. The concomitant use of erythromycin or strong CYP3A4 inhibitors (e.g., saquinavir, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil [ see Dosage and Administration (2.4) ]. In vivo studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with VIAGRA (50 mg) to healthy volunteers. When a single 100 mg dose of VIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C max and a 182% increase in sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Viagra (100 mg single dose) resulted in a 140% increase in sildenafil C max and a 210% increase in sildenafil AUC. Viagra had no effect on saquinavir pharmacokinetics. A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect than that seen with saquinavir. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [ see Dosage and Administration (2.4) and Drug Interactions (7.4) ]. In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with VIAGRA (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C max and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates.

increase in sildenafil C max and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. VIAGRA had no effect on ritonavir pharmacokinetics [ see Dosage and Administration (2.4) and Drug Interactions (7.4) ]. Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels. In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil C max . Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of VIAGRA. In healthy male volunteers, there was no evidence of a clinically significant effect of azithromycin (500 mg daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite. Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence. Effects of VIAGRA on Other Drugs In vitro studies: Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µM). Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that VIAGRA will alter the clearance of substrates of these isoenzymes. In vivo studies: No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates. VIAGRA (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg). Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in C max of bosentan (125 mg b.i.d.). Figure 5

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18–21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2 basis in a 50 kg subject. Mutagenesis Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. Impairment of Fertility There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18–21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2 basis in a 50 kg subject. Mutagenesis Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. Impairment of Fertility There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.

14 CLINICAL STUDIES In clinical studies, VIAGRA was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. VIAGRA was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). VIAGRA was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. VIAGRA demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo. Efficacy Endpoints in Controlled Clinical Studies The effectiveness of VIAGRA was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function - IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered. Efficacy Results from Controlled Clinical Studies The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Figure 6 shows that regardless of the baseline levels of function, subsequent function in patients treated with VIAGRA was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline. Figure 6. Effect of VIAGRA and Placebo on Maintenance of Erection by Baseline Score.

els of function, subsequent function in patients treated with VIAGRA was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline. Figure 6. Effect of VIAGRA and Placebo on Maintenance of Erection by Baseline Score. The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 7. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of VIAGRA, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar. Overall treatment p<0.0001 Figure 7. Percentage of Patients Reporting an Improvement in Erections. The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period. In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of VIAGRA on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50–100 mg of VIAGRA vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on VIAGRA vs about 20% on placebo. During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that VIAGRA improved their erections. Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. VIAGRA improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction. One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of VIAGRA; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on VIAGRA compared to placebo. On a global improvement question, 57% of VIAGRA patients reported improved erections versus 10% on placebo. Diary data indicated that on VIAGRA, 48% of intercourse attempts were successful versus 12% on placebo. One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted.

ns versus 10% on placebo. Diary data indicated that on VIAGRA, 48% of intercourse attempts were successful versus 12% on placebo. One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. On a global improvement question, 83% of patients reported improved erections on VIAGRA versus 12% on placebo. Diary data indicated that on VIAGRA, 59% of attempts at sexual intercourse were successful compared to 13% on placebo. Across all trials, VIAGRA improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo. Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of VIAGRA patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA . Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for VIAGRA and 29% for placebo. Figure 6 Figure 6 Figure 7 Efficacy Results in Subpopulations in Controlled Clinical Studies A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. VIAGRA was effective in a broad range of ED patients, including those with a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft (CABG), radical prostatectomy, transurethral resection of the prostate (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and anti-hypertensives/diuretics.

<table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td align="center" styleCode="Toprule " valign="top"><renderMultiMedia ID="id2198" referencedObject="ID_3cf6693e-4155-4fe7-b6ef-a54576bcb73c"/></td><td styleCode="Toprule " valign="top"/></tr><tr><td align="center" valign="top"><renderMultiMedia ID="id2203" referencedObject="ID_0997c1ff-a4e6-46b3-ad4d-f3b84c3bd339"/></td><td valign="top"/></tr><tr><td align="center" colspan="2" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Figure 6. Effect of VIAGRA and Placebo on Maintenance of Erection by Baseline Score.</content></paragraph></td></tr></tbody></table> <table width="100%"><col width="10%"/><col width="90%"/><tbody><tr><td align="center" colspan="2" styleCode="Toprule " valign="top"><renderMultiMedia ID="id2216" referencedObject="DF6BC8B4-2F53-44B8-A5BE-7A477E8B77C4"/></td></tr><tr><td valign="top"><paragraph> </paragraph></td><td valign="top"><paragraph>Overall treatment p&lt;0.0001</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Figure 7. Percentage of Patients Reporting an Improvement in Erections.</content></paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING VIAGRA (sildenafil citrate) is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil and debossed on the obverse and reverse sides as follows: 25 mg 50 mg 100 mg Obverse VGR25 VGR50 VGR100 Reverse PFIZER PFIZER PFIZER Bottle of 30 NDC-0069-4200-30 NDC-0069-4210-30 NDC-0069-4220-30 Bottle of 100 N/A NDC-0069-4210-66 NDC-0069-4220-66 Carton of 30 (1 tablet per Single Pack ) N/A NDC 0069-4210-33 NDC 0069-4220-33 Recommended Storage: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

<table width="75%"><col width="19%"/><col width="22%"/><col width="22%"/><col width="23%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">25 mg</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">50 mg</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">100 mg</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Obverse</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>VGR25</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>VGR50</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>VGR100</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Reverse</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>PFIZER</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>PFIZER</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>PFIZER</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Bottle of 30</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC-0069-4200-30</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC-0069-4210-30</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC-0069-4220-30</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Bottle of 100</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>N/A</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC-0069-4210-66</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC-0069-4220-66</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Carton of 30 (1 tablet per Single Pack )</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>N/A</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC 0069-4210-33</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC 0069-4220-33</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) Nitrates Physicians should discuss with patients the contraindication of VIAGRA with regular and/or intermittent use of nitric oxide donors, such as organic nitrates or organic nitrites in any form [ see Contraindications (4.1) ]. Guanylate Cyclase (GC) Stimulators Physicians should discuss with patients the contraindication of VIAGRA with use of guanylate cyclase stimulators such as riociguat [ see Contraindications (4.3) ]. Concomitant Use with Drugs Which Lower Blood Pressure Physicians should advise patients of the potential for VIAGRA to augment the blood pressure lowering effect of alpha-blockers and anti-hypertensive medications. Concomitant administration of VIAGRA and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, when VIAGRA is co-administered with alpha-blockers, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose [ see Warnings and Precautions (5.5) ]. Cardiovascular Considerations Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms (e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician [ see Warnings and Precautions (5.1) ]. Sudden Loss of Vision Physicians should advise patients to stop use of all PDE5 inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including possible permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a "crowded" optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including VIAGRA, for this uncommon condition [ see Warnings and Precautions (5.3) and Adverse Reactions (6.2) ]. Sudden Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including VIAGRA, 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 VIAGRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [ see Warnings and Precautions (5.4) and Adverse Reactions (6.2) ]. Priapism Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance.

cians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result [ see Warnings and Precautions (5.2) ]. Avoid Use with other PDE5 Inhibitors Physicians should inform patients not to take VIAGRA with other PDE5 inhibitors including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil. Sildenafil is also marketed as REVATIO for the treatment of PAH. The safety and efficacy of VIAGRA with other PDE5 inhibitors, including REVATIO, have not been studied [ see Warnings and Precautions (5.7) ]. Sexually Transmitted Disease The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered [ see Warnings and Precautions (5.9) ].

Patient Information VIAGRA ® (vi-AG-rah) (sildenafil citrate) Tablets What is the most important information I should know about VIAGRA? VIAGRA can cause your blood pressure to drop suddenly to an unsafe level if it is taken with certain other medicines. Do not take VIAGRA if you take any other medicines called "nitrates." Nitrates are used to treat chest pain (angina). A sudden drop in blood pressure can cause you to feel dizzy, faint, or have a heart attack or stroke. Do not take VIAGRA if you take medicines called guanylate cyclase stimulators which include: • Riociguat (Adempas®) a medicine that treats pulmonary arterial hypertension and chronic-thromboembolic pulmonary hypertension. Tell all your healthcare providers that you take VIAGRA. If you need emergency medical care for a heart problem, it will be important for your healthcare provider to know when you last took VIAGRA. Stop sexual activity and get medical help right away if you get symptoms such as chest pain, dizziness, or nausea during sex. Sexual activity can put an extra strain on your heart, especially if your heart is already weak from a heart attack or heart disease. Ask your doctor if your heart is healthy enough to handle the extra strain of having sex. VIAGRA does not protect you or your partner from getting sexually transmitted diseases, including HIV—the virus that causes AIDS. What is VIAGRA? VIAGRA is a prescription medicine used to treat erectile dysfunction (ED). You will not get an erection just by taking this medicine. VIAGRA helps a man with erectile dysfunction get and keep an erection only when he is sexually excited (stimulated). VIAGRA is not for use in women or children. It is not known if VIAGRA is safe and effective in women or children under 18 years of age. Who should not take VIAGRA? Do not take VIAGRA if you: • take medicines called nitrates (such as nitroglycerin) • use street drugs called "poppers" such as amyl nitrate or amyl nitrite, and butyl nitrate • take any medicines called guanylate cyclase stimulators such as riociguat (Adempas) • are allergic to sildenafil, as contained in VIAGRA and REVATIO, or any of the ingredients in VIAGRA. See the end of this leaflet for a complete list of ingredients in VIAGRA. What should I tell my healthcare provider before taking VIAGRA? Before you take VIAGRA, tell your healthcare provider if you: • have or have had heart problems such as a heart attack, irregular heartbeat, angina, chest pain, narrowing of the aortic valve or heart failure • have had heart surgery within the last 6 months • have pulmonary hypertension • have had a stroke • have low blood pressure, or high blood pressure that is not controlled • have a deformed penis shape • have had an erection that lasted for more than 4 hours • have problems with your blood cells such as sickle cell anemia, multiple myeloma, or leukemia • have retinitis pigmentosa, a rare genetic (runs in families) eye disease • have ever had severe vision loss, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION) • have bleeding problems • have or have had stomach ulcers • have liver problems • have kidney problems or are having kidney dialysis • have any other medical conditions Tell your healthcare provider about all the medicines you take The other brands listed are trademarks of their respective owners and are not trademarks of Pfizer Inc.

problems • have or have had stomach ulcers • have liver problems • have kidney problems or are having kidney dialysis • have any other medical conditions Tell your healthcare provider about all the medicines you take The other brands listed are trademarks of their respective owners and are not trademarks of Pfizer Inc. The makers of these brands are not affiliated with and do not endorse Pfizer Inc or its products. , including prescription and over-the-counter medicines, vitamins, and herbal supplements. VIAGRA may affect the way other medicines work, and other medicines may affect the way VIAGRA works causing side effects. Especially tell your healthcare provider if you take any of the following: • medicines called nitrates (see "Error! Hyperlink reference not valid." ) • medicines called guanylate cyclase stimulators, such as riociguat (Adempas) • medicines called alpha blockers such as Hytrin (terazosin HCl), Flomax (tamsulosin HCl), Cardura (doxazosin mesylate), Minipress (prazosin HCl), Uroxatral (alfuzosin HCl), Jalyn (dutasteride and tamsulosin HCl), or Rapaflo (silodosin). Alpha-blockers are sometimes prescribed for prostate problems or high blood pressure. In some patients, the use of VIAGRA with alpha-blockers can lead to a drop in blood pressure or to fainting. • medicines called HIV protease inhibitors, such as ritonavir (Norvir), indinavir sulfate (Crixivan), saquinavir (Fortovase or Invirase) or atazanavir sulfate (Reyataz) • some types of oral antifungal medicines, such as ketoconazole (Nizoral), and itraconazole (Sporanox) • some types of antibiotics, such as clarithromycin (Biaxin), telithromycin (Ketek), or erythromycin • other medicines that treat high blood pressure • other medicines or treatments for ED • VIAGRA contains sildenafil, which is the same medicine found in another drug called REVATIO. REVATIO is used to treat a rare disease called pulmonary arterial hypertension (PAH). VIAGRA should not be used with REVATIO or with other PAH treatments containing sildenafil or any other PDE5 inhibitors (such as Adcirca [tadalafil]). Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How should I take VIAGRA? • Take VIAGRA exactly as your healthcare provider tells you to take it. • Your healthcare provider will tell you how much VIAGRA to take and when to take it. • Your healthcare provider may change your dose if needed. • Take VIAGRA about 1 hour before sexual activity. You may take VIAGRA between 30 minutes to 4 hours before sexual activity if needed. • VIAGRA can be taken with or without food. If you take VIAGRA after a high fat meal (such as a cheeseburger and french fries), VIAGRA may take a little longer to start working • Do not take VIAGRA more than 1 time a day. • If you accidentally take too much VIAGRA, call your doctor or go to the nearest hospital emergency room right away. What are the possible side effects of VIAGRA? VIAGRA can cause serious side effects . Rarely reported side effects include: • an erection that will not go away (priapism). If you have an erection that lasts more than 4 hours, get medical help right away. If it is not treated right away, priapism can permanently damage your penis. • sudden vision loss in one or both eyes. Sudden vision loss in one or both eyes can be a sign of a serious eye problem called non-arteritic anterior ischemic optic neuropathy (NAION). It is uncertain whether PDE5 inhibitors directly cause the vision loss. Stop taking VIAGRA and call your healthcare provider right away if you have sudden vision loss in one or both eyes. • sudden hearing decrease or hearing loss.

of a serious eye problem called non-arteritic anterior ischemic optic neuropathy (NAION). It is uncertain whether PDE5 inhibitors directly cause the vision loss. Stop taking VIAGRA and call your healthcare provider right away if you have sudden vision loss in one or both eyes. • sudden hearing decrease or hearing loss. Some people may also have ringing in their ears (tinnitus) or dizziness. If you have these symptoms, stop taking VIAGRA and contact a doctor right away. The most common side effects of VIAGRA are: • headache • flushing • upset stomach • abnormal vision, such as changes in color vision (such as having a blue color tinge) and blurred vision • stuffy or runny nose • back pain • muscle pain • nausea • dizziness • rash In addition, heart attack, stroke, irregular heartbeats and death have happened rarely in men taking VIAGRA. Most, but not all, of these men had heart problems before taking VIAGRA. It is not known if VIAGRA caused these problems. Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of VIAGRA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store VIAGRA? • Store VIAGRA at room temperature between 68°F to 77°F (20°C to 25°C). Keep VIAGRA and all medicines out of the reach of children. General information about the safe and effective use of VIAGRA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VIAGRA for a condition for which it was not prescribed. Do not give VIAGRA to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about VIAGRA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about VIAGRA that is written for health professionals. For more information, go to www.viagra.com, or call 1-888-4VIAGRA What are the ingredients in VIAGRA? Active ingredient: sildenafil citrate Inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake This Patient Information has been approved by the U.S. Food and Drug Administration. This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com . Viagra (sildenafil citrate), Revatio (sildenafil), Cardura (doxazosin mesylate), and Minipress (prazosin HCl) are registered trademarks of Pfizer Inc. LAB-0220-11.0 Revised: 08/2017 Logo