SILDENAFIL

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 Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 longterm 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 ), Patient Counseling Information ( 17 )] .

4 CONTRAINDICATIONS Sildenafil 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 )

11 DESCRIPTION Sildenafil, 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 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 or almost white, slightly hygroscopic, crystalline powder and a molecular weight of 666.7. Sildenafil for Oral Suspension: Sildenafil for oral suspension is supplied as white to light yellow colored granular powder containing 1.57 g of sildenafil citrate (equivalent to1.12 g sildenafil) in an amber glass bottle intended for reconstitution. Following reconstitution with 90 mL water, the total volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil. The inactive ingredients include citric acid anhydrous, colloidal silicon dioxide, grape flavor, sodium benzoate, sodium citrate dihydrate, sorbitol, sucralose, titanium dioxide and xanthan gum. 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

2 DOSAGE AND ADMINISTRATION Adults: 20 mg 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. Tap the bottle to loosen the powder. Add 60 mL of water to the bottle. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. Add another 30 mL of water to the bottle. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. Remove cap and press the bottle adaptor into the neck of the bottle. Replace the cap on the bottle. 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

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 )

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.

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 )

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 PDE5 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 mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate * The number of patients per treatment group varied slightly for each parameter due to missing assessments. Placebo (n = 65)* Sildenafil 20 mg (n = 65)* mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) 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) Pediatric Patients Patients on Sildenafil medium and high dose groups achieved a 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 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. 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 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 ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on electrocardiogram (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 9.0 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 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%. 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). Sildenafil Injection: The pharmacokinetic profile of sildenafil has been characterized following intravenous administration. A 10 mg dose of sildenafil injection is predicted to provide a pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg 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 to 70 kg of body weight. Tmax 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. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax 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 Cmax (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 than150 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% reductions 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). Sildenafil Injection: Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less than those observed after oral sildenafil administration. 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%. Image 7 Image 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 PDE5 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 mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate * The number of patients per treatment group varied slightly for each parameter due to missing assessments. Placebo (n = 65)* Sildenafil 20 mg (n = 65)* mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) 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) Pediatric Patients Patients on Sildenafil medium and high dose groups achieved a 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 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. 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 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 ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on electrocardiogram (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 9.0 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 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%. 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). Sildenafil Injection: The pharmacokinetic profile of sildenafil has been characterized following intravenous administration. A 10 mg dose of sildenafil injection is predicted to provide a pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg 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 to 70 kg of body weight. Tmax 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. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax 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 Cmax (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 than150 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% reductions 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). Sildenafil Injection: Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less than those observed after oral sildenafil administration. 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%.

20230329

9

3 DOSAGE FORMS AND STRENGTHS Sildenafil for Oral Suspension White to light yellow colored granular powder containing 1.57 g of sildenafil citrate (equivalent to 1.12 g of sildenafil) in a bottle intended for reconstitution. Following reconstitution with 90 mL of water, the volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil. A 2 mL oral 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 )

SILDENAFIL Sildenafil SILDENAFIL CITRATE SILDENAFIL ANHYDROUS CITRIC ACID SILICON DIOXIDE SODIUM BENZOATE SODIUM CITRATE SORBITOL SUCRALOSE TITANIUM DIOXIDE XANTHAN GUM White to light yellow

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.

ANDA211638

SILDENAFIL

Sildenafil

68180-283

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 68180-283-01 Sildenafil for oral suspension 10 mg/mL Rx only Glass Bottle of 112 mL NDC 68180-283-01 Sildenafil for oral suspension 10 mg/mL Rx only Carton of 112 mL Glass Bottle image 20 image 21

RECENT MAJOR CHANGES Indications and Usage ( 1 ) 1/2023 Dosage and Administration ( 2.1 , 2.2 , 2.3 ) 1/2023

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. The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Manufactured by: Lupin Limited Goa - 403 722 India Revised: May 2023

14 CLINICAL STUDIES SUPER-1 (NCT00644605) - Sildenafil monotherapy [20 mg, 40 mg, and 80 mg three times a day] A randomized, double-blind, placebo-controlled study of Sildenafil (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 to 50 meters were observed with all doses of Sildenafil. These increases were significantly different from placebo, but the Sildenafil 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 Week 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 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 (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 group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil 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 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 (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-treated patients and that Sildenafil-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 (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 - 0.26) 0.062 (0.02 - 0.10) 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 compared to placebo. More than twice as many sildenafil-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 repair30%). 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 PVO2, 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 - 20 18 na 10 mg 15 20 mg 35 >20 - 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 VO2peak from baseline to week 16 assessed by CPET. Mean baseline peak volume of oxygen consumed (VO2) values were similar across the sildenafil treatment groups (17 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 VO2peak 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 short term 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 VO2 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 PVO2 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 )]. 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 0.68 0.51 99.7% CI 0.31, 1.49 0.22, 1.21 Hazard ratio relative to sildenafil 20 mg Hazard ratio estimate 0.74 99.7% CI 0.30 1.84 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 Note: Sildenafil 5 mg is not an approved dosage. Abbreviations: 6MWD = 6-minute walk distance; CI = confidence interval; PAH = pulmonary arterial hypertension. 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 6MWD at Months 6 and 12 At baseline, the median of 6MWD for the intent-to-treat (ITT) population was 332 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 )] . Image 9 Figure 10 Image 11 Image 12

8.5 Geriatric Use Clinical studies of sildenafil did not include sufficient numbers of subjects 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 )] .

8.2 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 ), 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.

8.1 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, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre-and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis).

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, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre-and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/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 ), 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 subjects 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 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Sildenafil powder for oral suspension is supplied in amber glass bottles. Each bottle contains white to light yellow colored granular powder 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 Powder for Oral Suspension Package Configuration Strength NDC Powder for oral suspension - bottle 10 mg/mL (when reconstituted) 68180-283-01 Recommended storage for Sildenafil for oral suspension: Store below 30°C (86°F) in the original package in order to protect from moisture. Recommended storage for reconstituted oral suspension Store below 30°C (86°F) or in refrigerator at 2° to 8°C (36° 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.