Sildenafil

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

1 INDICATIONS AND USAGE Adults Sildenafilfororal 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 use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 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 )

2 DOSAGE AND ADMINISTRATION Adults: 20 mg three times a day Dose may be increased based on symptoms and tolerability. (2.1) 2.1 Recommended Dosage in Adults Oral Dosage The recommended dosage of Sildenafil for Oral Suspension is 20 mg three times a day. [ see Clinical Studies (14) ] . Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) product. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Reconstitution of the Powder for Oral Suspension Note : Reconstitute the contents of the bottle with a total volume of 92 mL (60 mL followed by 32 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 32 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 crystalline 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 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 oral suspension. ( 4)

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) To report SUSPECTED ADVERSE REACTIONS, contact Virtus Pharmaceuticals, LLC at 1-888-848-3593 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 for Oral Suspension-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) ]. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) product. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 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 …

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 ) Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information.

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/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 effectiveness of sildenafil have not been established in pediatric patients younger than 1 year of age. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 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 )].

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 PDE-5 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 .

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 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 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. Sildenafil for oral suspension is supplied as white to off-white crystalline powders containing 1.57 g of sildenafil citrate USP (equivalent to 1.12 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 anhydrous citric acid, colloidal silicon dioxide, grape flavor, sodium benzoate, sorbitol, sucralose, titanium dioxide, tri sodium citrate dihydrate, 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. struct

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Sildenafil for Oral Suspension is supplied in amber glass bottles. Each bottle contains white to off-white crystalline powders containing 1.57 g of sildenafil citrate USP (equivalent to 1.12 g sildenafil). Following reconstitution, the total 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 - bottle 10 mg/mL (when reconstituted) 31722-136-31 Recommended storage for sildenafil for oral suspension: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature] 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°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.