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 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.

2.1 Recommended Dosage in Adults

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).

Sildenafil for Oral Suspension

White to off-white 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.

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 pressure less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with Sildenafil 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 for Oral Suspension 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 post marketing 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 for Oral Suspension.

There are no controlled clinical data on the safety or efficacy of Sildenafil for Oral Suspension 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 information 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.

6.1 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%.

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.

Nitrates

Concomitant use of Sildenafil for Oral Suspension with nitrates in any form is contraindicated [see Contraindications (4)] .

Strong CYP3A Inhibitors

Concomitant use of Sildenafil for Oral Suspension with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)] .

Moderate-to-Strong CYP3A Inducers

Concomitant use of Sildenafil for Oral Suspension with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of Sildenafil for Oral Suspension may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of Sildenafil for Oral Suspension 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)] .

8.1 Pregnancy

8.2 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) product. 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 for Oral Suspension 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 vitrohave shown that sildenafil is selective for PDE-5. 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 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, PDE-5 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

12.3 Pharmacokinetics

Drug Interaction Studies

In vitrostudies

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 vivostudies

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

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 2basis.

Sildenafil was negative in in vitrobacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitrohuman lymphocytes and in vivomouse 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.

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 for Oral Suspension 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 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. 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-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.

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-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 for Oral Suspension 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.

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.

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°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.