Revacio

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REVATIO (REVATIO®)

Composition:

Active substance: 1 tablet contains 28.09 mg of sildenafil citrate, equivalent to 20 mg of sildenafil.

Excipients: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium croscarmellose, magnesium stearate, Opadry® white (OY-LS-28914) [hypromellose; lactose monohydrate; glycerol triacetate; titanium dioxide (E 171)], Opadry® clear (YS-2-19114-A) (hypromellose; glycerol triacetate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets, white to almost white in color, with "RVT 20" debossed on one side and "Pfizer" on the other.

Pharmacotherapeutic group. Agents used in erectile dysfunction.

ATC code G04BE03.

Pharmacological Properties.

Pharmacodynamics.

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), the enzyme responsible for cGMP degradation. In addition to the presence of this enzyme in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vascular system. Thus, sildenafil increases cGMP levels in smooth muscle cells of pulmonary vessels, leading to their relaxation. In patients with pulmonary arterial hypertension, this may lead to vasodilation of the pulmonary vascular bed and, to a lesser extent, to systemic vascular dilation.

Pharmacodynamic Effects.

In vitro studies have demonstrated that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases. Its selectivity is 10 times higher for PDE5 than for PDE6, which is involved in phototransduction in the retina, and 80 times higher than for PDE1, and 700 times higher than for PDE2, 3, 4, 7, 8, 9, 10, and 11. In particular, sildenafil has more than 4,000-fold higher selectivity for PDE5 than for PDE3, the cAMP-specific phosphodiesterase isoform involved in regulation of cardiac contractility.

Sildenafil causes mild and transient reduction in systemic arterial pressure, which in most cases has no clinical manifestations. After long-term administration of 80 mg three times daily to patients with systemic hypertension, mean reductions in systolic and diastolic blood pressure compared to baseline values were 9.4 mm Hg and 9.1 mm Hg, respectively. After long-term administration of 80 mg three times daily to patients with pulmonary arterial hypertension, a less pronounced reduction in blood pressure was observed (a decrease in both systolic and diastolic pressure by 2 mm Hg). With the recommended dose of 20 mg three times daily, no reduction in either systolic or diastolic pressure was observed.

Single oral administration of sildenafil up to 100 mg in healthy volunteers did not lead to clinically significant effects on ECG parameters. Long-term administration of 80 mg three times daily in patients with pulmonary arterial hypertension did not result in clinically significant effects on ECG parameters.

In a study assessing hemodynamic effects of a single 100 mg oral dose of sildenafil in 14 patients with severe ischemic heart disease (>70% stenosis of at least one coronary artery), mean resting systolic and diastolic blood pressures decreased by 7% and 6%, respectively, compared to baseline values. Mean pulmonary systolic arterial pressure decreased by 9%. Sildenafil did not affect cardiac output and did not worsen blood flow in stenosed coronary arteries.

In several patients undergoing the 100-hue Farnsworth-Munsell color vision test, mild and transient color discrimination abnormalities (blue/green) were detected one hour after taking a 100 mg dose. These effects were not observed two hours later. The mechanism of this color vision change may be related to inhibition of PDE6, which participates in the phototransduction cascade in the retina. Sildenafil did not affect visual acuity or contrast sensitivity. In a small placebo-controlled study in patients with documented early age-related macular degeneration (n = 9), sildenafil (single 100 mg dose) did not demonstrate any significant changes in visual test results (visual acuity, Amsler grid, traffic light color recognition simulation, Humphrey perimetry, and photostress test).

Clinical Efficacy and Safety.

Efficacy in adult patients with pulmonary arterial hypertension. A randomized, double-blind, placebo-controlled study was conducted involving 278 patients with primary pulmonary hypertension, pulmonary arterial hypertension associated with connective tissue disease, and pulmonary arterial hypertension following surgical correction of congenital heart defects. Patients were randomized into one of four groups receiving placebo, sildenafil 20 mg, 40 mg, or 80 mg three times daily. Of the 278 randomized patients, 277 received at least one dose of the investigational drug. The study population included 68 (25%) men and 209 (75%) women; mean patient age was 49 years (range 18–81 years); baseline 6-minute walk distance ranged from 100 to 450 m (mean 344 m). Primary pulmonary hypertension was diagnosed in 175 (63%) of the included patients, pulmonary arterial hypertension associated with connective tissue disease in 84 (30%), and pulmonary arterial hypertension following surgical correction of congenital heart defects in 18 (7%). Most patients belonged to WHO functional class II (107/277, 39%) or III (160/277, 58%); a smaller proportion belonged to class I (1/277, 0.4%) or IV (9/277, 3%). Patients with left ventricular ejection fraction <45% or left ventricular fractional shortening <0.2 were not studied.

Sildenafil (or placebo) was added to patients' background therapy, which could include combinations of anticoagulants, digoxin, calcium channel blockers, diuretics, or oxygen. Concomitant use of prostacyclin, prostacyclin analogs, endothelin receptor antagonists, or arginine supplements during the study was not permitted. Patients with prior bosentan therapy that was ineffective were excluded from the study.

The primary endpoint was change in 6-minute walk distance at week 12 compared to baseline. Statistically significant improvement in 6-minute walk distance was observed with all sildenafil doses compared to placebo. Placebo-corrected increases in 6-minute walk distance were 45 m (p < 0.0001), 46 m (p < 0.0001), and 50 m (p < 0.0001) for sildenafil 20 mg, 40 mg, and 80 mg three times daily, respectively. No significant dose-dependent differences in sildenafil efficacy were observed. In patients with baseline 6-minute walk distance <325 m, improved efficacy was observed with higher doses (placebo-corrected improvements were 58 m, 65 m, and 87 m for 20 mg, 40 mg, and 80 mg three times daily, respectively).

In subgroup analysis by WHO functional class, statistically significant improvement in 6-minute walk distance was observed with the 20 mg dose. For classes II and III, placebo-corrected walk distance increased by 49 m (p = 0.0007) and 45 m (p = 0.0031), respectively, compared to placebo.

Improvement in walk distance was evident after 4 weeks of treatment, and this effect persisted at weeks 8 and 12. Overall results were consistent across subgroups based on etiology (primary or connective tissue disease-associated pulmonary arterial hypertension), WHO functional class, sex, race, region, mean pulmonary arterial pressure, and pulmonary vascular resistance index.

In patients across all sildenafil treatment groups, statistically significant reductions in mean pulmonary arterial pressure and pulmonary vascular resistance were achieved compared to placebo recipients. Placebo-corrected treatment effects on mean pulmonary arterial pressure were -2.7 mm Hg (p = 0.04), -3.0 mm Hg (p = 0.01), and -5.1 mm Hg (p < 0.0001) for sildenafil 20 mg, 40 mg, and 80 mg three times daily, respectively. Placebo-corrected treatment effects on pulmonary vascular resistance were -178 dyn·s/cm⁵ (p = 0.0051), -195 dyn·s/cm⁵ (p = 0.0017), and -320 dyn·s/cm⁵ (p < 0.0001) for sildenafil 20 mg, 40 mg, and 80 mg three times daily, respectively. The percentage reduction in pulmonary vascular resistance at 12 weeks for sildenafil 20 mg, 40 mg, and 80 mg three times daily (11.2%, 12.9%, 23.3%) was proportionally greater than the reduction in systemic vascular resistance (7.2%, 5.9%, 14.4%). The effect of sildenafil on mortality is unknown.

Improvement by at least one WHO functional class at 12 weeks was observed in a higher percentage of patients across all sildenafil groups (28%, 36%, and 42% receiving sildenafil 20 mg, 40 mg, and 80 mg three times daily, respectively) compared to placebo (7%). Odds ratios were 2.92 (p = 0.0087), 4.32 (p = 0.0004), and 5.75 (p < 0.0001), respectively.

Long-term survival data in treatment-naïve patients. Patients who participated in the core study met eligibility criteria for a long-term open-label extension study. Over three years, 87% of patients received 80 mg three times daily. Overall, 207 patients received Revatio in the core study; their long-term survival was assessed for at least 3 years. In this population, one-, two-, and three-year survival rates estimated by the Kaplan-Meier method were 96%, 91%, and 82%, respectively. One-, two-, and three-year survival rates in patients with WHO functional class II at study initiation were 99%, 91%, and 84%, respectively, while in patients with WHO functional class III at study initiation, these rates were 94%, 90%, and 81%, respectively.

Efficacy of sildenafil in adult patients with pulmonary arterial hypertension (in combination with epoprostenol). A randomized, double-blind, placebo-controlled study was conducted involving 267 patients with pulmonary arterial hypertension stabilized on intravenous epoprostenol. The study included patients with primary pulmonary arterial hypertension (212/267, 79%) and pulmonary arterial hypertension associated with connective tissue diseases (55/267, 21%). At baseline, most patients were in WHO functional class II (68/267, 26%) or III (175/267, 66%), with fewer in class I (3/267, 1%) or IV (16/267, 6%); functional class was unknown for a few patients (5/267, 2%). Patients were randomized to receive sildenafil or placebo (with fixed dose titration from 20 mg to 40 mg and then to 80 mg three times daily according to tolerability) in combination with intravenous epoprostenol. The primary endpoint was change in 6-minute walk distance at week 16 compared to baseline. Statistically significant improvement in 6-minute walk distance was observed in sildenafil-treated groups compared to placebo. A mean placebo-corrected increase in walk distance of 26 m favored sildenafil (95% CI: 10.8; 41.2) (p = 0.0009).

In patients with baseline walk distance ≥325 m, treatment effect was 38.4 m in favor of sildenafil; in patients with baseline walk distance <325 m, treatment effect was 2.3 m in favor of placebo. In patients with primary pulmonary arterial hypertension, treatment effect was 31.1 m compared to 7.7 m in patients with connective tissue disease-associated pulmonary arterial hypertension. The difference between these subgroups may have occurred by chance due to limited sample size.

Patients receiving sildenafil achieved statistically significant reductions in mean pulmonary arterial pressure compared to placebo recipients. A mean placebo-corrected treatment effect of -3.9 mm Hg favored sildenafil (95% CI: -5.7; -2.1) (p = 0.00003). Time to clinical worsening, a secondary endpoint, was defined as time from randomization to first occurrence of clinical worsening (death, lung transplantation, initiation of bosentan therapy, or clinical worsening requiring epoprostenol dose adjustment). Sildenafil significantly delayed time to clinical worsening compared to placebo (p = 0.0074). Clinical worsening occurred in 23 patients (17.6%) in the placebo group compared to 8 patients (6%) in the sildenafil group.

Long-term survival data from the epoprostenol combination study. Patients enrolled in the epoprostenol add-on study met inclusion criteria for a long-term open-label extension study. Over three years, 68% of patients received 80 mg three times daily. In the core study, 134 patients received Revatio; their long-term survival was assessed for at least 3 years. In this population, one-, two-, and three-year survival rates estimated by the Kaplan-Meier method were 92%, 81%, and 74%, respectively.

Efficacy and safety of sildenafil in adult patients with pulmonary arterial hypertension (in combination with bosentan). A randomized, double-blind, placebo-controlled study was conducted involving 103 clinically stable patients with pulmonary arterial hypertension (WHO functional classes II–III) receiving bosentan therapy for at least 3 months. Patients had primary pulmonary arterial hypertension or pulmonary arterial hypertension associated with connective tissue disease. Patients were randomized to receive sildenafil (20 mg three times daily) in combination with bosentan (62.5–125 mg twice daily) or placebo. The primary endpoint was change in 6-minute walk distance at week 12 compared to baseline. Results showed no significant difference in mean change in 6-minute walk distance at week 12 compared to baseline between sildenafil (20 mg three times daily) and placebo groups (13.62 m [95% CI: -3.89 to 31.12] and 14.08 m [95% CI: -1.78 to 29.95], respectively).

Differences in 6-minute walk distance were observed between patients with primary pulmonary arterial hypertension and those with connective tissue disease-associated pulmonary arterial hypertension. In patients with primary pulmonary arterial hypertension (67 patients), mean changes in 6-minute walk distance compared to baseline were 26.39 m (95% CI: 10.7–42.08) and 11.84 m (95% CI: -8.83 to 32.52) in sildenafil and placebo groups, respectively. In patients with connective tissue disease-associated pulmonary arterial hypertension (36 patients), mean changes compared to baseline were -18.32 m (95% CI: -65.66 to 29.02) and 17.50 m (95% CI: -9.41 to 44.41) in sildenafil and placebo groups, respectively.

Overall, adverse reactions were generally similar between the two treatment groups (sildenafil plus bosentan and bosentan monotherapy) and consistent with the known safety profile of sildenafil monotherapy (see sections "Special Instructions" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Mortality in adults with pulmonary arterial hypertension

A study was conducted to evaluate the effect of different sildenafil dose levels on mortality in adults with pulmonary arterial hypertension. The study was initiated following observation of increased mortality risk in children receiving high doses of sildenafil three times daily, weight-adjusted, compared to those receiving lower doses, in a long-term extension of a pediatric clinical trial (see below "Children. Pulmonary Arterial Hypertension").

A randomized, double-blind, parallel-group study was conducted involving 385 adults with pulmonary arterial hypertension. Patients were randomized 1:1:1 into one of three dose groups: up to 5 mg three times daily (four times lower than the recommended dose), up to 20 mg three times daily (recommended dose), and up to 80 mg (four times higher than the maximum recommended dose). Overall, most patients had not previously received treatment for pulmonary arterial hypertension (83.4%). In most subjects, pulmonary arterial hypertension was idiopathic (71.7%). The most common WHO functional class was class III (57.7% of subjects). All three treatment groups were well balanced with respect to baseline demographics, treatment history, etiology of pulmonary arterial hypertension, and WHO functional class.

Mortality rates were 26.4% (n = 34) with 5 mg three times daily, 19.5% (n = 25) with 20 mg three times daily, and 14.8% (n = 19) with 80 mg three times daily.

Children.

Pulmonary Arterial Hypertension. A randomized, double-blind, multicenter, placebo-controlled, parallel-group clinical trial was conducted to determine the optimal dose of the drug in 234 patients aged 1 to 17 years. Patients (38% male, 62% female) had body weight ≥8 kg and had primary pulmonary hypertension (33%) or secondary pulmonary arterial hypertension associated with congenital heart disease (systemic-to-pulmonary shunt – 37%, surgical defect correction – 30%). 63 of 234 (27%) patients were under 7 years of age (low sildenafil dose = 2; medium dose = 17; high dose = 28; placebo = 16), and 171 of 234 (73%) were aged 7 years and older (low sildenafil dose = 40; medium dose = 38; high dose = 49; placebo = 44). Most patients were initially classified as WHO functional class I (75/234, 32%) or II (120/234, 51%); a smaller proportion were class III (35/234, 15%) or IV (1/234, 0.4%); functional class was unknown in a few patients (3/234, 1.3%).

Patients had not previously received specific treatment for pulmonary arterial hypertension. Concomitant use of prostacyclin, prostacyclin analogs, and endothelin receptor antagonists during the study was not permitted. No patient received arginine supplements, nitrates, α-blockers, or potent CYP3A4 inhibitors.

The primary objective was to evaluate the efficacy of long-term oral sildenafil administration over 16 weeks in children to improve exercise tolerance, measured by cardiopulmonary exercise testing in patients developmentally capable of performing the test (n = 115). Secondary endpoints included hemodynamic monitoring, symptom assessment, WHO functional class, changes in background therapy, and quality of life measures.

Patients were assigned to one of three groups receiving low (10 mg), medium (10–40 mg), or high (20–80 mg) doses of Revatio three times daily or placebo. Actual drug doses administered in each group depended on body weight (see section "Adverse Reactions"). The proportion of patients receiving supportive therapy at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics, and/or oxygen) was similar in the combined sildenafil group (47.7%) and placebo group (41.7%).

The primary endpoint was placebo-corrected change in peak oxygen consumption (VO₂) as a percentage of baseline value at week 16. Peak VO₂ was measured by cardiopulmonary exercise testing in the combined dose group. Overall, 106 of 234 patients (45%) underwent cardiopulmonary exercise testing; these were children aged ≥7 years with developmental level sufficient to perform the test. Children under 7 years of age (combined sildenafil dose = 47; placebo = 16) were evaluated only on secondary endpoints. Mean baseline peak VO₂ values were comparable in the sildenafil group (17.37–18.03 mL/kg/min) and slightly higher in the placebo group (20.02 mL/kg/min). The primary analysis result (combined doses vs. placebo) was not statistically significant (p = 0.056). The estimated difference between medium sildenafil doses and placebo was 11.33% (95% CI: 1.72–20.94).

Dose-dependent increases in pulmonary vascular resistance index and mean pulmonary arterial pressure were observed. Administration of medium and high sildenafil doses demonstrated reductions in pulmonary vascular resistance index and mean pulmonary arterial pressure by 18% (95% CI: 2–32%) and 27% (95% CI: 14–39%), respectively, compared to placebo; low-dose sildenafil did not show a statistically significant difference compared to placebo (difference 2%). Medium and high sildenafil dose groups demonstrated changes in mean pulmonary arterial pressure from baseline compared to placebo of -3.5 mm Hg (95% CI: -8.9; 1.9) and -7.3 mm Hg (95% CI: -12.4; -2.1), respectively. The low-dose group showed a negligible difference compared to placebo (difference 1.6 mm Hg). Improvement in cardiac index was observed in all sildenafil groups (10%, 4%, and 15% with low, medium, and high sildenafil doses, respectively) compared to placebo.

Significant improvement in functional class compared to placebo was observed only with high-dose sildenafil. Odds ratios in low-, medium-, and high-dose sildenafil groups compared to placebo were 0.6 (95% CI: 0.18; 2.01), 2.25 (95% CI: 0.75; 6.69), and 4.52 (95% CI: 1.56; 13.10), respectively.

Long-term Study Data.

Of the 234 pediatric patients treated in the short-term placebo-controlled study, 220 participated in a long-term extension study. Patients who were in the placebo group during the short-term study were randomly reassigned to sildenafil groups. Patients with body weight ≤20 kg were assigned to medium or high-dose groups (1:1), while patients with body weight >20 kg were assigned to low-, medium-, or high-dose groups (1:1:1). Of 229 patients receiving sildenafil, 55, 74, and 100 were assigned to low-, medium-, and high-dose groups, respectively. Total treatment duration from the start of the double-blind phase ranged from 3 to 3129 days. For sildenafil groups, mean duration of sildenafil administration was 1696 days (excluding 5 patients who received placebo during the double-blind phase and did not receive treatment in the long-term extension study).

Three-year survival rates in patients with baseline body weight >20 kg, estimated by the Kaplan-Meier method, were 94%, 93%, and 85% for low-, medium-, and high-dose groups, respectively. For patients with baseline body weight ≤20 kg, survival rates were 94% and 93% for medium- and high-dose groups, respectively (see sections "Special Instructions" and "Adverse Reactions").

During the study, 42 deaths occurred during treatment or the subsequent survival follow-up period. 37 deaths occurred before the Data Monitoring Committee decided to reduce doses based on observed mortality imbalance with increasing sildenafil doses. Of these 37 cases, the number (%) of deaths in low-, medium-, and high-dose sildenafil groups was 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%), respectively. Five additional deaths occurred subsequently. Deaths were related to pulmonary arterial hypertension. Pediatric patients with pulmonary arterial hypertension should not receive sildenafil doses exceeding the recommended doses (see sections "Dosage and Administration" and "Special Instructions").

One year after initiation of the placebo-controlled study, peak VO₂ was assessed. In 52% (59/114) of patients receiving Revatio who were developmentally capable of performing cardiopulmonary exercise testing, no decline in peak VO₂ was observed compared to baseline values recorded at the start of Revatio treatment. Similarly, in 191 of 229 patients (83%) receiving sildenafil, functional status according to WHO classification remained stable or improved at one-year assessment.

Persistent Pulmonary Hypertension of the Newborn

A randomized, double-blind, placebo-controlled study was conducted in two parallel groups involving 59 neonates with persistent pulmonary hypertension of the newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN, with an oxygenation index (OI) >15 to <60. The primary objective was to evaluate the efficacy and safety of intravenous (IV) sildenafil in combination with inhaled nitric oxide (NO) compared to inhaled NO alone.

The primary composite endpoint consisted of: treatment failure rate, defined as need for additional PPHN therapy, requirement for extracorporeal membrane oxygenation (ECMO), or death during the study; and duration of inhaled NO after initiation of IV study drug in patients who benefited from treatment. The difference in treatment failure rates between the two treatment groups was not statistically significant (27.6% in the IV sildenafil + inhaled NO group vs. 20.0% in the inhaled NO + placebo group). Mean duration of inhaled NO after initiation of IV study drug in both groups of patients who benefited from treatment was approximately 4.1 days.

Treatment-emergent adverse events and serious adverse events were reported in 22 (75.9%) and 7 (24.1%) patients in the IV sildenafil + inhaled NO group, respectively, and in 19 (63.3%) and 2 (6.7%) patients in the inhaled NO + placebo group, respectively. Most common treatment-emergent adverse events in the IV sildenafil + inhaled NO group were hypotension (8 [27.6%] patients), hypokalemia (7 [24.1%] patients), anemia, and withdrawal syndrome (4 [13.8%] patients each), bradycardia (3 [10.3%] patients). In the inhaled NO + placebo group, adverse events were pneumothorax (4 [13.3%] patients), anemia, edema, hyperbilirubinemia, elevated C-reactive protein, and hypotension (3 [10.0%] patients each) (see section "Dosage and Administration").

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. Maximum plasma concentration is reached within 30 to 120 minutes (mean 60 minutes) after oral administration on an empty stomach. Mean absolute oral bioavailability is 41% (range 25–63%). After oral administration of sildenafil in the dose range of 20 to 40 mg three times daily, AUC and Cmax increase proportionally with dose. After administration of 80 mg three times daily orally, plasma sildenafil concentrations increase more than proportionally. In patients with pulmonary arterial hypertension, sildenafil bioavailability after administration of 80 mg three times daily is on average 43% (90% CI: 27–60%) higher than with lower doses.

When sildenafil is taken with food, absorption rate is slowed, with a mean delay in Tmax of 60 minutes and a mean 29% reduction in Cmax, although the extent of absorption is not significantly altered (AUC reduced by 11%).

Distribution. The mean volume of distribution at steady state for sildenafil is 105 L, indicating tissue distribution. After oral administration of 20 mg sildenafil three times daily, mean peak total plasma concentration at steady state is approximately 113 ng/mL. Sildenafil and its major circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentration.

Biotransformation. Sildenafil is metabolized primarily by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite results from N-demethylation of sildenafil. This metabolite, like sildenafil, is selective for phosphodiesterase, and its in vitro activity against PDE5 is approximately 50% that of the parent drug. The N-desmethyl metabolite is further metabolized with a half-life of about 4 hours. In patients with pulmonary arterial hypertension, plasma concentration of the N-desmethyl metabolite is approximately 72% of sildenafil concentration after administration of 20 mg three times daily (pharmacological activity of the metabolite was 36% of that of sildenafil). Further contribution to efficacy is unknown.

Elimination. Total clearance of sildenafil is 41 L/h with a terminal half-life of 3–5 hours. After oral or intravenous administration, sildenafil is excreted as metabolites, predominantly in feces (about 80% of orally administered dose) and to a lesser extent in urine (approximately 13% of orally administered dose).

Pharmacokinetics in Special Patient Populations.

Elderly Patients. Healthy elderly volunteers (65 years and older) had reduced sildenafil clearance, resulting in 90% higher plasma concentrations of sildenafil and active N-desmethyl metabolite compared to younger healthy volunteers (18–45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil concentration in plasma is approximately 40%.

Renal Impairment. In volunteers with mild or moderate renal impairment (creatinine clearance 30–80 mL/min), pharmacokinetics of sildenafil after a single 50 mg oral dose were unchanged. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax by 100% and 88%, respectively, compared to volunteers of the same age group without renal impairment. Additionally, in patients with severe renal impairment, AUC and Cmax of the N-desmethyl metabolite were significantly increased by 200% and 79%, respectively, 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 (85%) and Cmax (47%) compared to volunteers of the same age group without hepatic impairment. Additionally, in patients with severe hepatic impairment, AUC and Cmax of the N-desmethyl metabolite were significantly increased by 154% and 87%, respectively, compared to patients with normal liver function.

Pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Pharmacokinetics in Populations.

In patients with pulmonary arterial hypertension receiving the drug in the studied dose range of 20–80 mg three times daily, mean steady-state concentrations were 20–50% higher than in healthy volunteers. Cmin levels were also observed to increase twofold compared to healthy volunteers. These data suggest lower clearance and/or higher bioavailability of orally administered sildenafil in patients with pulmonary arterial hypertension compared to healthy volunteers.

Children. Analysis of the pharmacokinetic profile of sildenafil in patients participating in clinical trials demonstrated that drug exposure in children is body weight-dependent. The elimination half-life of sildenafil in plasma was 4.2–4.4 hours across body weights of 10–70 kg and showed no clinically significant differences. Cmax after single oral administration of 20 mg sildenafil was 49, 104, and 165 ng/mL for patients with body weights of 70, 20, and 10 kg, respectively. Cmax after single oral administration of 10 mg sildenafil was 24, 53, and 85 ng/mL for patients with body weights of 70, 20, and 10 kg, respectively. Tmax was approximately 1 hour and was practically independent of body weight.

Clinical characteristics.

Indications.

Adults. Treatment of patients with pulmonary arterial hypertension (WHO functional class II and III) to improve exercise tolerance. The efficacy of the drug has been demonstrated in the treatment of primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.

Children. Treatment of pulmonary arterial hypertension in children with body weight above 20 kg. Efficacy of the drug in improving exercise tolerance or hemodynamics has been demonstrated in the treatment of primary pulmonary arterial hypertension and pulmonary hypertension associated with congenital heart defects.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the drug.
• Concomitant use with nitric oxide donors (e.g., amyl nitrite) or nitrates in any form due to the hypotensive effect of nitrates (see section "Pharmacodynamics").
• Concomitant use of PDE5 inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated, as it may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with the most potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) (see section "Interaction with other medicinal products and other forms of interaction").
• Loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this condition was associated with prior use of PDE5 inhibitors or not (see section "Special precautions").
• The following diseases, as the safety of sildenafil has not been studied in patients with these conditions:
  • severe hepatic impairment;
  • recent stroke or myocardial infarction;
  • severe arterial hypotension (blood pressure < 90/50 mm Hg) at the start of treatment.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on sildenafil.

In vitro studies. Sildenafil metabolism is mediated primarily by the following cytochrome P450 (CYP) isoenzymes: 3A4 (major pathway) and 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, while inducers may increase it (see dosage recommendations in sections "Method of administration and dosage" and "Contraindications").

In vivo studies. An evaluation of the concomitant administration of oral sildenafil and intravenous epoprostenol has been conducted (see section "Adverse reactions" and "Pharmacological properties. Pharmacodynamics").

The efficacy and safety of concomitant use of sildenafil with other agents for the treatment of pulmonary arterial hypertension (e.g., ambrisentan, iloprost) have not been studied in controlled clinical trials. Therefore, these drugs should be used concomitantly with caution.

The safety and efficacy of concomitant use of Revatio with other PDE5 inhibitors have not been studied in patients with pulmonary arterial hypertension (see section "Special precautions").

Results of population pharmacokinetic analysis of data obtained from clinical studies in pulmonary arterial hypertension indicate reduced clearance and/or increased bioavailability of sildenafil when administered orally concomitantly with CYP3A4 substrates and in combination with CYP3A4 substrates and β-blockers. The use of these agents was the only factor that statistically significantly affected the pharmacokinetics of sildenafil in patients with pulmonary arterial hypertension. Exposure to sildenafil in patients taking CYP3A4 substrates and CYP3A4 substrates plus β-blockers was 43% and 66% higher, respectively, compared to patients not taking drugs from these classes. When a dose of 80 mg three times daily was administered, sildenafil exposure was five times higher than exposure observed with a dose of 20 mg three times daily. This concentration range encompasses the increased sildenafil exposure observed in specifically designed drug interaction studies with CYP3A4 inhibitors (except for the most potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir).

Inducers of CYP3A4 have a significant effect on the pharmacokinetics of sildenafil in patients with pulmonary arterial hypertension, as confirmed in a clinical interaction study with the CYP3A4 inducer bosentan in vivo.

Concomitant administration of 125 mg bosentan (a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19) twice daily and 80 mg sildenafil three times daily (at steady state) for 6 days resulted in a 63% reduction in sildenafil AUC. Population pharmacokinetic analysis of clinical trial data on sildenafil use in adult patients with pulmonary arterial hypertension, including a 12-week study evaluating the efficacy and safety of oral sildenafil 20 mg three times daily added to stable-dose bosentan therapy (62.5–125 mg twice daily), indicates reduced sildenafil exposure when coadministered with bosentan, similar to the reduction observed in healthy volunteers (see section "Special precautions" and "Pharmacodynamics").

Careful monitoring of sildenafil efficacy is required in patients who are concomitantly taking potent CYP3A4 inducers such as carbamazepine, phenytoin, phenobarbital, St. John's wort, and rifampicin.

Concomitant administration of the HIV protease inhibitor ritonavir, a potent P450 inhibitor, at steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300% increase (4-fold) in sildenafil Cmax and an 11-fold increase in sildenafil AUC in plasma. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL observed with sildenafil alone. This is due to the pronounced effect of ritonavir on a wide range of P450 substrates. Based on these pharmacokinetic data, concomitant use of sildenafil and ritonavir in patients with pulmonary arterial hypertension is contraindicated.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times daily) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil does not affect the pharmacokinetics of saquinavir. Dosage recommendations are provided in the section "Method of administration and dosage."

Administration of a single 100 mg dose of sildenafil together with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in systemic exposure to sildenafil (AUC). In healthy male volunteers, no evidence was obtained of azithromycin (500 mg daily for 3 days) affecting AUC, Cmax, Tmax, elimination rate constant, or half-life of sildenafil or its major circulating metabolite. Dose adjustment is not required. Cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, when coadministered with sildenafil (50 mg) in healthy volunteers, caused a 56% increase in plasma concentration of sildenafil. Dose adjustment is not required.

The effects of the most potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to be similar to those of ritonavir (see section "Contraindications"). The effects of CYP3A4 inhibitors such as clarithromycin, telithromycin, and nefazodone are expected to be less than those of ritonavir but greater than those of CYP3A4 inhibitors such as saquinavir or erythromycin. An increase in exposure by 7-fold is expected. Therefore, dose adjustment is recommended when using CYP3A4 inhibitors (see section "Method of administration and dosage").

Population pharmacokinetic analysis results in patients with pulmonary arterial hypertension indicate that concomitant use of sildenafil with a combination of β-blockers and CYP3A4 substrates may lead to additional increases in sildenafil exposure compared to its use with CYP3A4 substrates alone.

Grapefruit juice is a weak inhibitor of CYP3A4 metabolism in the intestinal wall and may lead to a moderate increase in plasma levels of sildenafil. Dose adjustment is not required, but concomitant use of grapefruit juice and sildenafil is not recommended.

Single doses of antacids (magnesium hydroxide/aluminum hydroxide) do not affect the bioavailability of sildenafil.

Concomitant use of oral contraceptives (30 μg ethinylestradiol and 150 μg levonorgestrel) did not affect the pharmacokinetics of sildenafil.

Nicorandil is a hybrid potassium channel activator and nitrate. Due to the presence of a nitrate component, it has the potential for serious interaction with sildenafil (see section "Contraindications").

Effect of sildenafil on other medicinal products.

In vitro studies. Sildenafil is a weak inhibitor of the following cytochrome P450 isoenzymes: 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 μM).

There are no data on interaction between sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.

In vivo studies. No significant interactions were observed when sildenafil (50 mg) was administered concomitantly with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by the CYP2C9 system.

Sildenafil had no significant effect on atorvastatin exposure (AUC increased by 11%), indicating no clinically significant effect of sildenafil on CYP3A4.

No interaction between sildenafil (100 mg single dose) and acenocoumarol was observed.

Sildenafil (50 mg) did not increase bleeding time caused by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers at mean peak blood alcohol levels of 80 mg/dL.

In a study in healthy volunteers, sildenafil at steady state (80 mg three times daily) led to a 50% increase in AUC of bosentan (125 mg twice daily).

Population pharmacokinetic analysis of data from a study in adult patients with pulmonary arterial hypertension on background bosentan therapy (62.5–125 mg twice daily) indicates a 20% (95% confidence interval (CI): 9.8–30.8) increase in bosentan AUC with concomitant use of sildenafil at steady state (20 mg three times daily), with a smaller magnitude than observed in healthy volunteers with concomitant use of 80 mg sildenafil three times daily (see section "Special precautions" and "Pharmacodynamics").

In a specific interaction study where sildenafil (100 mg) was administered concomitantly with amlodipine to patients with arterial hypertension, an additional reduction in systolic blood pressure in the supine position of 8 mm Hg was observed. The corresponding additional reduction in diastolic blood pressure in the supine position was 7 mm Hg. The magnitude of these additional blood pressure reductions was similar to those observed with sildenafil alone in healthy volunteers.

In three specific drug interaction studies, the α-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered concomitantly to patients with benign prostatic hyperplasia stabilized on doxazosin therapy. In these study groups, mean additional reductions in supine systolic and diastolic blood pressure were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, respectively, and mean additional reductions in blood pressure in the standing position were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Concomitant use of sildenafil and doxazosin in patients stabilized on doxazosin therapy has occasionally been associated with symptomatic orthostatic hypotension. Reports described episodes of dizziness and pre-syncope, but no syncope. Concomitant use of sildenafil in patients taking α-adrenergic blockers may lead to symptomatic hypotension in susceptible individuals (see section "Special precautions").

Sildenafil (100 mg single dose) does not affect the steady-state pharmacokinetic characteristics of the HIV protease inhibitor saquinavir, a CYP3A4 substrate/inhibitor.

Due to the known effect on nitric oxide/cGMP metabolism, sildenafil potentiates the hypotensive effects of nitrates; therefore, concomitant use with nitric oxide donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat. Preclinical studies have demonstrated an additive systemic effect on blood pressure reduction with concomitant use of PDE5 inhibitors and riociguat. Clinical studies have shown that riociguat potentiates the hypotensive effect of PDE5 inhibitors. In patients participating in the study, no positive clinical effect was observed from concomitant use of PDE5 inhibitors with riociguat. Concomitant use of riociguat with PDE5 inhibitors (including sildenafil) is contraindicated (see section "Contraindications").

Sildenafil had no clinically significant effect on plasma levels of oral contraceptives (ethinylestradiol 30 μg and levonorgestrel 150 μg). Administration of a single dose of sildenafil with sacubitril/valsartan at steady state in patients with arterial hypertension was associated with significantly greater blood pressure reduction compared to sacubitril/valsartan alone. Therefore, initiation of sildenafil therapy should be done with caution in patients receiving sacubitril/valsartan.

Children. Interaction studies have been conducted only in adults.

Special precautions for use.

The efficacy of Revatio in patients with severe pulmonary arterial hypertension (WHO functional class IV) has not been established. If clinical status worsens, medications recommended for the treatment of severe disease (e.g., epoprostenol) should be used. The benefit-risk profile of sildenafil in patients with pulmonary arterial hypertension WHO functional class I has not been determined.

Clinical trials evaluating the efficacy of sildenafil have been conducted in the following forms of pulmonary arterial hypertension: primary (idiopathic) pulmonary arterial hypertension and pulmonary arterial hypertension associated with connective tissue disease or congenital heart defects. The use of sildenafil in other forms of pulmonary arterial hypertension is not recommended.

Pigmentary retinal dystrophy. The safety of sildenafil has not been studied in patients with known hereditary retinal degenerative disorders such as retinitis pigmentosa (in some of these patients, genetic abnormalities of retinal phosphodiesterase are present); therefore, the use of this medication is not recommended in such patients.

Vasodilatory effect. Before administering sildenafil, physicians should carefully consider whether the mild to moderate vasodilatory effect of sildenafil may adversely affect patients with certain concomitant conditions, such as hypotension, hypovolemia, severe left ventricular outflow tract obstruction, or autonomic dysfunction.

Cardiovascular risk factors. During post-marketing use of sildenafil for the treatment of erectile dysfunction in men, serious cardiovascular adverse reactions have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, arterial hypertension, and hypotension, which occurred temporally close to sildenafil administration. Most (but not all) patients had pre-existing cardiovascular risk factors. Many adverse events occurred during or immediately after sexual activity, and several occurred shortly after sildenafil administration without sexual activity. Therefore, it is not possible to determine whether there is a direct relationship between these adverse reactions and sildenafil or other factors.

Priapism. Sildenafil should be used with caution in patients with anatomical deformation of the penis (e.g., penile angulation, cavernous fibrosis, or Peyronie’s disease) or in patients with conditions that may predispose to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Post-marketing reports have included cases of prolonged erection and priapism. If an erection lasts longer than 4 hours, patients should seek immediate medical attention. Without prompt treatment, priapism may lead to penile tissue damage and permanent loss of potency (see section "Adverse reactions").

Vaso-occlusive crises in patients with sickle cell anemia. Sildenafil should not be used in patients with pulmonary arterial hypertension secondary to sickle cell anemia. In a clinical trial, vaso-occlusive crises requiring hospitalization occurred more frequently in patients receiving Revatio compared to those receiving placebo, leading to premature termination of the study.

Ocular adverse reactions. Spontaneous reports of visual disturbances have been received with the use of sildenafil and other PDE5 inhibitors. Spontaneous reports of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition, have also been reported and were associated with sildenafil and other PDE5 inhibitors in observational studies (see section "Adverse reactions"). In case of any sudden visual disturbance, treatment should be discontinued immediately and alternative therapy initiated (see section "Contraindications").

Alpha-adrenergic blockers. Sildenafil should be used with caution in patients taking alpha-adrenergic blockers, as this combination may lead to symptomatic hypotension in some susceptible individuals (see section "Interaction with other medicinal products and other forms of interaction"). To minimize the risk of orthostatic hypotension, sildenafil therapy should only be initiated in hemodynamically stable patients receiving alpha-blockers. Patients should also be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Blood coagulation disorders. In vitro studies on human platelets have shown that sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside. There is no information on the safety of sildenafil use in patients with bleeding disorders or active peptic ulceration. Therefore, the use of sildenafil in such patients should only be considered after careful assessment of the benefit-risk ratio.

Vitamin K antagonists. In patients with pulmonary arterial hypertension, the risk of bleeding may be increased when sildenafil is initiated in patients already receiving vitamin K antagonists, particularly in those with pulmonary arterial hypertension associated with connective tissue disease.

Occlusive venous diseases. There are no data on the use of sildenafil in patients with pulmonary hypertension due to pulmonary veno-occlusive disease. In such patients, life-threatening pulmonary edema has been reported with vasodilators (mainly prostacyclin). Therefore, if signs of pulmonary edema occur during sildenafil treatment in patients with pulmonary hypertension, associated veno-occlusive disease should be suspected.

Information on excipients. The product contains lactose; therefore, it should not be administered to patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is essentially "sodium-free." This information may be useful for patients on a low-sodium diet.

Use of sildenafil in combination with bosentan. There are no convincing data on the efficacy of sildenafil in patients receiving bosentan therapy.

Concomitant use with other PDE5 inhibitors. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors, including Viagra®, have not been studied in patients with pulmonary arterial hypertension. Therefore, such combinations are not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

Women of childbearing potential and contraception for men and women. Due to insufficient data on the effects of Revatio in pregnant women, the use of this medication in women of childbearing potential who may become pregnant is not recommended, except when appropriate contraceptive measures are used.

Pregnancy. There are no data on the use of sildenafil in pregnant women. Animal studies do not indicate a direct or indirect harmful effect on pregnancy or embryonal/fetal development. However, animal studies have shown a toxic effect of the drug on postnatal development.

Due to insufficient data, Revatio should not be used during pregnancy except when there is a clear clinical need.

Breastfeeding. There are no adequate and well-controlled studies in women during breastfeeding. Data from a single woman indicate that sildenafil and its active metabolite N-desmethylsildenafil are excreted in breast milk in very small amounts. There are no clinical data on adverse reactions in breastfed infants; however, the amount transferred via milk is expected to be too low to cause adverse effects. Physicians prescribing this medication to breastfeeding mothers should carefully weigh the clinical need for the drug in the mother against any potential risk of adverse reactions in breastfed infants.

Fertility. Based on standard fertility studies and preclinical data, there is no specific risk identified for humans.

Ability to affect reaction speed when driving or operating machinery.

Revatio has a moderate influence on the ability to drive or operate machinery. Since dizziness and visual disturbances have been reported during clinical trials with sildenafil, patients should be informed about how Revatio may affect them before driving or operating machinery.

Method of Administration and Dosage

Revatio is intended for oral administration. Tablets should be taken at approximately 6-8 hour intervals, regardless of food intake.

Initiation and monitoring of treatment must be performed by a physician experienced in managing pulmonary arterial hypertension. If clinical deterioration occurs during treatment with Revatio, alternative therapies should be considered.

Adults

The recommended dose is 20 mg three times daily. If a dose is missed, the next dose should be taken as soon as possible, and treatment should continue according to the regular schedule. A double dose should not be taken to compensate for a missed dose.

Patients taking other medicinal products. Any dose adjustment should generally be made only after careful benefit-risk assessment. When prescribing sildenafil to patients already taking CYP3A4 inhibitors such as erythromycin or saquinavir, consideration should be given to reducing the dose of Revatio to 20 mg twice daily. When sildenafil is used concomitantly with stronger CYP3A4 inhibitors such as clarithromycin, telithromycin, and nefazodone, the dose of Revatio should be reduced to 20 mg once daily. For use of sildenafil in combination with the most potent CYP3A4 inhibitors, see section "Contraindications". Dose adjustment of sildenafil may be necessary when used concomitantly with CYP3A4 inducers (see section "Interaction with other medicinal products and other forms of interaction").

Elderly patients (aged 65 years and older). No dose adjustment is required in elderly patients. However, clinical efficacy, as measured by the 6-minute walk distance, may be lower in elderly patients.

Patients with renal impairment. No initial dose adjustment is required in patients with renal impairment, including severe renal impairment (creatinine clearance < 30 mL/min). Dose reduction to 20 mg twice daily may be considered after careful benefit-risk assessment and only if treatment is poorly tolerated.

Patients with hepatic impairment. No initial dose adjustment is required in patients with hepatic dysfunction (Child-Pugh class A and B). Dose reduction to 20 mg twice daily may be considered after careful benefit-risk assessment and only if treatment is poorly tolerated.

Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see section "Contraindications").

Discontinuation of treatment. Limited data suggest that abrupt discontinuation of Revatio is not associated with worsening of pulmonary arterial hypertension. However, to avoid potential sudden clinical deterioration upon discontinuation, the dose should be tapered gradually. Enhanced monitoring of the patient is recommended during the discontinuation period.

Children

The tablet formulation may be used in this patient population only when children are able to safely swallow tablets, which is typically possible from the age of 5 years.

The dose in children with body weight above 20 kg is 20 mg three times daily. Higher doses should not be used in this patient population. An increased number of deaths was observed in patients receiving doses higher than recommended during a long-term extension study. Therefore, higher than recommended doses should not be used in children with pulmonary arterial hypertension (see also section "Pharmacological properties").

Infants under 1 year of age and neonates

Sildenafil should not be used in neonates with persistent pulmonary hypertension of the newborn, as this indication is not approved and the risks of such treatment outweigh the potential benefits (see section "Pharmacodynamics").

The safety and efficacy of Revatio in children under 1 year of age for the treatment of other conditions have not been established; there is no available information. Therefore, the drug should not be used in children under 1 year of age with body weight less than 20 kg.

Overdose

In clinical studies involving healthy volunteers, adverse reactions following single doses of sildenafil up to 800 mg were similar to those observed with lower doses of sildenafil but occurred more frequently and were more severe. Administration of sildenafil at a dose of 200 mg caused an increased frequency of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In case of overdose, standard supportive measures should be applied as needed. Enhanced clearance of sildenafil by hemodialysis is unlikely due to the high degree of plasma protein binding and the absence of urinary elimination of sildenafil.

Adverse Reactions

In the main placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 207 patients were randomized and received treatment with Revatio at doses of 20 mg, 40 mg, or 80 mg three times daily, and 70 patients were randomized to receive placebo. The treatment duration was 12 weeks. The overall discontinuation rate among patients receiving sildenafil at doses of 20 mg, 40 mg, and 80 mg three times daily was 2.9%, 3.0%, and 8.5%, respectively, compared to 2.9% in the placebo group. Of the 277 patients who received treatment in the main study, 259 participated in a long-term extension study. They received doses up to 80 mg three times daily (four times the recommended dose of 20 mg three times daily), and after 3 years, 87% of the 183 patients in the investigational treatment group were receiving Revatio at a dose of 80 mg three times daily.

In a placebo-controlled study evaluating Revatio as add-on therapy to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients received Revatio (with fixed-dose titration starting at 20 mg, increasing to 40 mg, and then to 80 mg three times daily based on tolerability) plus epoprostenol; 131 patients received placebo plus epoprostenol. The treatment duration was 16 weeks. The overall discontinuation rate due to adverse reactions among patients receiving sildenafil/epoprostenol was 5.2%, compared to 10.7% in the placebo/epoprostenol group. Adverse reactions reported for the first time and observed more frequently in the sildenafil/epoprostenol group included eye redness, blurred vision, nasal congestion, night sweats, back pain, and dry mouth. Known adverse reactions such as headache, facial flushing, limb pain, and edema occurred more frequently in patients receiving sildenafil/epoprostenol compared to those receiving placebo/epoprostenol. Of the patients who completed the initial study, 242 participated in a long-term extension study. They received doses up to 80 mg three times daily, and after 3 years, 68% of the 133 patients in the investigational treatment group were receiving Revatio at a dose of 80 mg three times daily.

In two placebo-controlled studies of Revatio, adverse reactions were generally mild to moderate in severity. The most common adverse reactions (occurring at a frequency ≥ 10%) with Revatio compared to placebo were: headache, flushing, dyspepsia, diarrhea, and limb pain.

In a study evaluating different dose levels of sildenafil, safety data for 20 mg sildenafil three times daily (the recommended daily dose) and 80 mg sildenafil three times daily (four times the recommended daily dose) were consistent with the safety profile established in previous studies of sildenafil use in pulmonary arterial hypertension in adults.

Adverse reactions occurring in > 1% of patients treated with Revatio and observed more frequently (difference > 1%) with Revatio compared to placebo in the main study or based on combined results from both placebo-controlled studies of Revatio in the treatment of pulmonary arterial hypertension at doses of 20, 40, or 80 mg three times daily are listed below, categorized by system organ class and frequency of occurrence (very common ≥ 1/10, common ≥ 1/100 to < 1/10, rare ≥ 1/1000 to < 1/100, and frequency not known (cannot be estimated from available data)). Within each category, adverse reactions are listed in order of decreasing severity. Reactions reported post-marketing are indicated in italics.

Infections and infestations.

Common: cellulitis, influenza, bronchitis, sinusitis, rhinitis, gastroenteritis.

Blood and lymphatic system disorders.

Common: anemia.

Metabolism and nutrition disorders.

Common: fluid retention.

Psychiatric disorders.

Common: insomnia, anxiety.

Nervous system disorders.

Very common: headache.

Common: migraine, tremor, paresthesia, burning sensation, hypoesthesia.

Eye disorders.

Common: retinal hemorrhage, visual disturbance, blurred vision, photophobia, chromopsia, cyanopsia, eye irritation, hyperemia/eye redness.

Rare: decreased visual acuity, diplopia, unusual sensations in eyes.

Frequency not known: non-arteritic anterior ischemic optic neuropathy*, retinal vascular occlusion*, visual field defect*.

Ear and labyrinth disorders.

Common: dizziness.

Frequency not known: sudden hearing loss.

Vascular disorders.

Very common: flushing.

Frequency not known: arterial hypotension.

Respiratory, thoracic and mediastinal disorders.

Common: epistaxis, cough, nasal congestion.

Gastrointestinal disorders.

Very common: diarrhea, dyspepsia.

Common: gastritis, gastroesophageal reflux disease, hemorrhoids, abdominal distension, dry mouth.

Skin and subcutaneous tissue disorders.

Common: alopecia, erythema, night sweats.

Frequency not known: rash.

Musculoskeletal and connective tissue disorders.

Very common: limb pain.

Common: myalgia, back pain.

Renal and urinary disorders.

Uncommon: hematuria.

Reproductive system and breast disorders.

Rare: penile hemorrhage, hemospermia, gynecomastia.

Frequency not known: priapism, increased erection.

General disorders and administration site conditions.

Common: increased body temperature.

*Adverse events/adverse reactions observed at unknown frequency in men treated with sildenafil for erectile dysfunction.

Pediatric population.

In a placebo-controlled study of Revatio involving patients with pulmonary arterial hypertension aged 1–17 years, a total of 174 patients received low (10 mg for patients > 20 kg; no patients ≤ 20 kg in the low-dose group), medium (10 mg for patients 8–20 kg; 20 mg for patients 20–45 kg; 40 mg for patients > 45 kg), or high (20 mg for patients 8–20 kg; 40 mg for patients 20–45 kg; 80 mg for patients > 45 kg) doses of Revatio three times daily; 60 patients received placebo.

Adverse reactions observed in this study were generally consistent with those in adults. The most common adverse reactions observed (with frequency ≥ 1%) in patients treated with Revatio (combined doses) and occurring at a frequency > 1% compared to placebo were increased body temperature and upper respiratory tract infection (each 11.5%), vomiting (10.9%), increased erection (including spontaneous erections in males) (9.0%), nausea, bronchitis (each 4.6%), pharyngitis (4.0%), rhinitis (3.4%), pneumonia, and rhinitis (each 2.9%).

Of the 234 children who received treatment in the short-term placebo-controlled study, 220 patients participated in a long-term extension study. Patients receiving active sildenafil therapy continued on the same therapeutic regimen; patients who were in the placebo group in the short-term study were randomized to receive sildenafil.

The most common adverse reactions recorded during both short-term and long-term studies were generally similar to those observed during the short-term study. Adverse reactions occurring with a frequency > 10% in the 229 patients treated with sildenafil (combined dose group, including 9 patients who did not participate in the long-term study) included upper respiratory tract infection (31%), headache (26%), vomiting (22%), bronchitis (20%), pharyngitis (18%), increased body temperature (17%), diarrhea (15%), influenza, and epistaxis (each 12%). Most of these adverse reactions were considered mild or moderate in severity.

Serious adverse reactions were reported in 94 (41%) of the 229 patients treated with sildenafil. Of the 94 patients with serious adverse reactions, 14/55 (25.5%) were in the low-dose group, 35/74 (47.3%) in the medium-dose group, and 45/100 (45%) in the high-dose group. The most common serious adverse reactions observed with a frequency ≥ 1% in patients treated with sildenafil (combined doses) were pneumonia (7.4%), heart failure and pulmonary hypertension (each 5.2%), upper respiratory tract infection (3.1%), right ventricular heart failure and gastroenteritis (each 2.6%), syncope, bronchitis, bronchopneumonia, and pulmonary arterial hypertension (each 2.2%), chest pain and dental caries (each 1.7%), and cardiogenic shock, viral gastroenteritis, and urinary tract infection (each 1.3%).

Treatment-related serious adverse reactions included enterocolitis, convulsions, hypersensitivity, stridor, hypoxia, sensorineural hearing loss, and ventricular arrhythmia.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with applicable legal requirements.

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in a place inaccessible to children.

Packaging.

15 tablets in a blister, 6 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Fareva Amboise /
Fareva Amboise.

Manufacturer's address and location of operations.

Zone Industrielle, 29 route des Industries, 37530 Poce-sur-Cisse, France /
Zone Industrielle, 29 route des Industries, 37530 Poce-sur-Cisse, France.