Sildenafil-pharmak

INSTRUCTION for medical use of the medicinal product Sildenafil-Pharmak (Sildenafil-Pharmak)

Composition:

Active substance: sildenafil;

1 tablet contains 28.09 mg of sildenafil citrate, equivalent to 20 mg of sildenafil;

Excipients: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, titanium dioxide (E 171), talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex tablets, white to almost white, with a smooth surface, film-coated.

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 breakdown. In addition to being present in the corpus cavernosum of the penis, PDE5 is also found in the pulmonary vascular system. Thus, sildenafil increases cGMP levels in smooth muscle cells of the pulmonary vessels, leading to their relaxation. In patients with pulmonary arterial hypertension, this may result in pulmonary vasodilation and, to a lesser extent, systemic vasodilation.

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-fold higher for PDE5 than for PDE6, which is involved in phototransduction in the retina, 80-fold higher than for PDE1, and 700-fold higher than for PDE2, 3, 4, 7, 8, 9, 10, and 11. Specifically, sildenafil has more than 4,000-fold higher selectivity for PDE5 than for PDE3, a cAMP-specific phosphodiesterase isoform involved in regulating cardiac contractility.

Sildenafil causes mild and transient reduction in systemic arterial pressure, which in most cases has no clinical manifestations. After prolonged administration of 80 mg three times daily to patients with systemic arterial hypertension, the mean reduction in systolic and diastolic blood pressure compared to baseline values was 9.4 mm Hg and 9.1 mm Hg, respectively. After prolonged administration of 80 mg three times daily to patients with pulmonary arterial hypertension, a less pronounced reduction in blood pressure was observed (a 2 mm Hg reduction in both systolic and diastolic pressure). 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 result in clinically significant effects on ECG parameters. After prolonged administration of 80 mg three times daily in patients with pulmonary arterial hypertension, no clinically significant effects on ECG parameters were observed.

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 through stenosed coronary arteries.

In several patients who underwent the 100-hue Farnsworth–Munsell test, mild and transient color discrimination abnormalities (blue/green) were observed one hour after taking 100 mg. These effects were not observed two hours later. The mechanism of this color vision change may be related to inhibition of PDE6, which is involved in the phototransduction cascade in the retina. Sildenafil did not affect visual acuity or contrast sensitivity. In a small placebo-controlled study among patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose 100 mg) did not demonstrate any significant changes in visual function tests (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 in 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 treatment groups: 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%) males and 209 (75%) females; the mean 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%) 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 shortening fraction <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. Use of prostacyclin, prostacyclin analogs, endothelin receptor antagonists, or arginine supplements as additional therapy was not permitted during the study. 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) with 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, greater efficacy was observed with higher doses (placebo-corrected improvements of 58 m, 65 m, and 87 m with 20 mg, 40 mg, and 80 mg three times daily, respectively).

According to 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 6-minute walk distance increased by 49 m (p = 0.0007) and 45 m (p = 0.0031), respectively, compared to placebo.

Improvement in 6-minute walk distance was evident after 4 weeks of treatment and was maintained at weeks 8 and 12. Overall, results were comparable 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 all sildenafil treatment groups, statistically significant reductions in mean pulmonary arterial pressure and pulmonary vascular resistance were observed compared to placebo. 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) with 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) with sildenafil 20 mg, 40 mg, and 80 mg three times daily, respectively. The percentage reduction in pulmonary vascular resistance at 12 weeks with 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 of at least one WHO functional class at 12 weeks was observed in a higher percentage of patients in all sildenafil groups (28%, 36%, and 42% of patients 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 previously untreated patients.

Patients from the core study met eligibility criteria for participation in a long-term open-label extension study. Over 3 years, 87% of patients received 80 mg three times daily. Overall, 207 patients received sildenafil 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 were estimated using the Kaplan–Meier method and were 96%, 91%, and 82%, respectively. One-, two-, and three-year survival rates in patients with WHO functional class II at baseline were 99%, 91%, and 84%, respectively, while in patients with WHO functional class III at baseline, 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 in 267 patients with pulmonary arterial hypertension stabilized on intravenous epoprostenol. The study included patients with pulmonary arterial hypertension due to idiopathic pulmonary arterial hypertension (212/267, 79%) or associated with connective tissue disease (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 in a few patients (5/267, 2%). Patients were randomized to receive sildenafil or placebo (with dose escalation from 20 mg to 40 mg and then to 80 mg three times daily based on 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 patients compared to placebo. A mean placebo-corrected increase in 6-minute walk distance of 26 m favored sildenafil (95% CI [confidence interval]: 10.8; 41.2) (p = 0.0009).

In patients with baseline 6-minute walk distance ≥325 m, treatment effect was 38.4 m in favor of sildenafil; in patients with baseline 6-minute walk distance <325 m, treatment effect was 2.3 m in favor of placebo. In patients with idiopathic 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. The mean placebo-corrected treatment effect was 3.9 mm Hg in favor of 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 3 years, 68% of patients received 80 mg three times daily. In the initial study, 134 patients received sildenafil; 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 in 103 clinically stable patients with pulmonary arterial hypertension (WHO functional classes II–III) receiving bosentan therapy for at least 3 months. Patients had idiopathic 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 idiopathic pulmonary arterial hypertension and those with connective tissue disease-associated pulmonary arterial hypertension. In patients with idiopathic 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 vs. bosentan monotherapy) and comparable to the known safety profile of sildenafil monotherapy (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Children. A randomized, double-blind, multicenter, placebo-controlled, parallel-group clinical trial was conducted in 234 patients aged 1 to 17 years to determine optimal dosing. Patients (38% male, 62% female) with body weight ≥8 kg had primary pulmonary hypertension (33%) or secondary pulmonary arterial hypertension related to congenital heart disease (systemic-pulmonary shunt—37%, surgical defect correction—30%). 63 of 234 (27%) patients were under 7 years of age (low-dose sildenafil = 2; medium dose = 17; high dose = 28; placebo = 16), and 171 of 234 (73%) were aged 7 years or older (low-dose sildenafil = 40; medium dose = 38; high dose = 49; placebo = 44). Most patients were initially in WHO functional class I (75/234, 32%) or II (120/234, 51%); fewer were in 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. Use of prostacyclin, prostacyclin analogs, and endothelin receptor antagonists during the study was not permitted. No patients received arginine supplements, nitrates, α-blockers, or strong 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 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 randomized into one of three groups receiving low (10 mg), medium (10–40 mg), or high (20–80 mg) doses of sildenafil three times daily or placebo. Actual doses depended on body weight. The proportion of patients receiving background 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 sufficient developmental level to perform the test. Children under 7 years (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-dose sildenafil 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. With medium and high doses of sildenafil, reductions in pulmonary vascular resistance index and mean pulmonary arterial pressure were 18% (95% CI: 2–32%) and 27% (95% CI: 14–39%), respectively, compared to placebo; low-dose sildenafil did not show statistically significant differences compared to placebo (difference: 2%). Medium- and high-dose groups showed 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 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 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 who received treatment in the short-term placebo-controlled study, 220 participated in a long-term open-label 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 treatment was 1696 days (excluding 5 patients who received placebo during the double-blind phase and did not receive treatment in the long-term extension).

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

During the study, 42 deaths occurred during treatment or follow-up. 37 deaths occurred before the data monitoring committee decided to reduce doses due to observed mortality imbalance with higher sildenafil doses. Of these 37 deaths, the number (%) in low-, medium-, and high-dose sildenafil groups were 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%), respectively. Five additional deaths occurred later. Deaths were related to pulmonary arterial hypertension. Pediatric patients with pulmonary arterial hypertension should not receive sildenafil doses exceeding recommended levels (see sections "Dosage and administration" and "Special precautions for use").

One year after the start of the placebo-controlled study, peak VO₂ was assessed. In 52% (59/114) of patients receiving sildenafil and capable of performing cardiopulmonary exercise testing, peak VO₂ did not decrease compared to baseline values at the start of sildenafil 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 of 59 neonates with persistent pulmonary hypertension of the newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN with 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 included 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 included 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 (Cmax) is reached within 30–120 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 doses ranging from 20 mg to 40 mg three times daily, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionally with dose. After administration of 80 mg three times daily, plasma sildenafil concentrations increase more than proportionally. In patients with pulmonary arterial hypertension, bioavailability of sildenafil after administration of 80 mg three times daily is on average 43% higher (90% CI: 27–60%) compared to lower doses. When sildenafil is taken with food, the rate of absorption is slowed, with a mean delay in time to maximum plasma concentration (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 steady-state volume of distribution of sildenafil is 105 L, indicating tissue distribution. After oral administration of 20 mg three times daily, the mean peak total plasma concentration of sildenafil at steady state is approximately 113 ng/mL. Sildenafil and its major circulating N-desmethyl metabolite are approximately 96% protein-bound. Protein binding is independent of total drug concentration.

Biotransformation.

Sildenafil is primarily metabolized 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 an elimination half-life of approximately 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 is 36% that of sildenafil). Further contribution to efficacy is unknown.

Elimination.

Total clearance of sildenafil is 41 L/h with a terminal elimination half-life of 3–5 hours. After oral or intravenous administration, sildenafil is excreted as metabolites, predominantly in feces (approximately 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 (aged 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 (aged 18–45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration is approximately 40%.

Renal impairment.

In patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil after a single 50 mg oral dose were unchanged. In patients 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 healthy 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 patients 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 dysfunction have not been studied.

Pharmacokinetics in populations.

In patients with pulmonary arterial hypertension receiving doses in the studied range of 20–80 mg three times daily, mean steady-state concentrations were 20–50% higher than in healthy volunteers. There was also a twofold increase in minimum plasma drug concentration (Cmin) compared to healthy volunteers. These data indicate lower clearance and/or higher bioavailability of orally administered sildenafil in patients with pulmonary arterial hypertension compared to healthy volunteers.

Children.

Pharmacokinetic profile analysis of sildenafil in patients participating in clinical trials demonstrated that drug exposure in children is body weight-dependent. Elimination half-life of sildenafil in plasma ranged from 4.2 to 4.24 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 in patients with body weights of 70 kg, 20 kg, and 10 kg, respectively. Cmax after single oral administration of 10 mg sildenafil was 24 ng/mL, 53 ng/mL, and 85 ng/mL in patients with body weights of 70 kg, 20 kg, and 10 kg, respectively. Tmax was approximately 1 hour and was nearly independent of body weight.

Clinical characteristics.

Indications.

Adults.

Treatment of patients with pulmonary arterial hypertension (WHO functional class II–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 diseases.

Children.

Treatment of pulmonary arterial hypertension in children with body weight above 20 kg. Efficacy 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 medicinal product;
• 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 strong 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 is related to prior use of PDE5 inhibitors or not (see section "Special precautions for use");
• The following diseases — because 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. Metabolism of sildenafil is primarily mediated by cytochrome P450 (CYP) isoenzymes, mainly CYP3A4 (major pathway) and CYP2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may decrease sildenafil clearance, while inducers may increase it (see sections "Dosage and administration" and "Contraindications").

In vivo studies. Evaluation of concomitant administration of oral sildenafil and intravenous epoprostenol has been conducted (see sections "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 sildenafil with other PDE5 inhibitors have not been studied in patients with pulmonary arterial hypertension (see section "Special precautions for use").

Results of population pharmacokinetic analysis of data obtained from clinical studies in pulmonary arterial hypertension indicate reduced clearance and/or increased oral bioavailability of sildenafil when administered 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 was 43% and 66% higher, respectively, in patients receiving CYP3A4 substrates and those receiving both CYP3A4 substrates and β-blockers, compared to patients not receiving these classes of drugs. At a dose of 80 mg three times daily, sildenafil exposure was five times higher than at a dose of 20 mg three times daily. This concentration range encompasses the increased exposure to sildenafil observed in specifically designed drug interaction studies with CYP3A4 inhibitors (except for the most potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and 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 bosentan 125 mg (a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19) twice daily and sildenafil 80 mg three times daily (at steady state) for 6 days resulted in a 63% reduction in sildenafil AUC. Population pharmacokinetic analysis of clinical trial data of sildenafil use in adult patients with pulmonary arterial hypertension, including a 12-week efficacy and safety study of oral sildenafil 20 mg three times daily added to stable-dose bosentan therapy (62.5–125 mg twice daily), indicates reduced sildenafil exposure with concomitant bosentan use, similar to that observed in healthy volunteers (see sections "Pharmacodynamics" and "Special precautions for use"). Careful monitoring of sildenafil efficacy is required in patients who are concomitantly receiving strong 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 a 1000% increase (11-fold) in plasma AUC. 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 AUC. Sildenafil does not affect the pharmacokinetics of saquinavir. Dosage recommendations are provided in the section "Dosage and administration".

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 found of the effect of azithromycin (500 mg daily for 3 days) on 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 co-administered with sildenafil (50 mg) in healthy volunteers, increased plasma concentrations of sildenafil by 56%. 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 anticipated. Therefore, dose adjustment is recommended when using CYP3A4 inhibitors (see section "Dosage and administration").

Population pharmacokinetic analysis in patients with pulmonary arterial hypertension indicates 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 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 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 relevant effect of sildenafil on CYP3A4.

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

Sildenafil (50 mg) did not prolong bleeding time induced 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) increased the AUC of bosentan (125 mg twice daily) by 50%. Population pharmacokinetic analysis of data from a study in adult patients with pulmonary arterial hypertension receiving background bosentan therapy (62.5–125 mg twice daily) indicates a 20% increase (95% confidence interval (CI): 9.8–30.8) 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 receiving 80 mg sildenafil three times daily (see section "Pharmacodynamics" and "Special precautions for use").

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 of 8 mm Hg was observed in patients in the supine position. The corresponding additional reduction in diastolic blood pressure in the supine position was 7 mm Hg. These additional reductions in blood pressure were similar in magnitude to those observed when healthy volunteers received sildenafil alone.

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 whose condition had been 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 whose condition has been stabilized on doxazosin therapy has occasionally been associated with symptomatic orthostatic hypotension. Reports included 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 for use").

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 when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. No positive clinical effect was observed in patients participating in the study 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).

Adding a single dose of sildenafil to sacubitril/valsartan at steady state in patients with arterial hypertension was associated with a significantly greater reduction in blood pressure compared to sacubitril/valsartan alone. Therefore, caution is advised when prescribing sildenafil to patients receiving sacubitril/valsartan.

Children.

Interaction studies have been conducted only in adults.

Special precautions for use.

The efficacy of sildenafil in patients with severe pulmonary arterial hypertension (WHO functional class IV) has not been established. If the clinical condition worsens, medicinal products recommended for the treatment of severe disease (e.g., epoprostenol) should be used. The benefit-risk ratio 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: idiopathic (primary) 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 degenerative retinal disorders such as retinitis pigmentosa (in some of these patients, genetic defects of retinal phosphodiesterase are present); therefore, the use of the drug is not recommended in such patients.

Vasodilatory effect.

Before administering sildenafil, physicians should carefully consider whether mild or moderate vasodilatory effects of sildenafil may adversely affect patients with certain concomitant conditions, such as arterial hypotension, hypovolemia, severe left ventricular outflow 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 arterial hypotension, which temporally coincided with sildenafil use. Most patients already had risk factors for cardiovascular disease. Many of these adverse reactions occurred during or immediately after sexual activity, and several occurred shortly after sildenafil use without sexual activity. Therefore, it is not possible to determine whether there is a direct relationship between the aforementioned 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 curvature, 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).

After the drug was introduced to the market, cases of prolonged erection and priapism have been reported. 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 sildenafil compared to those receiving placebo, leading to premature termination of the study.

Ocular adverse reactions.

Spontaneous reports of visual disturbances have been received during the use of sildenafil and other PDE5 inhibitors. Cases of non-arteritic anterior ischemic optic neuropathy, a rare condition, have also been reported and associated with the use of 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-adrenoreceptor blockers.

Sildenafil should be used with caution in patients taking alpha-adrenoreceptor 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 already taking alpha-adrenoreceptor blockers. Additionally, patients should be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Blood coagulation disorders.

Studies on human platelets have demonstrated that sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside in vitro. There is no information on the safety of sildenafil use in patients with coagulation disorders or acute peptic ulcer. Therefore, the use of sildenafil in such patient groups is possible only after careful assessment of the benefit-risk ratio.

Vitamin K antagonists.

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

Pulmonary venous occlusive disease.

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

Information on excipients. This medicinal product contains less than 1 mmol of sodium per tablet, i.e., essentially "sodium-free." This information may be communicated to 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 sildenafil-containing products used for erectile dysfunction, 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 reproductive age.

Due to insufficient data on the effects of Sildenafil-Farmak in pregnant women, the use of this drug in women of reproductive age 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 adverse effect of Sildenafil-Farmak on pregnancy, embryonic/fetal development. However, animal studies have demonstrated a toxic effect of sildenafil on postnatal development.

Due to insufficient data, the medicinal product Sildenafil-Farmak should not be used during pregnancy, except when there is a clear medical 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 during drug use, but the amount transferred via milk is expected to be too low to cause adverse reactions. Physicians prescribing this drug to breastfeeding mothers should carefully weigh the clinical necessity of the drug for the mother against the potential risk of adverse reactions in the breastfed infant.

Fertility.

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

Ability to influence reaction speed when driving or operating machinery.

Sildenafil-Farmak has a moderate effect 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 the use of Sildenafil-Farmak may affect them before driving or operating machinery.

Method of Administration and Dosage

Sildenafil-Pharmak is intended for oral administration. Tablets should be taken approximately 6–8 hours apart, regardless of food intake.

Initiation and monitoring of treatment must be performed by a physician experienced in the management of pulmonary arterial hypertension. In case of clinical deterioration during treatment with Sildenafil-Pharmak, alternative therapy should be considered.

Adults.

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

Patients taking other medicinal products.

In general, any dose adjustment should be performed only after careful assessment of benefit-risk ratio. When prescribing sildenafil to patients already taking CYP3A4 inhibitors such as erythromycin or saquinavir, consideration should be given to reducing the dose of Sildenafil-Pharmak to 20 mg twice daily. When co-administering sildenafil with more potent CYP3A4 inhibitors such as clarithromycin, telithromycin, and nefazodone, the dose of Sildenafil-Pharmak 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 for elderly patients. 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). The need to reduce the dose to 20 mg twice daily may be considered after careful assessment of benefit and risk, 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). The need to reduce the dose to 20 mg twice daily may be considered after careful assessment of benefit and risk, and only if treatment is poorly tolerated.

Sildenafil-Pharmak 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 Sildenafil-Pharmak does not result in worsening of pulmonary arterial hypertension. However, to avoid potential sudden clinical deterioration upon discontinuation, the dose should be tapered gradually. Close monitoring of the patient is recommended during the period of treatment withdrawal.

Children.

The tablet form of the medicinal product may be used in this patient group only when children are able to swallow tablets safely, which is usually possible from the age of 5 years.

The dose of the drug in children with body weight above 20 kg is 20 mg three times daily. Higher doses should not be used in this patient group. In a long-term open-label study, an increased number of deaths was observed in patients who received doses higher than recommended. Therefore, children with pulmonary arterial hypertension should not be treated with doses higher than recommended (see section "Pharmacological properties").

Infants under 1 year of age and newborns.

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

The safety and efficacy of Sildenafil-Pharmak in children under 1 year of age have not been established, and information is lacking. Therefore, the drug should not be administered to 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, 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 necessary. 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.

Summary of data from the safety profile.

In the main placebo-controlled study of sildenafil use in pulmonary arterial hypertension, a total of 207 patients were randomized and received treatment at doses of 20 mg, 40 mg, or 80 mg three times a day, 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 (which is 4 times the recommended dose of 20 mg three times daily), and after 3 years, 87% of the 183 patients in the active treatment group were receiving sildenafil 80 mg three times daily.

In a placebo-controlled study evaluating sildenafil as an add-on therapy to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients received sildenafil (with fixed-dose titration starting at 20 mg, increasing to 40 mg, and then to 80 mg three times daily based on tolerability) and epoprostenol; 131 patients received placebo and epoprostenol. The treatment duration was 16 weeks. The overall rate of treatment discontinuation due to adverse reactions among patients receiving sildenafil/epoprostenol was 5.2%, compared to 10.7% in the placebo/epoprostenol group. Adverse reactions that were newly reported 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; after 3 years, 68% of the 133 patients in the active treatment group were receiving sildenafil 80 mg three times daily.

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

Adverse reactions occurring in > 1% of patients treated with sildenafil and observed more frequently (difference > 1%) with sildenafil use in the main study or according to combined results from both placebo-controlled studies of sildenafil in the treatment of pulmonary arterial hypertension at doses of 20 mg, 40 mg, 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), frequency not known (cannot be estimated from available data). Within each category, adverse reactions are listed in descending order of severity.

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, hypoaesthesia.

Eye disorders: common — retinal hemorrhage, visual disturbance, blurred vision, photophobia, chromatopsia, cyanopsia, eye irritation, hyperemia/eye redness; rare — decreased visual acuity, diplopia, unusual eye sensations; frequency not known — non-arteritic anterior ischemic optic neuropathy*, retinal vessel 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 sildenafil involving patients aged 1–17 years with pulmonary arterial hypertension, a total of 174 patients received low (10 mg for patients weighing > 20 kg; no patients with body weight ≤ 20 kg in the low-dose group), medium (10 mg for patients weighing ≥ 8–20 kg; 20 mg for patients weighing ≥ 20–45 kg; 40 mg for patients weighing > 45 kg), or high (20 mg for patients weighing ≥ 8–20 kg; 40 mg for patients weighing ≥ 20–45 kg; 80 mg for patients weighing > 45 kg) doses of sildenafil three times daily; 60 patients received placebo.

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

Of the 234 children who received treatment in the short-term placebo-controlled study, 220 patients participated in the long-term extension study. Patients receiving active sildenafil therapy continued on the same treatment 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) were: upper respiratory tract infections (31%), headache (26%), vomiting (22%), bronchitis (20%), pharyngitis (18%), increased body temperature (17%), diarrhea (15%), influenza, and epistaxis (each at 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 receiving 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 at a frequency ≥ 1% in patients receiving sildenafil (combined doses) were pneumonia (7.4%), heart failure and pulmonary hypertension (each 5.2%), upper respiratory tract infections (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 infections (each 1.3%).

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets per blister. 9 blisters (10×9) together with the instructions for medical use are placed in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM PHARMACEUTICAL COMPANY LLC.

Manufacturer's location and address of business activity.

5 Budyndustrії St., Kyiv, 01013, Ukraine.

Marketing Authorization Holder.

FARMAC, Public Joint-Stock Company, Ukraine.

Address of the Marketing Authorization Holder.

63 Kyrylivska St., Kyiv, 04080, Ukraine.

Sildenafil-Farmak

(Sildenafil-Farmak)

Composition:

Active substance: sildenafil;

One tablet contains 28.09 mg of sildenafil citrate, equivalent to 20 mg of sildenafil;

Excipients: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium croscarmellose, anhydrous colloidal silicon dioxide, magnesium stearate, hypromellose, titanium dioxide (E 171), talc.

Dosage form. Film-coated tablets.

Main physicochemical properties: white to almost white, biconvex tablets with smooth surface, film-coated.

Pharmacotherapeutic group.

Agents used in erectile dysfunction.

ATC code G04BE03.

Pharmacological properties.

Pharmacodynamics.

Sildenafil is a potent and selective inhibitor of type 5 cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE5)—the enzyme responsible for cGMP breakdown. In addition to its presence 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 the pulmonary vessels, leading to their relaxation. In patients with pulmonary arterial hypertension, this may result in vasodilation of the pulmonary vascular bed and, to a lesser extent, in systemic blood vessel 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 than for PDE6, which is involved in the phototransduction process in the retina, 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 4000-fold higher selectivity for PDE5 than for PDE3, the cAMP-specific phosphodiesterase isoform involved in the 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 arterial hypertension, the mean reduction in systolic and diastolic blood pressure compared to baseline values was 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 of 2 mm Hg in both systolic and diastolic pressure). 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. After long-term administration of 80 mg three times daily in patients with pulmonary arterial hypertension, no clinically significant effects on ECG parameters were observed.

In a study evaluating 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 pressure 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 through stenotic coronary arteries.

In several patients undergoing the 100-hue Farnsworth-Munsell test, mild and transient color discrimination abnormalities (blue/green) were detected one hour after taking 100 mg. These effects were not observed after two hours. The mechanism of this color vision change may be related to inhibition of PDE6, which is involved in the phototransduction cascade in the retina. Sildenafil did not affect visual acuity or contrast sensitivity. In a small placebo-controlled study among patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose 100 mg) did not demonstrate any significant changes in visual test results (visual acuity, Amsler grid, traffic light color discrimination 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 in 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%) males and 209 (75%) females; the mean age was 49 years (range 18–81 years); baseline 6-minute walk distance ranged from 100 to 450 meters (mean 344 meters). In 175 (63%) of the included patients, primary pulmonary hypertension was diagnosed; in 84 (30%), pulmonary arterial hypertension associated with connective tissue disease; and in 18 (7%), pulmonary arterial hypertension following surgical correction of congenital heart defects. The majority of patients belonged to WHO functional class II (107/277, 39%) or III (160/277, 58%), with mean baseline 6-minute walk distances of 378 m and 326 m, respectively; a smaller proportion initially belonged to class I (1/277, 0.4%) or IV (9/277, 3%). Patients with left ventricular ejection fraction < 45% or left ventricular shortening fraction < 0.2% were not studied.

Sildenafil (or placebo) was added to the patients' background therapy, which could include combinations of anticoagulants, digoxin, calcium channel blockers, diuretics, or oxygen. The use of prostacyclin, prostacyclin analogs, endothelin receptor antagonists as additional therapy, as well as arginine supplements, was not allowed during the study. Patients whose previous bosentan therapy was ineffective were excluded from the study.

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

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

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

In patients from all sildenafil treatment groups, statistically significant reductions in mean pulmonary artery pressure and pulmonary vascular resistance were achieved compared to placebo recipients. The treatment effect, placebo-corrected, for mean pulmonary artery pressure was –2.7 mm Hg (p = 0.04), –3.0 mm Hg (p = 0.01), and –5.1 mm Hg (p < 0.0001) with sildenafil 20 mg, 40 mg, and 80 mg three times daily, respectively. The treatment effect, placebo-corrected, for pulmonary vascular resistance was 178 dyn·s/cm⁵ (p = 0.0051), 195 dyn·s/cm⁵ (p = 0.0017), and 320 dyn·s/cm⁵ (p < 0.0001) with sildenafil 20 mg, 40 mg, and 80 mg three times daily, respectively. The percentage reduction in pulmonary vascular resistance at 12 weeks with 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 of at least one WHO functional class at 12 weeks was observed in a higher percentage of patients in all sildenafil treatment groups (28%, 36%, and 42% of patients receiving sildenafil 20 mg, 40 mg, and 80 mg three times daily, respectively) compared to placebo (7%). The 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 previously untreated patients.

Patients who participated in the baseline study met the eligibility criteria for enrollment in a long-term open-label extension study. Over 3 years, 87% of patients received 80 mg three times daily. Overall, 207 patients received sildenafil in the baseline study; their long-term survival was assessed for at least 3 years. In this population, one-, two-, and three-year survival rates were estimated using the Kaplan-Meier method and were 96%, 91%, and 82%, respectively. One-, two-, and three-year survival rates in patients with WHO functional class II at baseline were 99%, 91%, and 84%, respectively, while in patients with WHO functional class III at baseline, 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 in 267 patients with pulmonary arterial hypertension stabilized on intravenous epoprostenol. The study included patients with the following forms of pulmonary arterial hypertension: 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%), a smaller number were in class I (3/267, 1%) or IV (16/267, 6%); functional class was unknown in a few patients (5/267, 2%). Patients were randomized to receive either sildenafil or placebo (with fixed dose titration starting at 20 mg, increasing to 40 mg, and then to 80 mg three times daily according to tolerability) in combination with intravenous epoprostenol.

The primary endpoint was the change in 6-minute walk distance at week 16 compared to baseline. Statistically significant increases in 6-minute walk distance were observed in the sildenafil groups compared to placebo. A mean placebo-corrected increase in walk distance of 26 m was observed in favor of sildenafil (95% CI [confidence interval]: 10.8; 41.2) (p = 0.0009).

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

Patients receiving sildenafil achieved statistically significant reductions in mean pulmonary artery pressure compared to those receiving placebo. A mean placebo-corrected treatment effect of 3.9 mm Hg in favor of sildenafil was observed (95% CI: –5.7; –2.1) (p = 0.00003). Time to clinical worsening, a secondary endpoint, was defined as the time from randomization to the first occurrence of clinical worsening (death, lung transplantation, initiation of bosentan therapy, or clinical worsening requiring changes in epoprostenol therapy). Sildenafil significantly delayed the time to clinical worsening of pulmonary arterial hypertension 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 in the epoprostenol combination study.

Patients enrolled in the epoprostenol combination study met the criteria for inclusion in a long-term open-label extension study. Over 3 years, 68% of patients received 80 mg three times daily. In the initial study, a total of 134 patients received sildenafil therapy; 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 in 103 clinically stable patients with pulmonary arterial hypertension (WHO functional classes II–III) who had been on 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 either sildenafil (20 mg three times daily) in combination with bosentan (62.5–125 mg twice daily) or placebo. The primary endpoint was defined as the change in 6-minute walk distance at week 12 compared to baseline. The results showed no significant difference in mean changes in 6-minute walk distance at week 12 compared to baseline between the 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 pulmonary arterial hypertension associated with connective tissue disease. 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 the sildenafil and placebo groups, respectively. In contrast, in patients with pulmonary arterial hypertension associated with connective tissue disease (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 the sildenafil and placebo groups, respectively.

Overall, adverse reactions were generally similar in the two treatment groups (sildenafil in combination with bosentan and bosentan monotherapy) and comparable to the known safety profile of sildenafil monotherapy (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

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

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

The primary objective of the study 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 whose development allowed performance of this 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 sildenafil three times daily or placebo. Actual drug doses administered in each group depended on body weight. The proportion of patients receiving background supportive therapy (anticoagulants, digoxin, calcium channel blockers, diuretics, and/or oxygen) at baseline was similar in the combined sildenafil group (47.7%) and the placebo group (41.7%).

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

A dose-dependent increase in pulmonary vascular resistance index and mean pulmonary artery pressure was observed. With medium and high doses of sildenafil, reductions in pulmonary vascular resistance index and mean pulmonary artery pressure of 18% (95% CI: 2–32%) and 27% (95% CI: 14–39%), respectively, were demonstrated compared to placebo; whereas low-dose sildenafil did not show a statistically significant difference compared to placebo (difference 2%). Medium- and high-dose sildenafil groups demonstrated changes in mean pulmonary artery 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 treatment groups (10%, 4%, and 15% with low, medium, and high doses of sildenafil, 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 treatment groups. Patients with body weight ≤ 20 kg were included in medium- or high-dose groups (1:1), while patients with body weight > 20 kg were included in low-, medium-, and high-dose groups (1:1:1). Of the 229 patients receiving sildenafil, 55, 74, and 100 patients were assigned to low-, medium-, and high-dose groups, respectively. During both short- and long-term studies, the total treatment duration from the start of the double-blind phase for individual patients ranged from 3 to 3129 days. For sildenafil groups, the mean duration of sildenafil treatment 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 for patients with baseline body weight > 20 kg were estimated by the Kaplan-Meier method and were 94%, 93%, and 85% with low, medium, and high doses, respectively. For patients with baseline body weight ≤ 20 kg, survival rates were 94% and 93% with medium and high doses, respectively (see sections "Special precautions" 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 an observed imbalance in mortality rates 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 were subsequently recorded. Deaths were related to pulmonary arterial hypertension. Pediatric patients with pulmonary arterial hypertension should not receive sildenafil doses exceeding the recommended ones (see sections "Dosage and administration" and "Special precautions").

One year after the start of the placebo-controlled study, peak VO₂ was assessed. In 52% (59/114) of the total number of patients receiving sildenafil and capable of performing cardiopulmonary exercise testing, no decrease in peak VO₂ was observed compared to baseline levels recorded at the start of sildenafil administration. Similarly, in 191 of 229 patients (83%) receiving sildenafil, functional status according to WHO classification remained stable or improved at the one-year assessment.

Persistent pulmonary hypertension of the newborn (PPHN).

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) from >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 the following: treatment failure rate, defined as the need for additional PPHN therapy, requirement for extracorporeal membrane oxygenation (ECMO), or patient death during the study, and duration of NO inhalation 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% and 20.0% in the IV sildenafil + inhaled NO group and inhaled NO + placebo group, respectively). The mean duration of NO inhalation 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 recorded 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. The 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 drug withdrawal syndrome (4 [13.8%] patients each), bradycardia (3 [10.3%] patients). In the inhaled NO + placebo group, such 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 (Cmax) is reached within 30–120 minutes (mean 60 minutes) after oral administration on an empty stomach. The mean absolute bioavailability after oral administration is 41% (range 25–63%). After oral administration of sildenafil in doses ranging from 20 mg to 40 mg three times daily, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionally with dose. After administration of 80 mg three times daily orally, an increase in sildenafil plasma concentration greater than proportional is observed. In patients with pulmonary arterial hypertension, the bioavailability of sildenafil after administration of 80 mg three times daily is on average 43% higher (90% CI: 27–60%) compared to lower doses. When sildenafil is taken with food, the absorption rate is slowed, with a mean delay in time to maximum plasma concentration (Tmax) of 60 minutes and a mean reduction in Cmax of 29%, although the extent of absorption is not significantly altered (AUC decreases by 11%).

Distribution.

The mean apparent volume of distribution of sildenafil is 105 L, indicating its distribution into tissues. After oral administration of sildenafil 20 mg three times daily, the mean peak total plasma concentration of sildenafil 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 primarily metabolized 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% of the drug's activity. The N-desmethyl metabolite is further metabolized with an elimination half-life of approximately 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). The further impact on 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 eliminated as metabolites predominantly in feces (approximately 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 (aged 65 years and older) had reduced sildenafil clearance, resulting in a 90% increase in plasma concentrations of sildenafil and active N-desmethyl metabolite compared to younger healthy volunteers (aged 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 patients with mild or moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil after a single oral dose of 50 mg were unchanged. In patients with severe renal impairment (creatinine clearance < 30 mL/min), sildenafil clearance was reduced, leading to mean increases in AUC and Cmax by 100% and 88%, respectively, compared to values in healthy volunteers of the same age group without renal impairment. Additionally, in patients with severe renal impairment, AUC and Cmax values of the N-desmethyl metabolite were significantly increased by 200% and 79%, respectively, compared to values in patients with normal renal function.

Hepatic impairment.

In patients with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, leading to increases in AUC (85%) and Cmax (47%) compared to values in volunteers of the same age group without hepatic impairment. Additionally, in patients with severe hepatic impairment, AUC and Cmax values of the N-desmethyl metabolite were significantly increased by 154% and 87%, respectively, compared to values in patients with normal liver function. The pharmacokinetics of sildenafil in patients with severe hepatic dysfunction 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. A doubling of minimum plasma drug concentration (Cmin) levels was also observed compared to healthy volunteers. These data indicate lower clearance and/or higher bioavailability of sildenafil after oral administration in patients with pulmonary arterial hypertension compared to healthy volunteers.

Pediatrics.

Analysis of the pharmacokinetic profile of sildenafil in patients participating in clinical studies demonstrated that drug exposure in children is body weight-dependent. The elimination half-life of sildenafil in plasma was 4.2–4.24 hours at body weights of 10–70 kg and showed no clinically significant differences. Cmax after a single oral dose of 20 mg sildenafil was 49.104 and 165 ng/mL in patients with body weights of 70 kg, 20 kg, and 10 kg, respectively. Cmax after a single oral dose of 10 mg sildenafil was 24 ng/mL, 53 ng/mL, and 85 ng/mL in patients with body weights of 70 kg, 20 kg, and 10 kg, respectively. Tmax was approximately 1 hour and was almost 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. The 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 medicinal product;
• 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 is related to prior use of PDE5 inhibitors (see section "Special precautions for use");
• the following conditions — because 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 mmHg) 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. The metabolism of sildenafil is mediated primarily by the cytochrome P450 (CYP) isoenzymes 3A4 (main pathway) and 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce the clearance of sildenafil, while inducers may increase it (see sections "Dosage and administration" 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., bosentan, 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 sildenafil with other PDE5 inhibitors have not been studied in patients with pulmonary arterial hypertension (see section "Special precautions for use").

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 who used CYP3A4 substrates and CYP3A4 substrates plus β-blockers was 43% and 66% higher, respectively, compared to patients not using these classes of drugs. When administered at a dose of 80 mg three times daily, sildenafil exposure was five times higher than exposure observed with a dose of 20 mg three times daily. This concentration range encompasses the increased exposure to sildenafil 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, which was 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 the AUC of sildenafil. Population pharmacokinetic analysis of clinical trial data of 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 exposure to sildenafil when used concomitantly with bosentan, similar to the reduction observed in healthy volunteers (see sections "Pharmacodynamics" and "Special precautions for use"). Careful monitoring of sildenafil efficacy is required in patients who are concomitantly using such potent CYP3A4 inducers 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 Cmax of sildenafil and a 1000% increase (11-fold) in AUC of sildenafil 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 Cmax of sildenafil and a 210% increase in AUC of sildenafil. Sildenafil does not affect the pharmacokinetics of saquinavir. Dosage recommendations are provided in the section "Dosage and administration".

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 the effect of azithromycin (500 mg daily for 3 days) on 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 administered concomitantly 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 anticipated. Therefore, dose adjustment is recommended when using CYP3A4 inhibitors (see section "Dosage and administration").

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 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 also 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 prolong bleeding time induced by acetylsalicylic acid (150 mg).

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

In a study involving 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 receiving baseline therapy with bosentan (62.5–125 mg twice daily) indicates a 20% increase (95% confidence interval (CI): 9.8–30.8) in AUC of bosentan when sildenafil is used concomitantly at steady state (20 mg three times daily), with a smaller magnitude than observed in healthy volunteers receiving 80 mg sildenafil three times daily (see section "Pharmacodynamics" and "Special precautions for use").

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 patients lying supine was observed by 8 mmHg. The corresponding additional reduction in diastolic blood pressure in the supine position was 7 mmHg. In magnitude, these additional reductions in blood pressure were similar to those observed when healthy volunteers received sildenafil alone.

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 whose condition had been stabilized on doxazosin therapy. In these study groups, mean additional reductions in systolic and diastolic blood pressure in the supine position were 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, and mean additional reductions in blood pressure in the standing position were 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively. Concomitant use of sildenafil and doxazosin in patients whose condition has been stabilized on doxazosin therapy has occasionally been associated with symptomatic orthostatic hypotension. These reports described episodes of dizziness and pre-syncope, but without syncope. Concomitant use of sildenafil in patients taking α-adrenergic blockers may lead to symptomatic hypotension in susceptible individuals (see section "Special precautions for use").

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

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 additive systemic blood pressure-lowering effects when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. No positive clinical effect was observed in patients participating in the study 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).

Adding a single dose of sildenafil to sacubitril/valsartan at steady state in patients with arterial hypertension was associated with significantly greater blood pressure reduction compared to sacubitril/valsartan alone. Therefore, caution should be exercised when prescribing sildenafil to patients receiving sacubitril/valsartan.

Children.

Interaction studies have been conducted only in adults.

Special precautions for use.

The efficacy of sildenafil 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 ratio of sildenafil in patients with pulmonary arterial hypertension WHO functional class I has not been determined. Clinical studies on 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 retinopathy.

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 the drug is not recommended in this patient group.

Vasodilatory effect.

Before administering sildenafil, physicians should carefully consider whether the mild to moderate vasodilatory effect of sildenafil could adversely affect patients with certain underlying conditions, such as arterial 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 adverse cardiovascular events have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, arterial hypertension, and arterial hypotension, which temporally coincided with sildenafil use. Most patients already had risk factors for cardiovascular disease. Many adverse events occurred during or immediately after sexual activity, and several occurred shortly after sildenafil use without sexual activity. Therefore, it is not possible to determine whether there is a direct relationship between the reported adverse events and sildenafil or other factors.

Priapism.

Sildenafil should be used with caution in patients with anatomical deformation of the penis (e.g., penile angulation, cavernosal 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 help. 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 sildenafil compared to those receiving placebo, leading to the premature termination of the study.

Ocular adverse reactions.

Spontaneous reports of visual disturbances have been received during the use of sildenafil and other PDE5 inhibitors. Cases of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition, have also been reported in observational studies and were associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). In case of any sudden visual loss, 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-adrenergic blockers. Patients should also be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Blood coagulation disorders.

Studies on human platelets have demonstrated that sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside in vitro. There is no information on the safety of sildenafil use in patients with coagulation disorders or active peptic ulcer disease. Therefore, the use of sildenafil in these patient groups is possible only after careful assessment of the benefit-risk ratio.

Vitamin K antagonists.

In patients with pulmonary arterial hypertension, the risk of bleeding increases 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 the use of vasodilators (mainly prostacyclin). Therefore, if signs of pulmonary edema occur during sildenafil treatment in patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be suspected.

Information on excipients. This medicinal product contains less than 1 mmol of sodium per tablet, i.e., essentially "sodium-free." This information may be communicated to 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 sildenafil-containing products used for erectile dysfunction, have not been studied in patients with pulmonary arterial hypertension. Therefore, the use of such combinations is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

Women of reproductive age.

Due to insufficient data on the effects of Sildenafil-Pharmak in pregnant women, the use of this drug is not recommended in women of reproductive age who may become pregnant, 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 of Sildenafil-Pharmak on pregnancy, embryo/fetal development. However, animal studies have demonstrated a toxic effect of sildenafil on postnatal development.

Due to insufficient data, Sildenafil-Pharmak should not be used during pregnancy except in cases of urgent medical need.

Lactation.

There are no adequate and well-controlled studies in women during lactation. Data from one woman show 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 insufficient to cause adverse effects. Physicians prescribing this drug to breastfeeding mothers should carefully weigh the clinical need for the drug in the mother against the potential risk of adverse reactions in the breastfed infant.

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.

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

Method of Administration and Dosage

Sildenafil-Pharmak is intended for oral administration. The tablets should be taken at approximately 6–8 hour intervals, regardless of food intake.

Treatment initiation and monitoring should be performed by a physician experienced in managing pulmonary arterial hypertension. If clinical worsening occurs during treatment with Sildenafil-Pharmak, alternative therapies should be considered.

Adults.

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

Patients taking other medicinal products.

In general, any dose adjustment should only be performed after careful benefit-risk assessment. When sildenafil is prescribed to patients already taking CYP3A4 inhibitors such as erythromycin or saquinavir, consideration should be given to reducing the dose of Sildenafil-Pharmak to 20 mg twice daily. When co-administering sildenafil with more potent CYP3A4 inhibitors such as clarithromycin, telithromycin, and nefazodone, the dose of Sildenafil-Pharmak is recommended to be reduced to 20 mg once daily. For information on the 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 those with severe renal impairment (creatinine clearance < 30 mL/min). The need to reduce the dose 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). The need to reduce the dose to 20 mg twice daily may be considered after careful benefit-risk assessment and only if treatment is poorly tolerated.

Sildenafil-Pharmak 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 Sildenafil-Pharmak 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 patient monitoring is recommended during the treatment withdrawal period.

Children.

The tablet formulation may be administered to this patient group only when children are able to swallow tablets safely, which is generally possible from the age of 5 years.

The dose of the medicinal product for children with body weight above 20 kg is 20 mg three times daily. Higher doses should not be used in this patient group. In a long-term open-label study, an increased number of deaths was observed in patients who received doses higher than recommended. Therefore, children with pulmonary arterial hypertension should not be treated with doses higher than those recommended (see 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 included in the approved indications and the risks of such treatment outweigh the potential benefits (see section "Pharmacodynamics").

The safety and efficacy of Sildenafil-Pharmak in children under 1 year of age have not been established, and there is no available information. Therefore, the medicinal product should not be administered to children under 1 year of age or to children with body weight below 20 kg.

Overdose.

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

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

Adverse Reactions.

Summary of data from the safety profile.

In the core placebo-controlled study of sildenafil use in pulmonary arterial hypertension, a total of 207 patients were randomized and received treatment at doses of 20 mg, 40 mg, or 80 mg three times a day, 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 core study, 259 participated in the long-term extension study. They received doses up to 80 mg three times daily (which is 4 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 sildenafil at a dose of 80 mg three times daily.

In a placebo-controlled study evaluating sildenafil as an add-on therapy to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients received sildenafil (with fixed-dose titration starting at 20 mg, increasing to 40 mg, and then to 80 mg three times daily based on tolerability) and epoprostenol; 131 patients received placebo and 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% among those receiving placebo/epoprostenol. Adverse reactions that were newly reported 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, 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 the 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 sildenafil at a dose of 80 mg three times daily.

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

Adverse reactions occurring in > 1% of patients treated with sildenafil and observed more frequently (difference > 1%) with sildenafil use in the core study or based on combined results from both placebo-controlled studies of sildenafil in the treatment of pulmonary arterial hypertension at doses of 20 mg, 40 mg, 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 and < 1/10), rare (≥ 1/1000 and < 1/100), frequency not known (cannot be estimated from available data). Within each category, adverse reactions are listed in descending order of severity.

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, hypoaesthesia.

Eye disorders: common — retinal hemorrhage, visual disturbance, blurred vision, photophobia, chromatopsia, cyanopsia, eye irritation, hyperemia/eye redness; rare — decreased visual acuity, diplopia, unusual eye sensations; 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, hematospermia, 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 using sildenafil for the treatment of erectile dysfunction.

Children.

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

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

Of the 234 children who received treatment in the short-term placebo-controlled study, 220 patients participated in the 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 at a frequency > 10% in 229 patients receiving sildenafil treatment (combined dose group, including 9 patients who did not participate in the long-term study) were: upper respiratory tract infections (31%), headache (26%), vomiting (22%), bronchitis (20%), pharyngitis (18%), increased body temperature (17%), diarrhea (15%), influenza, and epistaxis (each at 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 receiving 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 at a frequency ≥ 1% in patients receiving sildenafil (combined doses) were pneumonia (7.4%), heart failure and pulmonary hypertension (each at 5.2%), upper respiratory tract infections (3.1%), right ventricular heart failure and gastroenteritis (each at 2.6%), syncope, bronchitis, bronchopneumonia, and pulmonary arterial hypertension (each at 2.2%), chest pain and dental caries (each at 1.7%), and cardiogenic shock, viral gastroenteritis, and urinary tract infections (each at 1.3%).

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister. 9 blisters (10×9) together with the instruction for medical use are placed in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC NFV "MIKROKHIM"

Manufacturer's location and address of its business activity.

24-V Promyslova Street, Severodonetsk, Luhansk Oblast, 93400, Ukraine.

Marketing authorization holder.

JSC "Farmak", Ukraine.

Address of the marketing authorization holder.

63 Kyrylivska Street, Kyiv, 04080, Ukraine.