Sildenafil 20 mg Tablet, Film Coated, 20-count — NDC 43353-345-20 (Billing 43353-0345-20)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.

Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE-6, greater than 80-fold for PDE-1, greater than 700-fold for PDE-2, PDE-3, PDE-4, PDE-7, PDE-8, PDE-9, PDE-10, and PDE-11). The approximately 4,000-fold selectivity for PDE-5 versus PDE-3 is important because PDE-3 is involved in control of cardiac contractility.

Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE-6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2) ] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets.

The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.

12.2Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [ Study 1 in Clinical Studies (14) ] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown.

Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65) The number of patients per treatment group varied slightly for each parameter due to missing assessments. Sildenafil 20 mg three times a day (n = 65) mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn∙s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn∙s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [Study 3 in Clinical Studies (14)] , there were no significant differences in the effects on hemodynamic variables between doses.

Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1–2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range.

Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4) ] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinical… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.

Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE-6, greater than 80-fold for PDE-1, greater than 700-fold for PDE-2, PDE-3, PDE-4, PDE-7, PDE-8, PDE-9, PDE-10, and PDE-11). The approximately 4,000-fold selectivity for PDE-5 versus PDE-3 is important because PDE-3 is involved in control of cardiac contractility.

Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE-6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2) ] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets.

The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.

12.3Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25–63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%.

The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.

Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug.

In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours.

After oral administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function.

None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20–50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers.

Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary hypertension compared to healthy volunteers. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18–45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively.

Renal Impairment In volunteers with mild (CLcr = 50–80 mL/min) and moderate (CLcr = 30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr < 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function.

Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. P… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [ Study 1 in Clinical Studies (14) ] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown.

Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65) The number of patients per treatment group varied slightly for each parameter due to missing assessments. Sildenafil 20 mg three times a day (n = 65) mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn∙s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn∙s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [Study 3 in Clinical Studies (14)] , there were no significant differences in the effects on hemodynamic variables between doses.

Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1–2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range.

Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4) ] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported.

After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).

Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE-6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry.

14 CLINICAL STUDIES Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World Health Organization (WHO) functional classes II–III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen.

The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.

Patients were randomized to receive placebo (n=70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18–81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343).

The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45–50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (Figure 4), indicating no additional clinical benefit from doses higher than 20 mg three times a day.

The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12. Figure 4. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval) Figure 5 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and secondary hemodynamic parameters.

Figure 5. Placebo Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval) Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily. Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study.

At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil. Without a control group, these data must be interpreted cautiously.

Figure 4 Figure 5 Study 2 (Sildenafil co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were stabilized on intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters).

Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO f… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis.

Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day.