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12 CLINICAL PHARMACOLOGY .

12.1Mechanism of Action The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum.

Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.

Binding Characteristics Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3.

PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [see Clinical Pharmacology ( 12.2 ) ] .

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo .

12.2Pharmacodynamics Effects of S ildenafil on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan®), after sildenafil administration compared with placebo. Most studies assessed the efficacy of sildenafil approximately 60 minutes post dose. The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration.

The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Effects of VYBRIQUE on Blood Pressure: Single oral doses (50 mg, 75 mg, 100 mg) of VYBRIQUE administered to 12 healthy young volunteers produced decreases in supine blood pressure. The placebo-subtracted mean maximum decreases in systolic/diastolic blood pressure were 6.1/2.8 mmHg after a single 100 mg dose.

Subjects were under fasting conditions and lay in the supine position for the first 4 hours post-dose and were not initially titrated. The decrease in supine blood pressure was most notable approximately 1-2 hours after dosing. Figure 1 : Mean Change from Baseline in Supine Systolic Blood Pressure, Healthy Volunteers Single oral doses of 50 mg, 75 mg, 100 mg of VYBRIQUE administered to 12 elderly volunteers produced decreases in supine blood pressure.

The placebo-subtracted maximum mean decreases in systolic/diastolic blood pressure were 13.7/8.5 mmHg after a single 100 mg dose. Subjects were under fasting conditions and lay in the supine position for the first 4 hours post-dose and were not initially titrated. The decrease in supine blood pressure was gen… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum.

Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.

Binding Characteristics Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3.

PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [see Clinical Pharmacology ( 12.2 ) ] .

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo .

12.3Pharmacokinetics Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25-63%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil.

Both sildenafil and the metabolite have terminal half-lives of about 4 hours. Figure 6 : Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers Absorption and Distribution: VYBRIQUE is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 300 minutes (median 80 minutes) of oral dosing in the fasted state.

After a single dose of 100 mg of VYBRIQUE in adult males, the mean (coefficient of variation, %) peak plasma concentration (Cmax) and area under the concentration curve (AUC) of sildenafil were 503.5 (37.7%) ng/mL and 1902.4 (36.3%) ng·h/mL, respectively. When VYBRIQUE is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 87 minutes and a mean reduction in Cmax of 45%. AUC is not impacted by food.

In a clinical study in 35 healthy males (18-55 years old) where VYBRIQUE 100 mg was administered in fed conditions with or without water, no clinically significant differences in pharmacokinetics of sildenafil and its major N-desmethyl metabolite was observed. 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. Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients. Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and 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 PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. 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.

After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach. Pharmacokinetics in Special Populations Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values 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 [ see Dosage and Administration ( 2.3 ), and Use in Specific Populations ( 8.5 ) ] 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) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment [ see Dosage and Administration ( 2.3 ), and Use in Specific Populations ( 8.6 ) ] .

In addition, N-desmethyl m… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Effects of S ildenafil on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan®), after sildenafil administration compared with placebo. Most studies assessed the efficacy of sildenafil approximately 60 minutes post dose. The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration.

The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Effects of VYBRIQUE on Blood Pressure: Single oral doses (50 mg, 75 mg, 100 mg) of VYBRIQUE administered to 12 healthy young volunteers produced decreases in supine blood pressure. The placebo-subtracted mean maximum decreases in systolic/diastolic blood pressure were 6.1/2.8 mmHg after a single 100 mg dose.

Subjects were under fasting conditions and lay in the supine position for the first 4 hours post-dose and were not initially titrated. The decrease in supine blood pressure was most notable approximately 1-2 hours after dosing. Figure 1 : Mean Change from Baseline in Supine Systolic Blood Pressure, Healthy Volunteers Single oral doses of 50 mg, 75 mg, 100 mg of VYBRIQUE administered to 12 elderly volunteers produced decreases in supine blood pressure.

The placebo-subtracted maximum mean decreases in systolic/diastolic blood pressure were 13.7/8.5 mmHg after a single 100 mg dose. Subjects were under fasting conditions and lay in the supine position for the first 4 hours post-dose and were not initially titrated. The decrease in supine blood pressure was generally observed from 15 min to 4 h post-dose.

Figure 2 : Mean Change from Baseline in Supine Systolic Blood Pressure, E lderly Effects of S ildenafil on Blood Pressure When Nitroglycerin is Subsequently Administered: Based on the pharmacokinetic profile of a single 100 mg sildenafil oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers.

Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Contraindications ( 4.1 ) ]. Effects of S ildenafil on Blood Pressure When Co-administered with Alpha-Blockers: Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of sildenafil with doxazosin, an alpha-adrenergic blocking agent. Study 1: S ildenafil with Doxazosin In the first study, a single oral dose of sildenafil 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH).

Following at least 14 consecutive daily doses of doxazosin, sildenafil 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the sildenafil dose was reduced to 25 mg. Thereafter, 17 subjects were treated with sildenafil 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects).

The mean subject age was 66.5 years. For the 17 subjects who received sildenafil 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES Efficacy Results in VYBRIQUE Clinical Study The efficacy of VYBRIQUE in the treatment of erectile dysfunction was established in part on the basis of efficacy data from trials with the tablet formulation of sildenafil. VYBRIQUE was evaluated in one randomized, double-blind, placebo-controlled, flexible-dose study (25 mg, 50 mg, 75 mg, 100 mg) over 12 weeks study to evaluate the erectile function of men with erectile dysfunction (ED). The co-primary efficacy endpoints included both a 4-week assessment of sexual function based on the International Index of Erectile Function (IIEF) questionnaire and an assessment of sexual function after each sexual intercourse based on the Sexual Encounter Profile (SEP) on the daily diary.

The six-item, 30-point, erectile function (EF) domain of the IIEF was assessed at baseline, at follow-up visits, and at the end of the study reflecting subjects’ sexual experience during the past 4 weeks. The SEP Question 2 (“Were you able to insert your penis into your partner’s vagina”) and Question 3 (“Did your erection last long enough for you to have successful intercourse?”) were answered immediately after each sexual attempt with binary response (Yes=success, No=failure). Sexual function data were recorded by patients in a daily diary.

A total of 475 patients were enrolled and received treatment with VYBRIQUE, including subjects with comorbidities such as diabetes, dyslipidemia, hypertension and obesity. Of these, 354 patients received VYBRIQUE and 121 patients received placebo without regard to food and alcohol concomitant intake. The initial dose was 50 mg for subjects under 65 years and 25 mg for subjects 65 years or older with dose adjustment permitted up to 50 mg (for subjects 65 years or older), 75 mg or 100 mg or down to 25 mg based on efficacy and tolerability.

By the end of the study, 94 (26.6%) and 115 (32.5%) patients in the VYBRIQUE group were receiving 75 mg or 100 mg respectively. The efficacy of VYBRIQUE, administered at flexible doses of 25 mg, 50 mg, 75 mg and 100 mg for the treatment of ED, was superior to placebo. Efficacy results are shown in Figure 6.

Subgroup analyses by age, race, and ethnicity showed efficacy results consistent with the overall population. *Statistically significant differences vs. placebo; p-value <0.001 IIEF= International Index of Erectile Function, EF = Erectile Function, SEP Q2=Sexual Encounter Profile Question 2, SEP Q3 = Sexual Encounter Profile Question 3, N = Number of Subjects, SD = Standard Deviation, LS = Least Squares, CI = Confidence Interval. Sildenafil was assessed in many clinical studies for its effect on the ability of men with ED to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity.

Sildenafil was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). Sildenafil was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. sildenafil citrate demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo.

Sildenafil Efficacy Results from Controlled Clinical Studies The effect of sildenafil on one of the major end points, maintenance of erections after penetration, is shown in Figure 7, for the pooled results of 5 sildenafil fixed-dose, dose-response studies of greater than one-month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at the 25 mg dose. The pattern of responses was similar for the ot… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2 basis in a 50 kg subject.

Mutagenesis 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. Impairment of Fertility There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.