Avanafil 50 mg Tablet, 100-count — NDC 31722-440-01 (Billing 31722-0440-01)

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 cGMP, producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Avanafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting PDE5, which is responsible for degradation of cGMP in the corpus cavernosum.

Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation. Studies in vitro have shown that avanafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (greater than 100-fold for PDE6; greater than 1,000-fold for PDE4, PDE8 and PDE10; greater than 5,000-fold for PDE2 and PDE7; greater than 10,000-fold for PDE1, PDE3, PDE9, and PDE11).

Avanafil is greater than 100-fold more potent for PDE5 than PDE6, which is found in the retina and is responsible for phototransduction. 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 these tissues by avanafil may be the basis for the enhanced platelet anti-aggregatory activity of NO observed in vitro and peripheral vasodilatation in vivo .

12.2Pharmacodynamics Effects of Avanafil on Erectile Response In a single-blind, placebo-controlled, single-dose trial of 82 patients with either organic and/or psychogenic ED, visual sexual stimulation resulted in improved erections after avanafil administration compared to placebo, as assessed by an objective measurement of hardness and duration of erections (RigiScan ® ). Efficacy was assessed by RigiScan at discrete time intervals ranging from 20 to 40 minutes after dosing to 100 to 120 minutes after dosing. Effects of Avanafil on Blood Pressure Single oral doses of avanafil (200 mg) administered to healthy male volunteers resulted in mean changes from baseline in systolic/diastolic blood pressure of -5.3/-3.7 mmHg at 1 hour after dosing, compared to mean changes from baseline in the placebo group of 2.7/-0.4 mmHg.

The reductions in systolic/diastolic blood pressure at 1 hour after dosing of avanafil 200 mg compared to placebo were 8.0/3.3 mmHg. Figure 1: Median Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers Day 4 Effects on Cardiac Electrophysiology The effect of single 100 or 800 mg doses of avanafil on the QT interval were evaluated in a randomized, double-blind, placebo, and active (moxifloxacin) –controlled crossover study in 52 healthy male subjects aged 18 to 45 years. There were no significant effects of the 100 mg dose.

The mean QTc (Fridericia QT correction) for avanafil 800 mg, relative to placebo was 9.4 milliseconds (two-sided 90% CI=7.2, 11.6). An 800 mg dose of avanafil (4 times the highest recommended dose) was chosen because this dose yields exposures greater than those observed upon co-administration of avanafil with strong CYP3A4 inhibitors. A double-blind, randomized, placebo- and active-controlled (moxifloxacin), thorough QT/QTc trial of avanafil (100 and 800 mg) in healthy male subjects demonstrated that avanafil did not cause any significant changes in QTc interval or ventricular repolarization.

Effects of Avanafil on Blood Pressure When Administered with Nitrates In a clinical pharmacology trial, a single dose of avanafil 200 mg was shown to potentiate the hypotensive effect of nitrates. The use of avanafil in patients taking any form of nitrates is contraindicated [see Contraindications ( 4.1 )]. A trial was conducted to assess the degree of interaction between ni… [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 cGMP, producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Avanafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting PDE5, which is responsible for degradation of cGMP in the corpus cavernosum.

Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation. Studies in vitro have shown that avanafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (greater than 100-fold for PDE6; greater than 1,000-fold for PDE4, PDE8 and PDE10; greater than 5,000-fold for PDE2 and PDE7; greater than 10,000-fold for PDE1, PDE3, PDE9, and PDE11).

Avanafil is greater than 100-fold more potent for PDE5 than PDE6, which is found in the retina and is responsible for phototransduction. 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 these tissues by avanafil may be the basis for the enhanced platelet anti-aggregatory activity of NO observed in vitro and peripheral vasodilatation in vivo .

12.3Pharmacokinetics Mean avanafil plasma concentrations measured after the administration of a single oral dose of 50 or 200 mg to healthy male volunteers are depicted in Figure 4. The pharmacokinetics of avanafil are dose proportional from 12.5 to 600 mg. Figure 4: Plasma Avanafil Concentrations (mean ± SD) Following a Single 50 mg or 200 mg Avanafil Dose Absorption and Distribution Avanafil is rapidly absorbed after oral administration, with a median T max of 30 to 45 minutes in the fasted state.

When avanafil (200 mg) is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T max of 1.12 to 1.25 hours and a mean reduction in C max of 39% (200 mg). There was an approximate 3.8% decrease in AUC. The small changes in avanafil C max and AUC are considered of minimal clinical significance; therefore, avanafil may be administered with or without food.

The mean accumulation ratio is approximately 1.2. Avanafil is approximately 99% bound to plasma proteins. Protein binding is independent of total drug concentrations, age, renal and hepatic function.

Based upon measurements of avanafil in semen of healthy volunteers 45 to 90 minutes after dosing, less than 0.0002% of the administered dose appeared in the semen of patients. Metabolism and Excretion Avanafil is cleared predominantly by hepatic metabolism, mainly by the CYP3A4 enzyme and to a minor extent by CYP2C isoform. The plasma concentrations of the major circulating metabolites, M4 and M16, are approximately 23% and 29% that of the parent compound, respectively.

The M4 metabolite has an in vitro inhibitory potency for PDE5 18% of that of avanafil and M4 accounts for approximately 4% of the pharmacologic activity of avanafil. The M16 metabolite was inactive against PDE5. Avanafil was extensively metabolized in humans.

After oral administration, avanafil is excreted as metabolites predominantly in the feces (approximately 62% of administered oral dose) and to a lesser extent in the urine (approximately 21% of the administered oral dose). Avanafil has a terminal elimination half-life of approximately 5 hours. Geriatric The pharmacokinetics of a single 200 mg avanafil administered to fourteen healthy elderly male volunteers (65 to 80 years) and eighteen healthy younger male volunteers (18 to 43 years of age) were compared.

AUC 0 to inf increased by 6.8% and C max decreased by 2.1% in the elderly group, compared to the younger group. However, greater sensitivity to medications in some older individuals should be considered [see Use in Specific Populations ( 8.5 )]. Renal Impairment The pharmacokinetics of a single 200 mg avanafil administered to nine patients with mild (creatinine clearance greater than or equal to 60 and less than 90 mL/min) and to ten patients with moderate (creatinine clearance greater than or equal to 30 to less than 60 mL/min) renal impairment were evaluated.

AUC 0-inf decreased by 2.9% and C max increased by 2.8% in patients with mild renal impairment, compared to healthy volunteers with normal renal function. AUC 0-inf increased by 9.1% and C max decreased by 2.8% in patients with moderate renal impairment, compared to healthy volunteers with normal renal function. There is no data available for subjects with severe renal insufficiency or end-stage renal disease on hemodialysis [see Use in Specific Populations ( 8.6 )].

Hepatic Impairment The pharmacokinetics of a single 200 mg avanafil administered to eight patients with mild hepatic impairment (Child-Pugh A) and eight patients with moderate hepatic impairment (Child-Pugh B) were evaluated. AUC 0-inf increased by 3.8% and C max decreased by 2.7% in patients with mild hepatic impairment, compared to healthy volunteers with normal hepatic function. AUC 0-inf increased by 11.2% and C max decreased by 51% in patients with moderate hepatic impairment, compared to healthy volunteers with normal hepatic function.

There is no data available for subjects with severe hepatic impairment (… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Effects of Avanafil on Erectile Response In a single-blind, placebo-controlled, single-dose trial of 82 patients with either organic and/or psychogenic ED, visual sexual stimulation resulted in improved erections after avanafil administration compared to placebo, as assessed by an objective measurement of hardness and duration of erections (RigiScan ® ). Efficacy was assessed by RigiScan at discrete time intervals ranging from 20 to 40 minutes after dosing to 100 to 120 minutes after dosing. Effects of Avanafil on Blood Pressure Single oral doses of avanafil (200 mg) administered to healthy male volunteers resulted in mean changes from baseline in systolic/diastolic blood pressure of -5.3/-3.7 mmHg at 1 hour after dosing, compared to mean changes from baseline in the placebo group of 2.7/-0.4 mmHg.

The reductions in systolic/diastolic blood pressure at 1 hour after dosing of avanafil 200 mg compared to placebo were 8.0/3.3 mmHg. Figure 1: Median Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers Day 4 Effects on Cardiac Electrophysiology The effect of single 100 or 800 mg doses of avanafil on the QT interval were evaluated in a randomized, double-blind, placebo, and active (moxifloxacin) –controlled crossover study in 52 healthy male subjects aged 18 to 45 years. There were no significant effects of the 100 mg dose.

The mean QTc (Fridericia QT correction) for avanafil 800 mg, relative to placebo was 9.4 milliseconds (two-sided 90% CI=7.2, 11.6). An 800 mg dose of avanafil (4 times the highest recommended dose) was chosen because this dose yields exposures greater than those observed upon co-administration of avanafil with strong CYP3A4 inhibitors. A double-blind, randomized, placebo- and active-controlled (moxifloxacin), thorough QT/QTc trial of avanafil (100 and 800 mg) in healthy male subjects demonstrated that avanafil did not cause any significant changes in QTc interval or ventricular repolarization.

Effects of Avanafil on Blood Pressure When Administered with Nitrates In a clinical pharmacology trial, a single dose of avanafil 200 mg was shown to potentiate the hypotensive effect of nitrates. The use of avanafil in patients taking any form of nitrates is contraindicated [see Contraindications ( 4.1 )]. A trial was conducted to assess the degree of interaction between nitroglycerin and avanafil, should nitroglycerin be required in an emergency situation after avanafil was taken.

This was a single-center, double-blind, randomized, 3-way crossover trial of healthy males from 30 to 60 years of age. Subjects were divided among 5 trial groups with the trial group being determined by the time interval between treatment with trial drug and glyceryl trinitrate administration. Subjects were assigned to trial groups sequentially and hemodynamic results from the previous group were reviewed for serious adverse events (SAEs) before the next group received treatment.

Each subject was dosed with all 3 study drugs (avanafil 200 mg, sildenafil citrate 100 mg, and placebo) in random order. Subjects were administered a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified time points, following their dose of trial drug (0.5, 1, 4, 8 or 12 hours). Overall, 14 (15%) subjects treated with placebo and 28 (28%) subjects treated with avanafil, had clinically significant decreases in standing SBP, defined as greater than or equal to 30 mmHg decrease in SBP, after glyceryl trinitrate administration.

Mean maximum decreases are shown in Table 5. Table 5: Mean Maximum Decreases from Baseline in Sitting and Standing Systolic Blood Pressure/Diastolic Blood Pressure (mmHg) following Placebo or 200 mg Avanafil with 0.4 mg sublingual nitroglycerin Placebo with nitroglycerin Sitting Standing 13.4/11.8 21.1/16.5 Avanafil with nitroglycerin Sitting Standing 21.6/18.2 28.0/23.5 Like other PDE5 inhibitors, avanafil administration with nitrates is contraindicated. In a patient who has taken avanafil… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES Avanafil was evaluated in four randomized, double-blind, placebo-controlled, parallel trials of 2 to 3 months in duration. Avanafil was taken as needed at doses of 50 mg, 100 mg, and 200 mg (Study 1) and 100 mg and 200 mg (Study 2, Study 3 and Study 4). Patients were instructed to take 1 dose of study drug approximately 30 minutes (Study 1 and Study 2) or approximately 15 minutes (Study 4) prior to initiation of sexual activity.

Food and alcohol intake was not restricted. In addition, a subset of patients from 2 of these trials were enrolled into an open-label extension trial. In the open-label extension trial, all eligible patients were initially assigned to avanafil 100 mg.

At any point during the trial, patients could request to have their dose of avanafil increased to 200 mg or decreased to 50 mg based on their individual response to treatment. The 3 primary outcome measures in Studies 1, 2 and 3 were the erectile function domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4-week recall questionnaire that was administered at baseline and at 4-week intervals during treatment.

The IIEF erectile function domain has a 30-point total score, where the higher scores reflect better erectile function. The SEP included diary-based measures of erectile function. Patients recorded information regarding each sexual attempt made throughout the trial.

Question 2 of the SEP asks “Were you able to insert your penis into your partner’s vagina?” Question 3 of the SEP asks “Did your erection last long enough for you to have successful intercourse?” In Study 4, the primary efficacy variable was the per-subject proportion of sexual attempts that had an erectogenic effect within approximately 15 minutes following dosing, where an erectogenic effect was defined as an erection sufficient for vaginal penetration and that enabled satisfactory completion of sexual intercourse.

Results are shown from the three, Phase 3, randomized, double-blind, placebo-controlled, parallel studies, one in the general ED population (Study 1), another in the diabetic population with ED (Study 2), and another in the radical prostatectomy population (Study 3). Results in the General ED Population (Study 1): Avanafil was evaluated in 646 men with ED of various etiologies (organic, psychogenic, mixed), in a randomized, double-blinded, parallel, placebo controlled fixed dose trial of 3 months duration. The mean age was 55.7 years (range 23 to 88 years).

The population was 85.6% White, 13.2% Black, 0.9% Asian, and 0.3% of other races. The mean duration of ED was approximately 6.5 years. Avanafil at doses of 50 mg, 100 mg, and 200 mg demonstrated statistically significant improvement in all 3 primary efficacy variables relative to placebo (see Table 7).

Table 7: Mean Change From Baseline for Primary Efficacy Variables in General ED Population (Study 1) Placebo (N=155) Avanafil 50 mg (N=154) Avanafil 100 mg (N=157) Avanafil 200 mg (N=156) IIEF EF Domain Score Endpoint 15.3 18.1 20.9

22.2Change from baseline † 2.9 5.4 8.3 9.5 p-value* 0.0014 <0.0001 <0.0001 Vaginal Penetration (SEP2) Endpoint 53.8% 64.3% 73.9% 77.3% Change from baseline † 7.1% 18.2% 27.2% 29.8% p-value* - 0.0009 <0.0001 <0.0001 Successful Intercourse (SEP3) Endpoint 27.0% 41.3% 57.1% 57.0% Change from baseline † 14.1% 27.8% 43.4% 44.2% p-value* - 0.0002 <0.0001 <0.0001 † least-squares estimate from ANCOVA model * comparison to placebo for change from baseline Results in the ED Population with Diabetes Mellitus (Study 2) Avanafil was evaluated in ED patients (n=390) with type 1 or type 2 diabetes mellitus in a randomized, double-blind, parallel, placebo-controlled fixed dose trial of 3 months in duration.

The mean age was 58 years (range 30 to 78 years). The population was 80.5% White, 17.2% Black, 1.5% Asian, and 0.8% of other races. The mean duration of ED was approximately 6 years.

In this trial, avanafil… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenesis Avanafil was not carcinogenic to CD-1 mice when administered daily at doses of 100, 200, or 600 mg/kg/day orally by gavage for at least 98 weeks (approximately 11 times the MRHD on an AUC basis) or to Sprague Dawley rats when administered daily at doses of 100, 300, or 1000 mg/kg/day orally by gavage for at least 100 weeks (approximately 8 times for males and 34 times for females above the MRHD on an AUC basis). Mutagenesis Avanafil was not genotoxic in a series of tests.

Avanafil was not mutagenic in Ames assays. Avanafil was not clastogenic in chromosome aberration assays using Chinese hamster ovary and lung cells, or in vivo in the mouse micronucleus assay. Avanafil did not affect DNA repair when tested in the rat unscheduled DNA synthesis assay.

Impairment of Fertility In a rat fertility and early embryonic development study administered 100, 300, or 1000 mg/kg/day for 28 days prior to pairing and continued until euthanasia for males, and 14 days prior to pairing to gestation day 7 for females, a decrease in fertility, no or reduced sperm motility, altered estrous cycles, and an increased percentage of abnormal sperm (broken sperm with detached heads) occurred at exposures in males approximately 11 times the human exposure at a dose of 200 mg. The altered sperm effects were reversible at the end of a 9-week drug-free period.

Systemic exposure at the NOAEL (300 mg/kg/day) was comparable to the human AUC at the MRHD of 200 mg.

13.2Animal Toxicology and/or Pharmacology Repeated oral administration of avanafil in multiple species resulted in signs of centrally-mediated toxicity including ataxia, tremor, convulsion, hypoactivity, recumbency, and/or prostration at doses resulting in exposures approximately 5 to 8 times the MRHD based on C max and 8 to 30 times the MRHD based on AUC.