Vardenafil 11.85 mg Tablet, 4-count — NDC 33342-203-37 (Billing 33342-0203-37)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum.

The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMP-specific PDE5; therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP.

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. In vitro studies have shown that vardenafil is a selective inhibitor of PDE5. The inhibitory effect of vardenafil is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).

12.2Pharmacodynamics The pharmacodynamic studies described below were conducted using vardenafil film-coated tablets. Effects on Blood Pressure In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg film-coated tablets caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing.

Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1. Vardenafil may add to the blood pressure lowering effects of antihypertensive agents [see Drug Interactions ( 7 )]. Effects on Blood Pressure and Heart Rate when Vardenafil is Combined with Nitrates A study was conducted in which the blood pressure and heart rate response to 0.4 mg nitroglycerin (NTG) sublingually was evaluated in 18 healthy subjects following pretreatment with vardenafil 20 mg film-coated tablets at various times before NTG administration.

Vardenafil 20 mg caused an additional time-related reduction in blood pressure and increase in heart rate in association with NTG administration. The blood pressure effects were observed when vardenafil 20 mg was dosed 1 or 4 hours before NTG and the heart rate effects were observed when 20 mg was dosed 1, 4, or 8 hours before NTG. Additional blood pressure and heart rate changes were not detected when vardenafil 20 mg film-coated tablet was dosed 24 hours before NTG (see Figure 1).

Figure 1: Placebo-subtracted point estimates (with 90% CI) of mean maximal blood pressure and heart rate effects of pre-dosing with vardenafil 20 mg at 24, 8, 4, and 1 hour before 0.4 mg NTG sublingually Because the disease state of patients requiring nitrate therapy is anticipated to increase the likelihood of hypotension, the use of vardenafil by patients on nitrate therapy or on nitric oxide donors is contraindicated [see Contraindications (4.1 )] . Blood Pressure Effects in Patients on Stable Alpha-Blocker Treatment Three clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment , consisting of alfuzosin, tamsulosin or terazosin.

Study 1: This study was designed to evaluate the effect of 5 mg vardenafil film-coated tablets compared to placebo when administered to BPH patients on chronic alpha-blocker therapy in two separate cohorts: tamsulosin 0.4 mg daily (cohort 1, n=21) and terazosin 5 or 10 mg daily… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum.

The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMP-specific PDE5; therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP.

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. In vitro studies have shown that vardenafil is a selective inhibitor of PDE5. The inhibitory effect of vardenafil is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).

12.3Pharmacokinetics The pharmacokinetics of vardenafil and its M1 metabolite from vardenafil orally disintegrating tablet have been evaluated in healthy male volunteers (18–50 years) and in young (18–45 years) and elderly (≥ 65 years) erectile dysfunction patients. Studies have shown that vardenafil orally disintegrating tablet provides higher systemic exposure of vardenafil compared to vardenafil 10 mg film-coated tablets. Absorption Mean vardenafil plasma concentrations measured after the administration of a single oral dose vardenafil orally disintegrating tablet to patients with erectile dysfunction (18-45 years) are depicted in Figure 8 .

Figure 8: Vardenafil Plasma Concentration (Mean ± SD) Profile for vardenafil orally disintegrating tablet in men age 18–45 years with erectile dysfunction The median time to reach C max (T max ) in patients receiving vardenafil orally disintegrating tablet in the fasted state was 1.5 h [range: 0.75 – 2.5 h]. After administration of vardenafil orally disintegrating tablet to elderly (≥ 65 years) and young (18–45 years) patients with erectile dysfunction, mean vardenafil AUC was increased by 21 to 29%, respectively while mean C max was lower by 19% and 8%, respectively, in comparison to 10 mg vardenafil (film-coated tablets).

In a study of healthy male volunteers (18–50 years), the mean C max and AUC of vardenafil from vardenafil orally disintegrating tablet were higher by 15% and 44%, respectively compared to 10 mg vardenafil film-coated tablets. Vardenafil was not found to accumulate in plasma when vardenafil orally disintegrating tablet was dosed daily over ten days. Effect of food: A high fat meal had no effect on vardenafil AUC and T max from vardenafil orally disintegrating tablet in healthy volunteers and reduced C max by 35%.

Clinical trials for vardenafil orally disintegrating tablet were conducted without regard to meals. Vardenafil orally disintegrating tablet can be taken with or without food. Effect of water: When vardenafil orally disintegrating tablet was swallowed with water, the AUC of vardenafil was reduced by 29% and median T max was shortened by 60 minutes while C max was not affected.

In clinical trials, dosing was done without water. Vardenafil orally disintegrating tablet should be taken without liquid. Distribution The mean steady-state volume of distribution (Vss) for vardenafil is 208 L, indicating extensive tissue distribution.

Vardenafil and its major circulating metabolite, M1, are highly bound to plasma proteins (about 95% for parent drug and M1). This protein binding is reversible and independent of total drug concentrations. Following a single oral dose of 20 mg vardenafil film-coated tablet in healthy volunteers, a mean of 0.00018% of the administered dose was obtained in semen 1.5 hours after dosing.

Metabolism Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 is subject to further metabolism.

The plasma concentration of M1 is approximately 26% that of the parent compound. This metabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. Therefore, M1 accounts for approximately 7% of total pharmacologic activity.

Excretion The mean terminal half-life of vardenafil in patients receiving vardenafil orally disintegrating tablets varied between about 4–6 hours. The elimination half-life of the metabolite M1 is between 3 to 5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the feces (approximately 91–95% of administered oral dose) and to a lesser extent in the urine (approximately 2–6% of administered oral dose).

Vardenafil is a high clearance drug with a plasma clearance of

56.4L/h following intravenous administration. Pharmacokinetics in Spec… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The pharmacodynamic studies described below were conducted using vardenafil film-coated tablets. Effects on Blood Pressure In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg film-coated tablets caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing.

Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1. Vardenafil may add to the blood pressure lowering effects of antihypertensive agents [see Drug Interactions ( 7 )]. Effects on Blood Pressure and Heart Rate when Vardenafil is Combined with Nitrates A study was conducted in which the blood pressure and heart rate response to 0.4 mg nitroglycerin (NTG) sublingually was evaluated in 18 healthy subjects following pretreatment with vardenafil 20 mg film-coated tablets at various times before NTG administration.

Vardenafil 20 mg caused an additional time-related reduction in blood pressure and increase in heart rate in association with NTG administration. The blood pressure effects were observed when vardenafil 20 mg was dosed 1 or 4 hours before NTG and the heart rate effects were observed when 20 mg was dosed 1, 4, or 8 hours before NTG. Additional blood pressure and heart rate changes were not detected when vardenafil 20 mg film-coated tablet was dosed 24 hours before NTG (see Figure 1).

Figure 1: Placebo-subtracted point estimates (with 90% CI) of mean maximal blood pressure and heart rate effects of pre-dosing with vardenafil 20 mg at 24, 8, 4, and 1 hour before 0.4 mg NTG sublingually Because the disease state of patients requiring nitrate therapy is anticipated to increase the likelihood of hypotension, the use of vardenafil by patients on nitrate therapy or on nitric oxide donors is contraindicated [see Contraindications (4.1 )] . Blood Pressure Effects in Patients on Stable Alpha-Blocker Treatment Three clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment , consisting of alfuzosin, tamsulosin or terazosin.

Study 1: This study was designed to evaluate the effect of 5 mg vardenafil film-coated tablets compared to placebo when administered to BPH patients on chronic alpha-blocker therapy in two separate cohorts: tamsulosin 0.4 mg daily (cohort 1, n=21) and terazosin 5 or 10 mg daily (cohort 2, n=21). The design was a randomized, double blind, cross-over study with four treatments: vardenafil 5 mg or placebo administered simultaneously with the alpha-blocker and vardenafil 5 mg or placebo administered 6 hours after the alpha-blocker.

Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. For blood pressure (BP) results, see Table 2. One patient, after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin, exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours.

For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of <85 mmHg.

A decrease in standing SBP of >30 mmHg was observed in two patients on tamsulosin receiving simultaneous vardenafil and in one patient receiving simultaneous placebo treatment. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP <85 mmHg and one patient had a decrease… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES The efficacy and safety of vardenafil orally disintegrating tablets were evaluated in two identical multi-national, randomized, double-blind, placebo-controlled trials (studies 1 and 2). Vardenafil orally disintegrating tablet was dosed without regard to meals on an as-needed basis in men with erectile dysfunction (ED), many of whom had multiple other medical conditions. In both pivotal studies, randomization was stratified so that approximately 50% of patients were ≥65 years old.

Primary efficacy assessment was by means of the Erectile Function (EF) Domain score of the validated International Index of Erectile Function (IIEF) Questionnaire and two questions from the Sexual Encounter Profile (SEP) dealing with the ability to achieve vaginal penetration (SEP2), and the ability to maintain an erection long enough for successful intercourse (SEP3). The primary endpoints were assessed at 3 months. Study 1 evaluated 355 mainly European (Belgium, France, Germany, Spain, South Africa, and Netherlands) patients (mean age 61.9; 67% White, 4% Black, 3% Asian, 26% Unknown).

The mean baseline EF domain scores were 13 for both placebo and vardenafil orally disintegrating tablet groups. Study 2 evaluated 331 mainly North American (USA, Canada, Mexico, and Australia) patients (mean age 61.7; 69% White, 5% Black, 4% Asian, 22% Hispanic). The mean baseline EF domain scores were 12 for vardenafil orally disintegrating tablet and 13 for placebo.

In both studies vardenafil orally disintegrating tablet demonstrated clinically meaningful and statistically significant improvements over placebo in all 3 primary efficacy variables (see Table 7). Table 7: Change from Baseline for the Primary Efficacy Variables in Studies 1 and 2 Study 1 Study 2 Placebo Vardenafil Orally Disintegrating Tablets p-value Placebo Vardenafil Orally Disintegrating Tablets p-value EF Domain Score (N=172) (N=181) (N=160) (N=167) Endpoint 14 21 14 21 Change from baseline 1.6 8.7 <.0001 1.5 8.5 <.0001 Insertion of Penis (SEP2) (N=169) (N=179) (N=161) (N=168) Endpoint 45% 74% 43% 69% Change from baseline 6.9% 35.9% <.0001 4.8% 30.8% <.0001 Maintenance of Erection (SEP3) (N=164) (N=178) (N=160) (N=168) Endpoint 26% 65% 27% 60% Change from baseline 11.6% 51.6% <.0001 12.4% 45.9% <.0001

14.1Other Vardenafil Clinical Trials Using Film-Coated Tablets Patients with ED and Diabetes Mellitus Vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a prospective, fixed-dose [10 and 20 mg vardenafil film-coated tablets], double-blind, placebo-controlled trial of patients with diabetes mellitus (n=439; mean age 57 years, range 33–81; 80% White, 9% Black, 8% Hispanic, and 3% Other). Significant improvements in the EF Domain were shown in this study (EF Domain scores of 17 on 10 mg vardenafil and 19 on 20 mg vardenafil compared to 13 on placebo; p <0.0001).

Vardenafil significantly improved the overall per-patient rate of achieving an erection sufficient for penetration (SEP2) (61% on 10 mg and 64% on 20 mg vardenafil compared to 36% on placebo; p <0.0001). Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (49% on 10 mg, 54% on 20 mg vardenafil compared to 23% on placebo; p <0.0001). Patients with ED after Radical Prostatectomy Vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a prospective, fixed-dose 10 and 20 mg vardenafil film-coated tablets, double-blind, placebo-controlled trial in post-prostatectomy patients (n=427, mean age 60, range 44–77 years; 93% White, 5% Black, 2% Other).

Significant improvements in the EF Domain were shown in this study (EF Domain scores of 15 on 10 mg vardenafil and 15 on 20 mg vardenafil compared to 9 on placebo; p <0.0001). Vardenafil significantly improved the overall per-patient rate of achievin… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis & Mutagenesis & Impairment of Fertility Carcinogenesis Vardenafil was not carcinogenic in rats and mice when administered daily for 24 months. In these studies systemic drug exposures (AUCs) for unbound (free) vardenafil and its major metabolite were approximately 400-and 170-fold for male and female rats, respectively, and 21-and 37-fold for male and female mice, respectively, the exposures observed in human males given the maximum recommended human dose (MRHD) of 20 mg. Mutagenesis Vardenafil was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward mutation assay in Chinese hamster V 79 cells.

Vardenafil was not clastogenic as assessed in either the in vitro chromosomal aberration test or the in vivo mouse micronucleus test. Impairment of Fertility Vardenafil did not impair fertility in male and female rats administered doses up to 100 mg/kg/day for 28 days prior to mating in males, and for 14 days prior to mating and through day 7 of gestation in females. In a corresponding 1-month rat toxicity study, this dose produced an AUC value for unbound vardenafil 200 fold greater than AUC in humans at the MRHD of 20 mg.