Levitra Tablets (Luh-VEE-Trah) (vardenafil HCl)

Clinical Pharmacology

Mechanism of Action
Pharmacokinetics
Pharmacokinetics in Special Populations
Pharmacodynamics

Mechanism 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 if cyclic guanosine monophosophate (cGMP) in the smooth muscles 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 phosphodiestrases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMP-specific phosphodiesterase type 5 (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)

Pharmacokinetics

The pharmacokinetics of vardenafil are approximately dose proportional over the recommended dose range. Vardenafil is eliminated predominately by hepatic metabolism, mainly by CYP3A4 and to minor extent, CYP2C isoforms. Concomitant use with strong CTP3A4 inhibitors such as ritonavir, indinavir, ketoconazole, itraconazole as well as moderate CYP3A inhibitors such as erythromycin results in significant increases of the plasma levels of vardenafil (see PRECAUTIONS, WARNING and DOSAGE AND ADMINISTRATION).

Absorption: Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%. Maximum observed plasma concentrations after a single 20 mg dose in healthy volunteers are usually reached between 30 minutes and 2 hours (median 60 Minutes) after oral dosing in the fasted state. Two food-effect studies were conducted which showed that high-fat meals caused a reduction in Cmax by 18% -50%.

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 in healthy volunteer, a mean of 0.00018% of the administered dose was obtained in semen 1.5 hours after dosing.

Metabolism: Vardenafil is metabolised predominately by the hepatic enzyme CYP3A4, with contribution from 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 total body clearance of vardenafil is 56 L/h, and the terminal half-life of vardenafil and its primary metabolite (M1) is approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites predominately on the feces (approximately 91-95% of administered oral dose) and to a lesser extent in the urine (approximately 2-6% of administered oral dose).

Pharmacokinetics in Special Populations

Pediatrics: Vardenafil trials were not conducted in the pediatric population.

Geriatrics: In a healthy study of elderly males (= 65 years) and younger males (18 – 45 years), mean Cmax and AUC were 34% and 52& higher, respectively, in the elderly males (see PRECAUTIONS, Geriatric Use and DOSAGE AND ADMINISTRATION). Consequently, a lower starting dose of Levitra (5 mg) in patients = 65 years of age should be considered.

Renal Insufficiency: In volunteers with mild renal impairment (CLcr = 50 -80 ml/min), the pharmacokinetics of vardenafil were similar to those observed in a control group with normal renal function. In moderate (CLcr = 30 -50 ml/min), or severe (CLcr = <30 ml/min), renal impairment groups, the AUC of vardenafil was 20 – 30% higher compared to that observed in a control group with normal renal function (CLcr = >80 ml/min). Vardenafil pharmacokinetics have not been evaluated in patients requiring renal dialysis (see PRECAUTIONS, Renal Insufficiency and DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. In volunteers with moderate hepatic impairment (Child-Pugh B), the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Consequently, a starting dose of 5 mg is recommended for patients with moderate hepatic impairment, and the maximum dose should not exceed 10 mg (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Vardenafil has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment.

Pharmacodynamics

Effects on Blood Pressure: In a clinical study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8mm Hg 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 CONTRAINDICATIONS, PRECAUTIONS, Drug interactions).

Effects on Blood Pressure and Heart Rate When Levitra 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 pre-treatment with Levitra 20 mg at various times before NTG administration. Levitra 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 Levitra 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 Levitra 20 mg was dosed 24 hours before NTG.

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).

Electrophysiology: The effect of 10 mg and 80 mg vardenafil on QT interval was evaluated in a single-dose, double-blind, randomized, placebo-and active-controlled (moxifloacin 400mg) crossover study in 59 healthy males (81% White, 12% Black, 7% Hispanic) aged 45-60 years. The QT interval was measured at one hour post dose because this time point approximates the average time of peak vardenafil concentration. The 80 mg dose of Levitra (four times the highest recommended dose) was chosen because this dose yields plasma concentrations covering those observed upon co-administration of a low-dose of Levitra (5 mg) and 600 mg BID of ritonavir. Of the CYP3A4 inhibitors that have been studied, ritonavir causes the most significant drug-drug interaction with vardenafil. Table 1 summarizes the effect on mean uncorrected QT and mean corrected QT interval (QTc) with different methods of correction (Fridericia and linear individual correction method) at one hour post-dose. No single correction method is known to be more valid than the other. In this study, the mean increase in heart rate associated with 10 mg dose of Levitra compared to placebo was 5 beats/minute and with an 80 mg dose of Levitra the mean increase was 6 beats/minute.

Table 1. Mean QT and QTc changes in msec (90% CI) from baseline relative to placebo at 1 hour post-dose with different methodologies to correct for the effect of heart rate.

* Active control (drug known to prolong QT)

Therapeutic and supratherapeutic doses of vardenafil and the active control moxifloxacin produced similar increases in QTc interval. This study, however, was not designed to make direct statistical comparisons between the drugs or the dose levels. The actual clinical impact of these QTc changes is unknown. (See PRECAUTIONS).

Effects on Exercise Treadmill Test in Patients with Coronary Artery Disease (CAD): In two independent trials that assessed 10 mg (n=41) and 20 mg (n=39) vardenafil, respectively, vardenafil did not alter the total treadmill exercise time compared to placebo. The patient population included men ages 40 – 80 years with stable exercise-induces angina documented by at least one of the following: 1) prior history of MI, CABG, PTCA, or stenting (not within 6 months); 2) positive coronary angiogram showing at least 60% narrowing of the diameter of at least one major coronary artery; or 3) a positive stress echocardiogram or stress nuclear perfusion study.

Results of these studies showed that Levitra did not alter the total treadmill exercise time compared to placebo (10 mg Levitra vs. placebo: 433±109 and 426±105 seconds, respectively; 20 mg Levitra vs. placebo: 414±114 and 411±124 seconds, respectively). The total time to angina was not altered by Levitra when compared to placebo (10 mg Levitra vs. placebo: 291±123 and 292±110 seconds, respectively; 20 mg Levitra vs. placebo: 354±137 and 347±143 seconds, respectively). The total time to 1 mm or greater ST-segment depression was similar to placebo in both 10 mg and 20 mg Levitra groups (10 mg Levitra vs. placebo: 380±108 and 334±108 seconds, respectively; 20 mg Levitra vs. placebo: 3644±101 and 366±105 seconds, respectively).

Effects on Vision: Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green) using the Farnsworth-Munsell 100-hue test and reductions in electroretinogram (ERG) b-wave amplitudes, with peak effects near the time of peak plasma levels. These findings are consistent with the inhibition of PDE6 in rods and cones, which is involved in phototransduction in the retina. The findings were most evident one hour after administration, diminishing but still present 6 hours after administration. In a single dose study in 25 normal males, Levitra 40 mg, twice the maximum daily recommended dose, did not alter visual acuity, intraocular pressure, fundoscopic and slit lamp findings.

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