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 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 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 predominantly by hepatic metabolism, mainly by CYP3A4 and to a minor extent, CYP2C isoforms. Concomitant
use with potent CYP3A4 inhibitors such as ritonavir, indinavir, ketoconazole,
as well as moderate CYP3A inhibitors such as erythromycin results in significant
increases of plasma levels of vardenafil (see PRECAUTIONS,
WARNINGS and DOSAGE
AND ADMINISTRATION). Mean vardenafil plasma concentrations measured
after the administration of a single oral dose of 20 mg to healthy male volunteers
are depicted in Figure 1.
Figure 1: Plasma Vardenafil Concentration (Mean ± SD) Curve
for a Single 20 mg LEVITRA Dose
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 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 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 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).
Pharmacokinetics in Special Populations
Pediatrics: Vardenafil trials were not conducted in the pediatric
population.
Geriatrics: In a healthy volunteer 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 the 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 pharmacology 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 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
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 pretreatment 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. (See Figure
2.)
Figure 2: Placebo-subtracted point estimates (with 90% CI)
of mean maximal blood pressure and heart rate effects of pre-dosing with LEVITRA
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).
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 (moxifloxacin 400 mg) 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 a 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 a 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.
| Drug/Dose |
QT Uncorrected
(msec) |
Fridericia QT Correction
(msec) |
Individual QT Correction
(msec) |
| Vardenafil 10 mg |
-2
(-4, 0) |
8
(6, 9) |
4
(3, 6) |
| Vardenafil 80 mg |
-2
(-4, 0) |
10
(8, 11) |
6
(4, 7) |
| Moxifloxacin* 400 mg |
3
(1, 5) |
8
(6, 9) |
7
(5, 8) |
| * 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 drug or
the dose levels. The clinical impact of these QTc changes is unknown
(see PRECAUTIONS).
In a separate postmarketing study of 44 healthy volunteers, single doses of
10 mg LEVITRA resulted in a placebo-subtracted mean change from baseline of
QTcF (Fridericia correction) of 5 msec (90% CI: 2,8). Single doses of gatifloxacin
400mg resulted in a placebo-subtracted mean change from baseline QTcF of 4 msec
(90% CI: 1,7). When LEVITRA 10mg and gatifloxacin 400 mg were co-administered,
the mean QTcF change from baseline was additive when compared to either drug
alone and produced a mean QTcF change of 9 msec from baseline (90% CI: 6,11).
The clinical impact of these QT changes is unknown (see PRECAUTIONS,
Congenital or Acquired QT Prolongation).
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 aged
40-80 years with stable exercise-induced 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; 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 the 10 mg
and the 20 mg LEVITRA groups (10 mg LEVITRA vs. placebo: 380±108 and 334±108
seconds; 20 mg LEVITRA vs. placebo: 364±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.
In another double-blind, placebo controlled clinical trial, at least 15 doses of 20 mg vardenafil were administered over 8 weeks versus placebo to 52 males. Thirty-two (32) males (62%) of the patients completed the trial. Retinal function was measured by ERG and FM-100 test 2, 6 and 24 hours after dosing. The trial was designed to detect changes in retinal function that might occur in more than 10% of patients. Vardenafil did not produce clinically significant ERG or FM-100 effects in healthy men compared to placebo. Two patients on vardenafil in the trial reported episodes of transient cyanopsia (objects appear blue).
Clinical Studies
LEVITRA was evaluated in four major double-blind, randomized, placebo-controlled,
fixed-dose, parallel design, multicenter trials in 2431 men aged 20-83 (mean
age 57 years; 78% White, 7% Black, 2% Asian, 3% Hispanic and 10% Other/Unknown).
The doses of LEVITRA in these studies were 5 mg, 10 mg, and 20 mg. Two of these
trials were conducted in the general ED population and two in special ED populations
(one in patients with diabetes mellitus and one in post-prostatectomy patients).
LEVITRA 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.
The primary endpoints were assessed at 3 months.
Primary efficacy assessment in all four major trials 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).
In all four fixed-dose efficacy trials, LEVITRA showed clinically meaningful
and statistically significant improvement in the EF Domain, SEP2, and SEP3 scores
compared to placebo. The mean baseline EF Domain score in these trials was 11.8
(scores range from 0-30 where lower scores represent more severe disease). LEVITRA
(5 mg, 10 mg, and 20 mg) was effective in all age categories ( < 45, 45 to
< 65, and ≥ 65 years) and was also effective regardless of race (White, Black,
Other).
Trials in a General Erectile Dysfunction Population: In the major North
American fixed-dose trial, 762 patients (mean age 57, range 20-83 years; 79%
White, 13% Black, 4% Hispanic, 2% Asian and 2% Other) were evaluated. The mean
baseline EF Domain scores were 13, 13, 13, 14 for the LEVITRA 5 mg, 10 mg, 20
mg and placebo groups, respectively. There was significant improvement (p < 0.0001)
at 3 months with LEVITRA (EF Domain scores of 18, 21, 21, for the 5 mg, 10 mg,
and 20 mg dose groups, respectively) compared to the placebo group (EF Domain
score of 15). The European trial (total N=803) confirmed these results. The
improvement in mean score was maintained at all doses at 6 months in the North
American trial.
In the North American trial, LEVITRA significantly improved the rates of achieving
an erection sufficient for penetration (SEP2) at doses of 5 mg, 10 mg, and 20
mg compared to placebo (65%, 75%, and 80%, respectively, compared to a 52% response
in the placebo group at 3 months; p < 0.0001). The European trial confirmed
these results.
LEVITRA demonstrated a clinically meaningful and statistically significant
increase in the overall per-patient rate of maintenance of erection to successful
intercourse (SEP3) (51% on 5 mg, 64% on 10 mg, and 65% on 20 mg, respectively,
compared to 32% on placebo; p < 0.0001) at 3 months in the North American
trial. The European trial showed comparable efficacy. This improvement in mean
score was maintained at all doses at 6 months in the North American trial.
Trial in Patients with ED and Diabetes Mellitus: LEVITRA demonstrated
clinically meaningful and statistically significant improvement in erectile
function in a prospective, fixed-dose (10 and 20 mg LEVITRA), 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 LEVITRA and 19 on 20 mg LEVITRA compared to 13 on placebo;
p < 0.0001). LEVITRA significantly improved the overall per-patient rate of
achieving an erection sufficient for penetration (SEP2) (61% on 10 mg and 64%
on 20 mg LEVITRA compared to 36% on placebo; p < 0.0001).
LEVITRA 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 LEVITRA compared to 23% on placebo;
p < 0.0001).
Trial in Patients with ED after Radical Prostatectomy: LEVITRA demonstrated
clinically meaningful and statistically significant improvement in erectile
function in a prospective, fixed-dose (10 and 20 mg LEVITRA), 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 LEVITRA and 15 on 20 mg LEVITRA compared to 9 on placebo;
p < 0.0001). LEVITRA significantly improved the overall per-patient rate of
achieving an erection sufficient for penetration (SEP2) (47% on 10 mg and 48%
on 20 mg LEVITRA compared to 22% on placebo; p < 0.0001).
LEVITRA demonstrated a clinically meaningful and statistically significant
increase in the overall per-patient rate of maintenance of erection to successful
intercourse (SEP3) (37% on 10 mg, 34% on 20 mg LEVITRA compared to 10% on placebo;
p < 0.0001).
Last updated on RxList: 8/25/2008