Mechanism 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 has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the 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.
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). The approximately 4,000-fold selectivity for PDE5 versus
PDE3 is important because 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 observed with higher doses or plasma levels (see
Pharmacodynamics
).
In addition to human corpus cavernosum smooth muscle, PDE5 is also found in
lower concentrations in other tissues including platelets,
vascular
and
visceral
smooth muscle, and
skeletal muscle
. The inhibition of PDE5 in these tissues
by sildenafil may be the basis for the enhanced platelet antiaggregatory activity
of nitric oxide observed
in vitro
, an inhibition of platelet thrombus
formation
in vivo
and peripheral arterial-venous dilatation
in vivo
.
Pharmacokinetics and Metabolism
VIAGRA is rapidly absorbed after oral administration, with absolute bioavailability
of about 40%. Its pharmacokinetics are dose-proportional over the recommended
dose range. It is eliminated predominantly by hepatic metabolism (mainly cytochrome
P450 3A4) and is converted to an active metabolite with properties similar to
the parent, sildenafil. The concomitant use of potent cytochrome P450 3A4 inhibitors
(e.g., erythromycin, ketoconazole, itraconazole) as well as the nonspecific
CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil
(see
DOSAGE AND ADMINISTRATION
). Both sildenafil and the metabolite have
terminal half lives of about 4 hours.
Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below:
Figure 1: Mean Sildenafil Plasma Concentrations in Healthy
Male Volunteers.
Absorption and Distribution
:
VIAGRA is rapidly absorbed. Maximum
observed plasma concentrations are reached within 30 to 120 minutes (median
60 minutes) of oral dosing in the fasted state. When VIAGRA is taken with a
high fat meal, the rate of absorption is reduced, with a mean delay in Tmax
of 60 minutes and a mean reduction in Cmax of 29%. 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, with free plasma concentrations approximately
40% greater than those seen in healthy younger volunteers (18-45 years).
Renal Insufficiency
:
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 VIAGRA (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.
Hepatic Insufficiency
:
In volunteers with hepatic
cirrhosis
(Child-Pugh
A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%)
and Cmax (47%) compared to age-matched volunteers with no hepatic impairment.
Therefore, age > 65, hepatic impairment and severe renal impairment are
associated with increased plasma levels of sildenafil. A starting oral dose
of 25 mg should be considered in those patients (see
DOSAGE
AND ADMINISTRATION
).
Pharmacodynamics
Effects of VIAGRA 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 VIAGRA
administration compared with placebo. Most studies assessed the efficacy of
VIAGRA 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 VIAGRA on Blood Pressure:
Single oral doses of sildenafil
(100 mg) administered to healthy volunteers produced decreases in supine blood
pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.4/5.5
mmHg). The decrease in blood pressure was most notable approximately 1-2 hours
after dosing, and was not different than placebo at 8 hours. Similar effects
on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA, therefore
the effects are not related to dose or plasma levels within this dosage range.
Larger effects were recorded among patients receiving concomitant nitrates (see
CONTRAINDICATIONS
).
Figure 2: Mean Change from Baseline in Sitting Systolic Blood
Pressure, Healthy Volunteers.
Effects of VIAGRA on Cardiac Parameters:
Single oral doses of sildenafil
up to 100 mg produced no clinically relevant changes in the ECGs of normal male
volunteers.
Studies have produced relevant data on the effects of VIAGRA on
cardiac output
.
In one small, open-label, uncontrolled, pilot study, eight patients with stable
ischemic heart disease underwent Swan-Ganz catheterization. A total dose of
40 mg sildenafil was administered by four intravenous infusions.
The results from this pilot study are shown in Table 1; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients. Mean resting values for right
atrial
pressure,
pulmonary artery
pressure,
pulmonary
artery
occluded pressure and cardiac output decreased by 28%, 28%, 20% and 7% respectively. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients.
TABLE 1. HEMODYNAMIC DATA IN PATIENTS WITH STABLE ISCHEMIC
HEART DISEASE AFTER IV ADMINISTRATION OF 40 MG SILDENAFIL
Means ± SD
|
At rest
|
After 4 minutes of exercise
|
|
n
|
Baseline (B2)
|
n
|
Sildenafil (D1)
|
n
|
Baseline
|
n
|
Sildenafil
|
PAOP (mmHg)
|
8
|
8.1 ± 5.1
|
8
|
6.5 ± 4.3
|
8
|
36.0 ± 13.7
|
8
|
27.8 ± 15.3
|
Mean PAP (mmHg)
|
8
|
16.7 ± 4
|
8
|
12.1 ± 3.9
|
8
|
39.4 ± 12.9
|
8
|
31.7 ± 13.2
|
Mean RAP (mmHg)
|
7
|
5.7 ± 3.7
|
8
|
4.1 ± 3.7
|
-
|
-
|
-
|
-
|
Systolic SAP (mmHg)
|
8
|
150.4 ± 12.4
|
8
|
140.6 ± 16.5
|
8
|
199.5 ± 37.4
|
8
|
187.8 ± 30.0
|
Diastolic SAP (mmHg)
|
8
|
73.6 ± 7.8
|
8
|
65.9 ± 10
|
8
|
84.6 ± 9.7
|
8
|
79.5 ± 9.4
|
Cardiac output (L/min)
|
8
|
5.6 ± 0.9
|
8
|
5.2 ± 1.1
|
8
|
11.5 ± 2.4
|
8
|
10.2 ± 3.5
|
Heart rate (bpm)
|
8
|
67 ± 11.1
|
8
|
66.9 ± 12
|
8
|
101.9 ± 11.6
|
8
|
99.0 ± 20.4
|
In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or VIAGRA 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (N=70) and placebo, respectively. These results demonstrated that the effect of VIAGRA on the primary endpoint was statistically non-inferior to placebo.
Effects of VIAGRA on Vision:
At single oral doses of 100 mg and 200
mg, transient dose-related impairment of color discrimination (blue/green) was
detected using the Farnsworth-Munsell 100-hue test, with peak effects near the
time of peak plasma levels. This finding is consistent with the inhibition of
PDE6, which is involved in phototransduction in the retina. An evaluation of
visual function at doses up to twice the maximum recommended dose revealed no
effects of VIAGRA on
visual acuity
,
intraocular pressure
, or pupillometry.
Clinical Studies
In clinical studies, VIAGRA was assessed for its effect on the ability of men
with erectile dysfunction (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. VIAGRA 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). VIAGRA 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. VIAGRA 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.
The effectiveness of VIAGRA was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function - IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered.
The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 3, for the pooled results of 5 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 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Figure 3 shows that regardless of the baseline levels of function, subsequent function in patients treated with VIAGRA was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline.
Effect of VIAGRA on Maintenance of Erection by Baseline Score
Effect of Placebo on Maintenance of Erection by Baseline
Score
Figure 3. Effect of VIAGRA and Placebo on Maintenance of
Erection by Baseline Score.
The frequency of patients reporting improvement of erections in response to
a global question in four of the randomized, double-blind, parallel, placebo-controlled
fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure
4. These patients had erectile dysfunction at baseline that was characterized
by median categorical scores of 2 (a few times) on principal IIEF questions.
Erectile dysfunction was attributed to organic (58%; generally not characterized,
but including diabetes and excluding spinal cord injury), psychogenic (17%),
or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients
on 25 mg, 50 mg and 100 mg of VIAGRA, respectively, reported an improvement
in their erections, compared to 24% on placebo. In the titration studies (n=644)
(with most patients eventually receiving 100 mg), results were similar.
Overall treatment p < 0.0001
Figure 4. Percentage of Patients Reporting an Improvement
in Erections.
The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period.
In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of VIAGRA on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50-100 mg of VIAGRA vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on VIAGRA vs about 20% on placebo.
During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that VIAGRA improved their erections.
Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. VIAGRA improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction.
One randomized, double-blind, flexible-dose, placebo-controlled study included
only patients with erectile dysfunction attributed to complications of diabetes
mellitus (n=268). As in the other titration studies, patients were started on
50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of VIAGRA;
all patients, however, were receiving 50 mg or 100 mg at the end of the study.
There were highly statistically significant improvements on the two principal
IIEF questions (frequency of successful penetration during sexual activity and
maintenance of erections after penetration) on VIAGRA compared to placebo. On
a global improvement question, 57% of VIAGRA patients reported improved erections
versus 10% on placebo. Diary data indicated that on VIAGRA, 48% of intercourse
attempts were successful versus 12% on placebo.
One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. On a global improvement question, 83% of patients reported improved erections on VIAGRA versus 12% on placebo. Diary data indicated that on VIAGRA, 59% of attempts at sexual intercourse were successful compared to 13% on placebo.
Across all trials, VIAGRA improved the erections of 43% of
radical prostatectomy
patients compared to 15% on placebo.
Subgroup analyses of responses to a global improvement question in patients with psychogenic
etiology
in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of VIAGRA patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for VIAGRA and 29% for placebo.
A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. VIAGRA was effective in a broad range of ED patients, including those with a history of
coronary artery disease
,
hypertension
, other cardiac disease,
peripheral vascular disease
,
diabetes mellitus
,
depression
,
coronary artery bypass graft
(
CABG
), radical
prostatectomy
,
transurethral resection
of the prostate (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and antihypertensives/diuretics.
Analysis of the safety database showed no apparent difference in the side effect profile in patients taking VIAGRA with and without
antihypertensive
medication
. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions.