Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg\/mL in water and a
molecular weight of 666.7.
VIAGRA is formulated as blue, film-coated rounded-diamond-shaped tablets equivalent to 25 mg, 50 mg and
100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet
contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate,
croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C
Blue #2 aluminum lake.
12 CLINICAL PHARMACOLOGY
12.1 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 enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for
degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human
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.
Binding Characteristics
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). Sildenafil is approximately 4,000-fold more selective for PDE5
compared to PDE3. 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
[see Clinical Pharmacology (12.2)].
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 some of these tissues by sildenafil may be the
basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet
thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.
Reference ID: 3466301This label may not be the latest approved by FDA.
For current labeling information, please visit https:\/\/www.fda.gov\/drugsatfda12.2 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\u00ae), 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\u00ae, 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 sitting blood pressure (mean maximum decrease in systolic\/diastolic blood
pressure of 8.3\/5.3 mmHg). The decrease in sitting 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 (4.1)].
Figure 1: Mean Change from Baseline in Sitting
Systolic Blood Pressure, Healthy Volunteers.
Effects of VIAGRA on Blood Pressure When Nitroglycerin is Subsequently Administered: Based on the
pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of
sildenafil at 24 hours post dose are approximately 2 ng\/mL (compared to peak plasma levels of approximately
440 ng\/mL). In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal
impairment (e.g., creatinine clearance <30 mL\/min), and concomitant use of erythromycin or strong CYP3A4
inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those
seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours post dose are much lower than at
peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [see
Contraindications (4.1)].
Effects of VIAGRA on Blood Pressure When Co-administered with Alpha-Blockers: Three double-blind,
placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of
VIAGRA with doxazosin, an alpha-adrenergic blocking agent.
Reference ID: 3466301This label may not be the latest approved by FDA.
For current labeling information, please visit https:\/\/www.fda.gov\/drugsatfdaStudy 1: VIAGRA with Doxazosin
In the first study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 2-period
crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14
consecutive daily doses of doxazosin, VIAGRA 100 mg or matching placebo was administered simultaneously
with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the
VIAGRA dose was reduced to 25 mg. Thereafter, 17 subjects were treated with VIAGRA 25 mg or matching
placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). The mean subject
age was 66.5 years.
For the 17 subjects who received VIAGRA 25 mg and matching placebo, the placebo-subtracted mean
maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:
Placebo-subtracted mean maximum decrease
in systolic blood pressure (mm Hg) VIAGRA 25 mg
Supine 7.4 (-0.9, 15.7)
Standing 6.0 (-0.8, 12.8)
The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with
doxazosin in combination with 25 mg VIAGRA or matching placebo are shown in Figure 2.
Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline
Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8
hours after VIAGRA or matching placebo. Outliers were defined as subjects with a standing systolic blood
pressure of <85 mmHg or a decrease from baseline in standing systolic blood pressure of >30 mmHg at one or
more timepoints. There were no subjects treated with VIAGRA 25 mg who had a standing SBP < 85mmHg.
There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following VIAGRA
25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and
two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and
placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.
Of the four subjects who received VIAGRA 100 mg in the first part of this study, a severe adverse event related
to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing
with VIAGRA with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure
effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness,
lightheadedness and nausea at 4 hours after dosing). There were no reports of syncope among these patients.
For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing
Reference ID: 3466301This label may not be the latest approved by FDA.
For current labeling information, please visit https:\/\/www.fda.gov\/drugsatfdasystolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively. Two of these subjects had a standing
SBP < 85mmHg. Both of these subjects were protocol violators, one due to a low baseline standing SBP, and
the other due to baseline orthostatic hypotension.
Study 2: VIAGRA with Doxazosin
In the second study, a single oral dose of VIAGRA 50 mg or matching placebo was administered in a 2-period
crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin,
VIAGRA 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or
with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63.9 years.
Twenty subjects received VIAGRA 50 mg, but only 19 subjects received matching placebo. One patient
discontinued the study prematurely due to an adverse event of hypotension following dosing with VIAGRA 50
mg. This patient had been taking minoxidil, a potent vasodilator, during the study.
For the 19 subjects who received both VIAGRA and matching placebo, the placebo-subtracted mean maximum
decreases from baseline (95% CI) in systolic blood pressure were as follows:
Placebo-subtracted mean maximum decrease
in systolic blood pressure (mm Hg) VIAGRA 50 mg (95% CI)
Supine 9.08 (5.48, 12.68)
Standing 11.62 (7.34, 15.90)
The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with
doxazosin in combination with 50 mg VIAGRA or matching placebo are shown in Figure 3.
Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline
Blood pressure was measured after administration of VIAGRA at the same times as those specified for the first
doxazosin study. There were two subjects who had a standing SBP of < 85 mmHg. In these two subjects,
hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after
administration of VIAGRA 50 mg and resolving after approximately 7.5 hours. There was one subject with a
decrease from baseline in standing systolic BP >30mmHg following VIAGRA 50 mg and one subject with a
decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA 50 mg and placebo. There
were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this
study.
Reference ID: 3466301This label may not be the latest approved by FDA.
For current labeling information, please visit https:\/\/www.fda.gov\/drugsatfdaStudy 3: VIAGRA with Doxazosin
In the third study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 3-period
crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-
label doxazosin and a single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of
doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the
study. Subjects who had successfully completed the previous doxazosin interaction study (using VIAGRA 50
mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with
doxazosin continued for at least 7 days after dose period 1. Thereafter, VIAGRA 100 mg or matching placebo
was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard
crossover fashion. The mean subject age in this study was 66.4 years.
Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose
screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse
event 30 minutes after dosing with open-label VIAGRA 50 mg. Of the twenty subjects who were ultimately
assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully
completed the previous doxazosin study (using VIAGRA 50 mg).
For the 20 subjects who received VIAGRA 100 mg and matching placebo, the placebo-subtracted mean
maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:
Placebo-subtracted mean maximum decrease
in systolic blood pressure (mm Hg) VIAGRA 100 mg
Supine 7.9 (4.6, 11.1)
Standing 4.3 (-1.8,10.3)
The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with
doxazosin in combination with 100 mg VIAGRA or matching placebo are shown in Figure 4.
Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline
Blood pressure was measured after administration of VIAGRA at the same times as those specified for the
previous doxazosin studies. There were three subjects who had a standing SBP of < 85 mmHg. All three were
taking VIAGRA 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP,
including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing
systolic BP > 30 mmHg following VIAGRA 100 mg, one subject with a decrease from baseline in standing
systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic
BP > 30 mmHg following both VIAGRA and placebo. While there were no severe adverse events potentially
Reference ID: 3466301This label may not be the latest approved by FDA.
For current labeling information, please visit https:\/\/www.fda.gov\/drugsatfdarelated to blood pressure reported in this study, one subject reported moderate vasodilatation after both
VIAGRA 50 mg and 100 mg. There were no episodes of syncope reported in this study.
Effect of VIAGRA on Blood Pressure When Co-administered with Anti-hypertensives: When VIAGRA
100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean
additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.
Effect of VIAGRA on Blood Pressure When Co-administered with Alcohol: VIAGRA (50 mg) did not
potentiate the hypotensive effect of alcohol (0.5 g\/kg) in healthy volunteers with mean maximum blood alcohol
levels of 0.08%. The maximum observed decrease in systolic blood pressure was -18.5 mmHg when sildenafil
was co-administered with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum
observed decrease in diastolic blood pressure was -17.2 mmHg when sildenafil was co-administered with
alcohol versus -11.1 mmHg when alcohol was administered alone. There were no reports of postural dizziness
or orthostatic hypotension. The maximum recommended dose of 100 mg sildenafil was not evaluated in this
study [see Drug Interactions (7.5)].
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 3; 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 3. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous
Administration of 40 mg of Sildenafil
Means \u00b1 SD At rest After 4 minutes of exercise
N Baseline
(B2)
n Sildenafil
(D1)
n Baseline n Sildenafil
PAOP (mmHg) 8 8.1 \u00b1 5.1 8 6.5 \u00b1 4.3 8 36.0 \u00b1 13.7 8 27.8 \u00b1 15.3
Mean PAP (mmHg) 8 16.7 \u00b1 4 8 12.1 \u00b1 3.9 8 39.4 \u00b1 12.9 8 31.7 \u00b1 13.2
Mean RAP (mmHg) 7 5.7 \u00b1 3.7 8 4.1 \u00b1 3.7 – – – –
Systolic SAP (mmHg) 8 150.4 \u00b1 12.4 8 140.6 \u00b1 16.5 8 199.5 \u00b1 37.4 8 187.8 \u00b1 30.0
Diastolic SAP (mmHg) 8 73.6 \u00b1 7.8 8 65.9 \u00b1 10 8 84.6 \u00b1 9.7 8 79.5 \u00b1 9.4
Cardiac output (L\/min) 8 5.6 \u00b1 0.9 8 5.2 \u00b1 1.1 8 11.5 \u00b1 2.4 8 10.2 \u00b1 3.5
Heart rate (bpm) 8 67 \u00b1 11.1 8 66.9 \u00b1 12 8 101.9 \u00b1 11.6 8 99.0 \u00b1 20.4
Reference ID: 3466301This label may not be the latest approved by FDA.
For current labeling information, please visit https:\/\/www.fda.gov\/drugsatfdaIn 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 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. Subjects in the study reported this finding as difficulties in discriminating
blue\/green. 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.
Effects of VIAGRA on Sperm: There was no effect on sperm motility or morphology after single 100 mg oral
doses of VIAGRA in healthy volunteers.
12.3 Pharmacokinetics
VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25-
63%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is
eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite
with properties similar to the parent, sildenafil. 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 5: 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 C max 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.
Reference ID: 3466301This label may not be the latest approved by FDA.
For current labeling information, please visit https:\/\/www.fda.gov\/drugsatfdaBased 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\u2019s 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, resulting in
approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite,
respectively, compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in
plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active
N-desmethyl metabolite were 45% and 57%, respectively [see Dosage and Administration (2.5), and Use in
Specific Populations (8.5)]
Renal Impairment: 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 C max compared to age-matched volunteers with no renal impairment [see Dosage and
Administration (2.5), and Use in Specific Populations (8.6)].
In addition, N-desmethyl metabolite AUC and C max values significantly increased by 200% and 79%,
respectively in subjects with severe renal impairment compared to subjects with normal renal function.
Hepatic Impairment: In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance
was reduced, resulting in increases in AUC (85%) and C max (47%) compared to age-matched volunteers with no
hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function
(Child-Pugh Class C) have not been studied [see Dosage and Administration (2.5), and Use in Specific
Populations (8.7)].
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 (2. 5)].
Drug Interaction Studies
Effects of Other Drugs on VIAGRA
Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route).
Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes
may increase sildenafil clearance. The concomitant use of erythromycin or strong CYP3A4 inhibitors (e.g.,
saquinavir, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with
increased plasma levels of sildenafil [see Dosage and Administration (2.4)].
Reference ID: 3466301This label may not be the latest approved by FDA.
For current labeling information, please visit https:\/\/www.fda.gov\/drugsatfdaIn vivo studies:
Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations
when co-administered with VIAGRA (50 mg) to healthy volunteers.
When a single 100 mg dose of VIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, at
steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C max and a 182% increase in
sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV
protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Viagra (100 mg single
dose) resulted in a 140% increase in sildenafil C max and a 210% increase in sildenafil AUC. Viagra had no
effect on saquinavir pharmacokinetics. A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole
could be expected to have greater effect than that seen with saquinavir. Population pharmacokinetic data from
patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with
CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [see Dosage and Administration (2.4)
and Drug Interactions (7.4)].
In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which
is a highly potent P450 inhibitor, at steady state (500 mg bid) with VIAGRA (100 mg single dose) resulted in a
300% (4-fold) increase in sildenafil C max and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24
hours the plasma levels of sildenafil were still approximately 200 ng\/mL, compared to approximately 5 ng\/mL
when sildenafil was dosed alone. This is consistent with ritonavir\u2019s marked effects on a broad range of P450
substrates. VIAGRA had no effect on ritonavir pharmacokinetics [see Dosage and Administration (2.4) and
Drug Interactions (7.4)].
Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant
use is expected to increase sildenafil levels.
In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with
endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19)
at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil
C max. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater
decreases in plasma levels of sildenafil.
Single doses of antacid (magnesium hydroxide\/aluminum hydroxide) did not affect the bioavailability of
VIAGRA.
In healthy male volunteers, there was no evidence of a clinically significant effect of azithromycin (500 mg
daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolit<\/p>\n\n\n\n