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69-5485-00-2
VIAGRA®
(sildenafil citrate)
Tablets
DESCRIPTION
VIAGRA®, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selectiveinhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has thefollowing structural formula: Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in waterand a molecular weight of 666.7. VIAGRA (sildenafil citrate) is formulated as blue, film-coatedrounded-diamond-shaped tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oraladministration. In addition to the active ingredient, sildenafil citrate, each tablet contains thefollowing inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate,croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide,lactose, triacetin, and FD & C Blue #2 aluminum lake.
CLINICAL PHARMACOLOGY
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 doseshas 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 (>80-fold for PDE1, >1,000-fold for PDE2,
PDE3, and PDE4). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important
because that PDE 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; 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 lowerconcentrations in other tissues including platelets, vascular and visceral smooth muscle, andskeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for theenhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of plateletthrombus 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 of100 mg to healthy male volunteers is depicted below: Figure 1: Mean Sildenafil Plasma Concentrations 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 predominantlyin 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 pharmacokineticparameters were seen in normal volunteers and in the patient population, using a populationpharmacokinetic 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 presssure (mean maximum decrease 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. 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 underwentSwan-Ganz catheterization. A total dose of 40 mg sildenafil was administered by four intravenousinfusions.
The results from this pilot study are shown in Table 1; the mean resting systolic and diastolicblood pressures decreased by 7% and 10% compared to baseline in these patients. Mean restingvalues for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressureand cardiac output decreased by 28%, 28%, 20% and 7% respectively. Even though this totaldosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higherthan the mean maximum plasma concentrations following a single oral dose of 100 mg in healthymale 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
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, electroretinograms, 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 assessmentinstruments. The primary measure in the principal studies was a sexual function questionnaire (theInternational Index of Erectile Function - IIEF) administered during a 4-week treatment-freerun-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 sufficientfor sexual intercourse and (2) the maintenance of erections after penetration. The patientaddressed both questions at the final visit for the last 4 weeks of the study. The possiblecategorical responses to these questions were (0) no attempted intercourse, (1) never or almostnever, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Alsocollected 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 sexualsatisfaction. 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 wasadministered.
The effect on one of the major end points, maintenance of erections after penetration, is shown inFigure 3, for the pooled results of 5 fixed-dose, dose-response studies of greater than one monthduration, showing response according to baseline function. Results with all doses have beenpooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. Thepattern of responses was similar for the other principal question, the ability to achieve an erectionsufficient for intercourse. The titration studies, in which most patients received 100 mg, showedsimilar results. Figure 3 shows that regardless of the baseline levels of function, subsequentfunction in patients treated with VIAGRA was better than that seen in patients treated withplacebo. At the same time, on-treatment function was better in treated patients who were lessimpaired at baseline.
Effect of VIAGRA on Maintenance of Erection by Effect of Placebo on Maintenance of Erection by 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 infour 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 erectiledysfunction at baseline that was characterized by median categorical scores of 2 (a few times) onprincipal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally notcharacterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), ormixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and100 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.
Percentage patients reporting improvement Figure 4. Percentage of Patients Reporting The patients in studies had varying degrees of ED. One-third to one-half of the subjects in thesestudies reported successful intercourse at least once during a 4-week, treatment-free run-inperiod.
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 ofVIAGRA on rates of attempted intercourse (about 2 per week), but there was cleartreatment-related improvement in sexual function: per patient weekly success rates averaged 1.3on 50-100 mg of VIAGRA vs 0.4 on placebo; similarly, group mean success rates (total successesdivided 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, fewpatients withdrew from active treatment for any reason, including lack of effectiveness. At the endof 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 functionmeasured (again using a 5-point scale) in the IIEF. VIAGRA improved these aspects of sexualfunction: frequency, firmness and maintenance of erections; frequency of orgasm; frequency andlevel of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationshipsatisfaction.
One randomized, double-blind, flexible-dose, placebo-controlled study included only patients witherectile 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 ordown to 25 mg of VIAGRA; all patients, however, were receiving 50 mg or 100 mg at the end ofthe study. There were highly statistically significant improvements on the two principal IIEFquestions (frequency of successful penetration during sexual activity and maintenance of erectionsafter penetration) on VIAGRA compared to placebo. On a global improvement question, 57% ofVIAGRA patients reported improved erections versus 10% on placebo. Diary data indicated thaton VIAGRA, 48% of intercourse attempts were successful versus 12% on placebo.
One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) studyof patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. Thechanges from baseline in scoring on the two end point questions (frequency of successfulpenetration during sexual activity and maintenance of erections after penetration) were highlystatistically significantly in favor of VIAGRA. On a global improvement question, 83% of patientsreported improved erections on VIAGRA versus 12% on placebo. Diary data indicated that onVIAGRA, 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 patientscompared 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 ahistory 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 takingantidepressants/antipsychotics and antihypertensives/diuretics.
Analysis of the safety database showed no apparent difference in the side effect profile in patientstaking VIAGRA with and without antihypertensive medication. This analysis was performedretrospectively, and was not powered to detect any pre-specified difference in adverse reactions.
INDICATION AND USAGE
VIAGRA is indicated for the treatment of erectile dysfunction.
CONTRAINDICATIONS
Consistent with its known effects on the nitric oxide/cGMP pathway (see CLINICAL
PHARMACOLOGY
), VIAGRA was shown to potentiate the hypotensive effects of nitrates,
and its administration to patients who are using organic nitrates, either regularly and/or
intermittently, in any form is therefore contraindicated.
After patients have taken VIAGRA, it is unknown when nitrates, if necessary, can be safely
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) (see CLINICAL
PHARMACOLOGY: Pharmacokinetics and Metabolism
). In the following patients: age >65,
hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatine clearance
<30 mL/min), and concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin),
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
coadministered at this time point.
VIAGRA is contraindicated in patients with a known hypersensitivity to any component of thetablet.
WARNINGS
There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovasculardisease. Therefore, treatments for erectile dysfunction, including VIAGRA, should not begenerally used in men for whom sexual activity is inadvisable because of their underlyingcardiovascular status.
VIAGRA has systemic vasodilatory properties that resulted in transient decreases in supine blood
pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), (see CLINICAL
PHARMACOLOGY: Pharmacodynamics
). While this normally would be expected to be of
little consequence in most patients, prior to prescribing VIAGRA, physicians should carefully
consider whether their patients with underlying cardiovascular disease could be affected adversely
by such vasodilatory effects, especially in combination with sexual activity.
There is no controlled clinical data on the safety or efficacy of VIAGRA in the following groups;if prescribed, this should be done with caution.
• Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia • Patients with resting hypotension (BP <90/50) or hypertension (BP >170/110); • Patients with cardiac failure or coronary artery disease causing unstable angina; • Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours induration) have been reported infrequently since market approval of VIAGRA. In the event of anerection that persists longer than 4 hours, the patient should seek immediate medical assistance. Ifpriapism is not treated immediately, penile tissue damage and permanent loss of potency couldresult.
PRECAUTIONS
General
The evaluation of erectile dysfunction should include a determination of potential underlying
causes and the identification of appropriate treatment following a complete medical assessment.
Before prescribing VIAGRA, it is important to note the following: Patients on multiple antihypertensive medications were included in the pivotal clinical trials for
VIAGRA. In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and VIAGRA,
100 mg were orally administered concomitantly to hypertensive patients mean additional blood
pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted (see Drug
Interactions
). Controlled studies of drug interactions between VIAGRA and other
antihypertensive medications have not been performed.
The safety of VIAGRA is unknown in patients with bleeding disorders and patients with activepeptic ulceration.
VIAGRA should be used with caution in patients with anatomical deformation of the penis (suchas angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions whichmay predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
The safety and efficacy of combinations of VIAGRA with other treatments for erectiledysfunction have not been studied. Therefore, the use of such combinations is not recommended.
In humans, VIAGRA has no effect on bleeding time when taken alone or with aspirin. In vitrostudies with human platelets indicate that sildenafil potentiates the antiaggregatory effect ofsodium nitroprusside (a nitric oxide donor). The combination of heparin and VIAGRA had anadditive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studiedin humans.
Information for Patients
Physicians should discuss with patients the contraindication of VIAGRA with regular and/or
intermittent use of organic nitrates.
Physicians should discuss with patients the potential cardiac risk of sexual activity in patients withpreexisting cardiovascular risk factors. Patients who experience symptoms (e.g., angina pectoris,dizziness, nausea) upon initiation of sexual activity should be advised to refrain from furtheractivity and should discuss the episode with their physician.
Physicians should warn patients that prolonged erections greater than 4 hours and priapism(painful erections greater than 6 hours in duration) have been reported infrequently since marketapproval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patientshould seek immediate medical assistance. If priapism is not treated immediately, penile tissuedamage and permanent loss of potency may result.
The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling ofpatients about the protective measures necessary to guard against sexually transmitted diseases,including the Human Immunodeficiency Virus (HIV), may be considered.
Drug Interactions
Effects of Other Drugs on VIAGRA
In vitro
studies: Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP)
isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may
reduce sildenafil clearance.
In vivo studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in
plasma sildenafil concentrations when coadministered with VIAGRA (50 mg) to healthy
volunteers.
When a single 100 mg dose of VIAGRA was administered with erythromycin, a specific CYP3A4inhibitor, at steady state (500 mg bid for 5 days), there was a 182% increase in sildenafil systemicexposure (AUC). Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole would beexpected to have still greater effects, and population data from patients in clinical trials didindicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors(such as ketoconazole, erythromycin, or cimetidine). It can be expected that concomitantadministration of CYP3A4 inducers, such as rifampin, will decrease plasma levels of sildenafil.
Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect thebioavailability of VIAGRA.
Pharmacokinetic data from patients in clinical trials showed no effect on sildenafilpharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (suchas selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics,ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethylsildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecificbeta-blockers. These effects on the metabolite are not expected to be of clinical consequence.
Effects of VIAGRA on Other Drugs
In vitro
studies: Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19,
2D6, 2E1 and 3A4 (IC50 >150 µM). Given sildenafil peak plasma concentrations of
approximately 1 µM after recommended doses, it is unlikely that VIAGRA will alter the clearance
of substrates of these isoenzymes.
In vivo studies: When VIAGRA 100 mg oral was coadministered 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.
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both ofwhich are metabolized by CYP2C9.
VIAGRA (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
VIAGRA (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers withmean maximum blood alcohol levels of 0.08%.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in
total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29- and
42-times, for male and female rats, respectively, the exposures observed in human males given the
Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic
when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose
(MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m2 basis.
Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detectmutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detectclastogenicity.
There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days tofemales and 102 days to males, a dose producing an AUC value of more than 25 times the humanmale AUC.
There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRAin healthy volunteers.
Pregnancy, Nursing Mothers and Pediatric Use
VIAGRA is not indicated for use in newborns, children, or women.
Pregnancy Category B. No evidence of teratogenicity, embryotoxicity or fetotoxicity was
observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These
doses represent, respectively, about 20 and 40 times the MRHD on a mg/m2 basis in a 50 kg
subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was
30 mg/kg/day given for 36 days. In the nonpregnant rat the AUC at this dose was about 20 timeshuman AUC. There are no adequate and well-controlled studies of sildenafil in pregnant women.
Geriatric Use: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil
(see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations). Since
higher plasma levels may increase both the efficacy and incidence of adverse events, a starting
dose of 25 mg should be considered (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
PRE-MARKETING EXPERIENCE:
VIAGRA was administered to over 3700 patients (aged 19-87 years) during clinical trials
worldwide. Over 550 patients were treated for longer than one year.
In placebo-controlled clinical studies, the discontinuation rate due to adverse events for VIAGRA(2.5%) was not significantly different from placebo (2.3%). The adverse events were generallytransient and mild to moderate in nature.
In trials of all designs, adverse events reported by patients receiving VIAGRA were generallysimilar. In fixed-dose studies, the incidence of some adverse events increased with dose. Thenature of the adverse events in flexible-dose studies, which more closely reflect the recommendeddosage regimen, was similar to that for fixed-dose studies.
When VIAGRA was taken as recommended (on an as-needed basis) in flexible-dose,placebo-controlled clinical trials, the following adverse events were reported: TABLE 2. ADVERSE EVENTS REPORTED BY 2% OF PATIENTS TREATED WITH
VIAGRA AND MORE FREQUENT ON DRUG THAN PLACEBO IN PRN FLEXIBLE-DOSE
PHASE II/III STUDIES
†Abnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision.
Other adverse reactions occurred at a rate of >2%, but equally common on placebo: respiratorytract infection, back pain, flu syndrome, and arthralgia.
In fixed-dose studies, dyspepsia (17%) and abnormal vision (11%) were more common at 100 mgthan at lower doses. At doses above the recommended dose range, adverse events were similar tothose detailed above but generally were reported more frequently.
The following events occurred in <2% of patients in controlled clinical trials; a causal relationshipto VIAGRA is uncertain. Reported events include those with a plausible relation to drug use;omitted are minor events and reports too imprecise to be meaningful: Body as a whole: face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental
fall, abdominal pain, allergic reaction, chest pain, accidental injury.
Cardiovascular: angina pectoris, AV block, migraine, syncope, tachycardia, palpitation,
hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart
failure, abnormal electrocardiogram, cardiomyopathy.
Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis,
dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis.
Hemic and Lymphatic: anemia and leukopenia.
Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral
edema, hyperuricemia, hypoglycemic reaction, hypernatremia.
Musculoskeletal: arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain,
myasthenia, synovitis.
Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression,
insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia.
Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased,
cough increased.
Skin and Appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact
dermatitis, exfoliative dermatitis.
Special Senses: mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, deafness, ear pain, eye
hemorrhage, cataract, dry eyes.
Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence,
abnormal ejaculation, genital edema and anorgasmia.
POST-MARKETING EXPERIENCE:
Cardiovascular
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular
arrhythmia, cerebrovascular hemorrhage, transient ischemic attack and hypertension, have been
reported post-marketing in temporal association with the use of VIAGRA. Most, but not all, of
these patients had preexisting cardiovascular risk factors. Many of these events were reported to
occur during or shortly after sexual activity, and a few were reported to occur shortly after the
use of VIAGRA without sexual activity. Others were reported to have occurred hours to days
after the use of VIAGRA and sexual activity. It is not possible to determine whether these events
are related directly to VIAGRA, to sexual activity, to the patient’s underlying cardiovascular
disease, to a combination of these factors, or to other factors (see WARNINGS for further
important cardiovascular information).
Other events
Other events reported post-marketing to have been observed in temporal association with
VIAGRA and not listed in the pre-marketing adverse reactions section above include:
Nervous: seizure and anxiety.
Urogenital: prolonged erection, priapism (see WARNINGS) and hematuria.
Ocular: diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot
appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal
vascular disease or bleeding, vitreous detachment/traction and paramacular edema.
OVERDOSAGE
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar tothose seen at lower doses but incidence rates were increased.
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysisis not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is noteliminated in the urine.
DOSAGE AND ADMINISTRATION
For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour beforesexual activity. However, VIAGRA may be taken anywhere from 4 hours to 0.5 hour beforesexual activity. Based on effectiveness and toleration, the dose may be increased to a maximumrecommended dose of 100 mg or decreased to 25 mg. The maximum recommended dosingfrequency is once per day.
The following factors are associated with increased plasma levels of sildenafil: age >65 (40%increase in AUC), hepatic impairment (e.g., cirrhosis, 80%), severe renal impairment (creatinineclearance <30 mL/min, 100%), and concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin, ketoconazole, itraconazole, 200%). Since higher plasma levels may increase boththe efficacy and incidence of adverse events, a starting dose of 25 mg should be considered inthese patients.
VIAGRA was shown to potentiate the hypotensive effects of nitrates and its administration inpatients who use nitric oxide donors or nitrates in any form is therefore contraindicated.
HOW SUPPLIED
VIAGRA® (sildenafil citrate) is supplied as blue, film-coated, rounded-diamond-shaped tabletscontaining sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: Recommended Storage: Store at controlled room temperature, 15° to 30°C (59° to 86°F).
1998 PFIZER INC
Pfizer Labs
Division of Pfizer Inc, NY, NY 10017

Source: http://www.drugbank.ca/system/fda_labels/DB00203.pdf?1265922808

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