Basic
Information
| Viagara |
| Brand
Name: |
Viagara |
| Active
Ingredient: |
sildenafil
citrate |
| Strength(s):
|
25mg,
50mg & 100mg |
| Dosage
Form(s): |
Oral
tablet |
| Company
Name: |
Pfizer
Inc. |
| Availability:
|
Prescription
only |
| Date
Approved by FDA: |
March
27, 1998 |
Viagara Molecule
©
1998 PFIZER INC
Description
Viagara™, an oral therapy for erectile dysfunction, is the
citrate salt of sildenafil, a selective inhibitor 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 the following structural formula:
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. Viagara
(sildenafil citrate) 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, 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 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
(>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).
Pharmacokinetics
and Metabolism
Viagara 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. Both sildenafil and the metabolite have terminal half
lives of about 4 hours.
Absorption
and Distribution:
Viagara 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 Viagara 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 Viagara (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.
Pharmacodynamics
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 penile plethysmography, after Viagara administration compared
with placebo. Most studies assessed the efficacy of Viagara approximately
60 minutes post dose. The erectile response, as assessed by penile
plethysmography, 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.
Single oral doses of sildenafil up to 100 mg produced no clinically
relevant changes in the ECGs of normal male volunteers. Single
oral doses of sildenafil (100 mg) produced an average decrease
of about 10 mmHg in normals, similar to the effect in patients
with ischemic heart disease given 40 mg of sildenafil I.V. Larger
but similarly transient effects on blood pressure were recorded
among patients receiving concomitant nitrates (see CONTRAINDICATIONS).
These effects are possibly related to PDE5 in vascular smooth
muscle.
A
comprehensive battery of visual function tests was conducted at
doses up to twice the maximum recommended dose. Mild, 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. In flexible titration studies of 4 to 26 weeks,
3% of patients on sildenafil reported visual disturbances, described
as color tinge or light sensitivity, compared to no such findings
in placebo-treated patients.
Clinical
Studies
In clinical studies, Viagara 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.
Viagara 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). Viagara 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. Viagara demonstrated statistically significant improvement
compared to placebo in all 21 studies.
The effectiveness of Viagara 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. Both questions
were addressed by the patient 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, includeing
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 endpoints, maintenance of erections
after penetration, is shown in Figure 1, 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 1 shows that regardless of the baseline levels of function,
subsequent function in patients treated with Viagara 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.
Figure
1.
Effect of Viagara 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 2. 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 Viagara, 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.
Figure
2.
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 Viagara 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
Viagara vs 0.4 on placebo; similarly, group mean success rates
(total successes divided by total attempts) were about 66% on
Viagara 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
Viagara 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. Viagara 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 Viagara; 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 Viagara compared to placebo. On a global improvement question,
57% of Viagara patients reported improved erections versus 10%
on placebo. Diary data indicated that on Viagara, 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 Viagara. On a global improvement question, 83% of
patients reported improved erections on Viagara versus 12% on
placebo. Diary data indicated that on Viagara, 59% of attempts
at sexual intercourse were successful compared to 13% on placebo.
Across
all trials, Viagara 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 Viagara
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 Viagara. Diary data in two of the studies
(n=178) showed rates of successful intercourse per attempt of
70% for Viagara and 29% for placebo.
A
review of population subgroups demonstrated efficacy regardless
of baseline severity, etiology, race and age. Viagara 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, trans-urethral
resection of the prostate (TURP) and spinal cord injury, and in
patients taking anti-depressants/anti-psychotics and anti-hypertensives/diuretics.
Indication
and Usage
Viagara is indicated for the treatment of erectile dysfunction.
The studies that established benefit demonstrated improvements
in success rates for sexual intercourse compared with placebo.
Contraindications
Use of Viagara is contraindicated in patients with a known hypersensitivity
to any component of the tablet. Consistent with its known effects
on the nitric oxide/cGMP pathway, Viagara was shown to potentiate
the hypotensive effects of nitrates, and its administration to
patients who are concurrently using organic nitrates in any form
is therefore contraindicated.
Precautions
General
A thorough medical history and physical examination should be
undertaken to diagnose erectile dysfunction, determine potential
underlying causes, and identify appropriate treatment.
There
is a degree of cardiac risk associated with sexual activity; therefore,
physicians may wish to consider the cardiovascular status of their
patients prior to initiating any treatment for erectile dysfunction.
Agents
for the treatment of erectile dysfunction should be used with
caution in patients with anatomical deformation of the penis (such
as angulation, cavernosal fibrosis or Peyronie's disease), or
in patients who have conditions which may predispose them to priapism
(such as sickle cell anemia, multiple myeloma, or leukemia).
The
safety and efficacy of combinations of Viagara with other treatments
for erectile dysfunction have not been studied. Therefore, the
use of such combinations is not recommended.
Viagara
has no effect on bleeding time when taken alone or with aspirin.
In vitro studies with human platelets indicate that sildenafil
potentiates the antiaggregatory effect of sodium nitroprusside
(a nitric oxide donor). There is no safety information on the
administration of Viagara to patients with bleeding disorders
or active peptic ulceration. Therefore, Viagara should be administered
with caution to these patients. A minority of patients with the
inherited condition retinitis pigmentosa have genetic disorders
of retinal phosphodiesterases. There is no safety information
on the administration of Viagara to patients with retinitis pigmentosa.
Therefore, Viagara should be administered with caution to these
patients.
Information
for Patients
Physicians should discuss with patients the contraindication of
Viagara with concurrent organic nitrates.
The
use of Viagara offers no protection against sexually transmitted
diseases. Counseling of patients 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 Viagara
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 non-specific CYP inhibitor, caused a 56%
increase in plasma sildenafil concentrations when co-administered
with Viagara (50 mg) to healthy volunteers.
When
a single 100 mg dose of Viagara was administered with erythromycin,
a specific CYP3A4 inhibitor, at steady state (500 mg bid for 5
days), there was a 182% increase in sildenafil systemic exposure
(AUC). Stronger CYP3A4 inhibitors such as ketoconazole, itraconazole
or mibefradil would be expected to have still greater effects,
and population data from patients in clinical trials did indicate
a reduction in sildenafil clearance when it was co-administered
with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or
cimetidine). It can be expected that concomitant administration
of CYP3A4 inducers, such as rifampin, will decrease plasma levels
of sildenafil.
Single
doses of antacid (magnesium hydroxide/aluminum hydroxide) did
not affect the bioavailability of Viagara.
Pharmacokinetic
data from patients in clinical trials showed no effect on sildenafil
pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin),
CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors,
tricyclic antidepressants), thiazide and related diuretics, ACE
inhibitors, and calcium channel blockers. The AUC of the active
metabolite, N-desmethyl sildenafil, was increased 62% by loop
and potassium-sparing diuretics and 102% by non-specific beta-blockers.
These effects on the metabolite are not expected to be of clinical
consequence.
Effects
of Viagara 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 µ M). Given
sildenafil peak plasma concentrations of approximately 1 µ
M after recommended doses, it is unlikely that Viagara will alter
the clearance of substrates of these isoenzymes.
In
vivo studies:
No significant interactions were shown with tolbutamide (250 mg)
or warfarin (40 mg), both of which are metabolized by CYP2C9.
Viagara (50 mg) did not potentiate the increase in bleeding time
caused by aspirin (150 mg).
Viagara (50 mg) did not potentiate the hypotensive effect of alcohol
in healthy volunteers with mean maximum blood alcohol levels of
0.08%.
No
interaction was seen when Viagara (100 mg) was co-administered
with amlodipine in hypertensive patients. The mean additional
reduction on supine blood pressure (systolic, 8 mmHg; diastolic,
7 mmHg) was of a similar magnitude to that seen when Viagara was
administered alone to healthy volunteers (see CLINICAL PHARMACOLOGY).
Analysis
of the safety database showed no difference in the side effect
profile in patients taking Viagara with and without anti-hypertensive
medication.
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 detect mutagenicity, and in vitro human lymphocytes
and in vivo mouse micronucleus assays to detect clastogenicity.
There
was no impairment of fertility in rats given sildenafil up to
60 mg/kg/day for 36 days to females and 102 days to males, a dose
producing an AUC value of more than 25 times the human male AUC.
There
was no effect on sperm motility or morphology after single 100
mg oral doses of Viagara in healthy volunteers.
Pregnancy,
Nursing Mothers and Pediatric Use
Viagara
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 non-pregnant
rat the AUC at this dose was about 20 times human AUC. There are
no adequate and well-controlled studies of sildenafil in pregnant
women.
Adverse
Reactions
Viagara 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 Viagara (2.5%) was not significantly
different from placebo (2.3%). The adverse events were generally
transient and mild to moderate in nature.
In trials of all designs, adverse events reported by patients
receiving Viagara were generally similar. In fixed-dose studies,
the incidence of some adverse events increased with dose. The
nature of the adverse events in flexible-dose studies, which more
closely reflect the recommended dosage regimen, was similar to
that for fixed-dose studies.
When Viagara was taken as recommended (on an as-needed basis)
in flexible-dose, placebo-controlled clinical trials the following
adverse events were reported:
Table
1. Adverse Events Reported by > 2% of patients treated with
Viagara and more frequent on drug than placebo in PRN flexible
- dose phase II / III studies
| Adverse
Event |
Percentage
of Patients
Reporting Event |
| |
Viagara
N=734 |
Placebo
N=725 |
| Headache |
16% |
4%
|
| Flushing
|
10%
|
1%
|
| Dyspepsia |
7% |
2% |
| Nasal
Congestion |
4% |
2% |
| Urinary
Tract Infection |
3% |
2% |
| Abnormal
Vision† |
3% |
0% |
| Diarrhea
|
3% |
1% |
| Dizziness
|
2% |
1% |
| Rash |
2% |
1% |
†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: respiratory tract infection, back pain, flu syndrome,
and arthralgia.
In
fixed-dose studies, dyspepsia (17%) and abnormal vision (11%)
were more common at 100 mg than at lower doses. At doses above
the recommended dose range, adverse events were similar to those
detailed above but generally were reported more frequently.
No
cases of priapism were reported.
The
following events occurred in <2% of patients in controlled
clinical trials; a causal relationship to Viagara 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.
Overdosage
In studies with healthy volunteers of single doses up to 800 mg,
adverse events were similar to those seen at lower doses but incidence
rates were increased.
In cases of overdose, standard supportive measures should be adopted
as required. Renal dialysis is not expected to accelerate clearance
as sildenafil is highly bound to plasma proteins and it is not
eliminated in the urine.
Dosage
and Administration
For most patients, the recommended dose is 50 mg taken, as needed,
approximately 1 hour before sexual activity. However, Viagara
may be taken anywhere from 4 hours to 0.5 hour before sexual activity.
Based on effectiveness and toleration, the dose may be increased
to a maximum recommended dose of 100 mg or decreased to 25 mg.
The maximum recommended dosing frequency 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 (creatinine clearance
<30 mL/min, 100%), and concomitant use of potent cytochrome
P450 3A4 inhibitors (erythromycin, ketoconazole, itraconazole,
200%). Since higher plasma levels may increase both the efficacy
and incidence of adverse events, a starting dose of 25 mg should
be considered in these patients.
Viagara was shown to potentiate the hypotensive effects of nitrates
and its administration in patients who use nitric oxide donors
or nitrates in any form is therefore contraindicated.
How supplied
Viagara™ (sildenafil citrate) is supplied as blue, film-coated,
rounded-diamond-shaped tablets containing 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).
CAUTION: Federal law prohibits dispensing without prescription.
© 1998 PFIZER INC
