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| 1. NAME OF THE
MEDICINAL PRODUCT |
 |
|
VIAGRA ® 25 mg film-coated tablets.
VIAGRA ® 50 mg film-coated tablets.
VIAGRA ® 100 mg film-coated tablets.
|
|
| 2. QUALITATIVE
AND QUANTITATIVE COMPOSITION |
|
|
Each tablet contains 25mg, 50mg or 100mg of sildenafil, as
the citrate.
VIAGRA tablets also contain lactose.
For a full list of excipients, see Section 6.1.
|
|
| 3. PHARMACEUTICAL
FORM |
|
|
Film-coated tablet.
The 25 mg tablets are blue film-coated, rounded
diamond-shaped tablets, marked “PFIZER” on one side and “VGR 25” on
the other.
The 50 mg tablets are blue film-coated, rounded
diamond-shaped tablets, marked “PFIZER” on one side and “VGR 50” on
the other.
The 100 mg tablets are blue film-coated, rounded
diamond-shaped tablets, marked “PFIZER” on one side and “VGR 100” on
the other.
|
|
| 4. CLINICAL
PARTICULARS |
|
|
4.1
Therapeutic indications |
|
|
Treatment of men with erectile dysfunction, which is the
inability to achieve or maintain a penile erection sufficient for
satisfactory sexual performance.
In order for VIAGRA to be effective, sexual stimulation is
required.
|
|
|
4.2 Posology
and method of administration |
|
|
For oral use.
Use in adults
The recommended dose is 50mg taken as needed approximately
one hour before sexual activity. Based on efficacy and toleration,
the dose may be increased to 100mg or decreased to 25mg. The maximum
recommended dose is 100 mg. The maximum recommended dosing frequency
is once per day. If VIAGRA is taken with food, the onset of activity
may be delayed compared to the fasted state (see Section 5.2).
Use in the
elderly
Dosage adjustments are not required in elderly patients.
Use in patients with impaired
renal function
The dosing recommendations described in “Use in adults” apply
to patients with mild to moderate renal impairment (creatinine
clearance = 30-80 ml/min).
Since sildenafil clearance is reduced in patients with severe
renal impairment (creatinine clearance < 30 ml/min) a 25mg dose
should be considered. Based on efficacy and toleration, the dose may
be increased to 50mg and 100mg.
Use in patients with impaired
hepatic function
Since sildenafil clearance is reduced in patients with
hepatic impairment (e.g. cirrhosis) a 25mg dose should be
considered. Based on efficacy and toleration, the dose may be
increased to 50mg and 100mg.
Use in
children
VIAGRA is not indicated for individuals below 18 years of
age. There is no relevant indication for use in children.
Use in patients using other
medicines
With the exception of ritonavir for which co-administration
with sildenafil is not advised (see Section 4.4) a starting dose of
25mg should be considered in patients receiving concomitant
treatment with CYP3A4 inhibitors (see Section 4.5).
In order to minimise the potential for developing postural
hypotension, patients should be stable on alpha-blocker therapy
prior to initiating sildenafil treatment. In addition, initiation of
sildenafil at a dose of 25 mg should be considered (see Sections 4.4
and 4.5).
|
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4.3
Contraindications |
|
|
Hypersensitivity to the active substance or to any of the
excipients.
Consistent with its known effects on the nitric oxide/cyclic
guanosine monophosphate (cGMP) pathway (see Section 5.1), sildenafil
was shown to potentiate the hypotensive effects of nitrates, and its
co-administration with nitric oxide donors (such as amyl nitrite) or
nitrates in any form is therefore contraindicated.
Agents for the treatment of erectile dysfunction, including
sildenafil, should not be used in men for whom sexual activity is
inadvisable (e.g. patients with severe cardiovascular disorders such
as unstable angina or severe cardiac failure).
VIAGRA is contraindicated in patients who have loss of vision
in one eye because of non-arteritic anterior ischaemic optic
neuropathy (NAION), regardless of whether this episode was in
connection or not with previous PDE5 inhibitor exposure (see section
4.4).
The safety of sildenafil has not been studied in the
following sub-groups of patients and its use is therefore
contraindicated: severe hepatic impairment, hypotension (blood
pressure < 90/50 mmHg), recent history of stroke or myocardial
infarction and known hereditary degenerative retinal disorders such
as retinitis pigmentosa (a minority of these patients have genetic
disorders of retinal phosphodiesterases).
|
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4.4 Special
warnings and precautions for use |
|
|
A medical history and physical examination should be
undertaken to diagnose erectile dysfunction and determine potential
underlying causes, before pharmacological treatment is considered.
Prior to initiating any treatment for erectile dysfunction,
physicians should consider the cardiovascular status of their
patients, since there is a degree of cardiac risk associated with
sexual activity. Sildenafil has vasodilator properties, resulting in
mild and transient decreases in blood pressure (see Section 5.1).
Prior to prescribing sildenafil, physicians should carefully
consider whether their patients with certain underlying conditions
could be adversely affected by such vasodilatory effects, especially
in combination with sexual activity. Patients with increased
susceptibility to vasodilators include those with left ventricular
outflow obstruction (e.g., aortic stenosis, hypertrophic obstructive
cardiomyopathy), or those with the rare syndrome of multiple system
atrophy manifesting as severely impaired autonomic control of blood
pressure.
VIAGRA potentiates the hypotensive effect of nitrates (see
Section 4.3).
Serious cardiovascular events, including myocardial
infarction, unstable angina, sudden cardiac death, ventricular
arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack,
hypertension and hypotension have been reported post-marketing in
temporal association with the use of VIAGRA. Most, but not all, of
these patients had pre-existing cardiovascular risk factors. Many
events were reported to occur during or shortly after sexual
intercourse and a few were reported to occur shortly after the use
of VIAGRA without sexual activity. It is not possible to determine
whether these events are related directly to these factors or to
other factors.
Agents for the treatment of erectile dysfunction, including
sildenafil, 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 anaemia, multiple
myeloma or leukaemia).
The safety and efficacy of combinations of sildenafil with
other treatments for erectile dysfunction have not been studied.
Therefore the use of such combinations is not recommended.
Visual defects and cases of non-arteritic anterior ischaemic
optic neuropathy have been reported in connection with the intake of
sildenafil and other PDE5 inhibitors. The patient should be advised
that in case of sudden visual defect, he should stop taking VIAGRA
and consult a physician immediately (see section 4.3).
Co-administration of sildenafil with ritonavir is not advised
(see Section 4.5).
Caution is advised when sildenafil is administered to
patients taking an alpha-blocker, as the coadministration may lead
to symptomatic hypotension in a few susceptible individuals (see
Section 4.5). This is most likely to occur within 4 hours post
sildenafil dosing. In order to minimise the potential for developing
postural hypotension, patients should be hemodynamically stable on
alpha-blocker therapy prior to initiating sildenafil treatment.
Initiation of sildenafil at a dose of 25 mg should be considered
(see Section 4.2). In addition, physicians should advise patients
what to do in the event of postural hypotensive symptoms.
Studies with human platelets indicate that sildenafil
potentiates the antiaggregatory effect of sodium nitroprusside in
vitro. There is no safety information on the administration of
sildenafil to patients with bleeding disorders or active peptic
ulceration. Therefore sildenafil should be administered to these
patients only after careful benefit-risk assessment.
The film coating of the VIAGRA tablet contains lactose.
VIAGRA should not be administered to men with rare hereditary
problems of galactose intolerance, Lapp lactase deficiency or
glucose-galactose malabsorption.
VIAGRA is not indicated for use by women.
|
|
|
4.5
Interaction with other medicinal products and other forms of
interaction |
|
|
Effects of other medicinal
products on sildenafil
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:
Population pharmacokinetic analysis of clinical trial data
indicated a reduction in sildenafil clearance when co-administered
with CYP3A4 inhibitors (such as ketoconazole, erythromycin,
cimetidine). Although no increased incidence of adverse events was
observed in these patients, when sildenafil is administered
concomitantly with CYP3A4 inhibitors, a starting dose of 25mg should
be considered.
Co-administration of the HIV protease inhibitor ritonavir,
which is a highly potent P450 inhibitor, at steady state (500mg
twice daily) with sildenafil (100mg single dose) resulted in a 300%
(4-fold) increase in sildenafil Cmax and a 1,000%
(11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma
levels of sildenafil were still approximately 200ng/ml, compared to
approximately 5ng/ml when sildenafil was administeredalone. This is
consistent with ritonavir's marked effects on a broad range of P450
substrates. Sildenafil had no effect on ritonavir pharmacokinetics.
Based on these pharmacokinetic results co-administration of
sildenafil with ritonavir is not advised (see Section 4.4) and in
any event the maximum dose of sildenafil should under no
circumstances exceed 25mg within 48 hours.
Co-administration of the HIV protease inhibitor saquinavir, a
CYP3A4 inhibitor, at steady state (1200mg three times a day) with
sildenafil (100mg single dose) resulted in a 140% increase in
sildenafil Cmax and a 210% increase in sildenafil AUC.
Sildenafil had no effect on saquinavir pharmacokinetics (see Section
4.2). Stronger CYP3A4 inhibitors such as ketoconazole and
itraconazole would be expected to have greater effects.
When a single 100mg dose of sildenafil was administered with
erythromycin, a specific CYP3A4 inhibitor, at steady state (500mg
twice daily for 5 days), there was a 182% increase in sildenafil
systemic exposure (AUC). In normal healthy male volunteers, there
was no evidence of an effect of azithromycin (500mg daily for 3
days) on the AUC, Cmax, Tmax, elimination rate
constant, or subsequent half-life of sildenafil or its principal
circulating metabolite. Cimetidine (800mg), a cytochrome P450
inhibitor and non-specific CYP3A4 inhibitor, caused a 56% increase
in plasma sildenafil concentrations when co-administered with
sildenafil (50mg) to healthy volunteers.
Grapefruit juice is a weak inhibitor of CYP3A4 gut wall
metabolism and may give rise to modest increases in plasma levels of
sildenafil.
Single doses of antacid (magnesium hydroxide/aluminium
hydroxide) did not affect the bioavailability of sildenafil.
Although specific interaction studies were not conducted for
all medicinal products, population pharmacokinetic analysis showed
no effect of concomitant medication on sildenafil pharmacokinetics
when grouped as CYP2C9 inhibitors (such as tolbutamide, warfarin,
phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake
inhibitors, tricyclic antidepressants), thiazide and related
diuretics, loop and potassium sparing diuretics, angiotensin
converting enzyme inhibitors, calcium channel blockers,
beta-adrenoreceptor antagonists or inducers of CYP450 metabolism
(such as rifampicin, barbiturates).
Nicorandil is a hybrid of potassium channel activator and
nitrate. Due to the nitrate component it has the potential to have
serious interaction with sildenafil.
Effects of sildenafil on
other medicinal products
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.
There are no data on the interaction of sildenafil and
non-specific phosphodiesterase inhibitors such as theophylline or
dipyridamole.
In vivo studies:
Consistent with its known effects on the nitric oxide/cGMP
pathway (see Section 5.1), sildenafil was shown to potentiate the
hypotensive effects of nitrates, and its co-administration with
nitric oxide donors or nitrates in any form is therefore
contraindicated (see Section 4.3).
Concomitant administration of sildenafil to patients taking
alpha-blocker therapy may lead to symptomatic hypotension in a few
susceptible individuals. This is most likely to occur within 4 hours
post sildenafil dosing (see Sections 4.2 and 4.4). In three specific
drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and
8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered
simultaneously to patients with benign prostatic hyperplasia (BPH)
stabilized on doxazosin therapy. In these study populations, mean
additional reductions of supine blood pressure of 7/7 mmHg, 9/5
mmHg, and 8/4 mmHg, and mean additional reductions of standing blood
pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were
observed. When sildenafil and doxazosin were administered
simultaneously to patients stabilized on doxazosin therapy, there
were infrequent reports of patients who experienced symptomatic
postural hypotension. These reports included dizziness and
light-headedness, but not syncope.
No significant interactions were shown when sildenafil (50mg)
was co-administered with tolbutamide (250mg) or warfarin (40mg),
both of which are metabolised by CYP2C9.
Sildenafil (50mg) did not potentiate the increase in bleeding
time caused by acetyl salicylic acid (150mg).
Sildenafil (50mg) did not potentiate the hypotensive effects
of alcohol in healthy volunteers with mean maximum blood alcohol
levels of 80 mg/dl.
Pooling of the following classes of antihypertensive
medication; diuretics, beta-blockers, ACE inhibitors, angiotensin II
antagonists, antihypertensive medicinal products (vasodilator and
centrally-acting), adrenergic neurone blockers, calcium channel
blockers and alpha-adrenoceptor blockers, showed no difference in
the side effect profile in patients taking sildenafil compared to
placebo treatment. In a specific interaction study, where sildenafil
(100mg) was co-administered with amlodipine in hypertensive
patients, there was an additional reduction on supine systolic blood
pressure of 8 mmHg. The corresponding additional reduction in supine
diastolic blood pressure was 7 mmHg. These additional blood pressure
reductions were of a similar magnitude to those seen when sildenafil
was administered alone to healthy volunteers (see Section 5.1).
Sildenafil (100mg) did not affect the steady state
pharmacokinetics of the HIV protease inhibitors, saquinavir and
ritonavir, both of which are CYP3A4 substrates.
|
|
|
4.6 Pregnancy
and lactation |
|
|
VIAGRA is not indicated for use by women.
No relevant adverse effects were found in reproduction
studies in rats and rabbits following oral administration of
sildenafil.
|
|
|
4.7 Effects on
ability to drive and use machines |
|
|
No studies on the effects on the ability to drive and use
machines have been performed.
As dizziness and altered vision were reported in clinical
trials with sildenafil, patients should be aware of how they react
to VIAGRA, before driving or operating machinery.
|
|
|
4.8
Undesirable effects |
|
|
Adverse reactions (with incidence of  1%) were reported in patients treated with the
recommended dosing regimen in placebo-controlled clinical trials.
Adverse reactions were mild to moderate in nature and the incidence
and severity increased with dose. In fixed dose studies, dyspepsia
(12%) and altered vision (11%) were more common at 100 mg than at
lower doses. The most commonly reported adverse reactions were
headache and flushing, see Table 1.
Very common: 1/10
Common: 1/100 and < 1/10
Uncommon: 1/1000 and < 1/100
Rare: 1/10,000 and < 1/1000
Very Rare: < 1/10,000
Not known: cannot be estimated from available data
|
Table 1 |
|
MedDRA System Organ Class |
Adverse Reaction |
Sildenafil
(%)
N=3350 |
Placebo
(%)
N=2995 |
|
Nervous system disorders
Very common |
Headache |
10.8 |
2.8 |
|
Common |
Dizziness |
2.9 |
1.0 |
|
Eye disorders
Common |
Altered vision (increased perception of light, blurred
vision) |
2.5 |
0.4 |
|
Common |
Chromatopsia (mild and transient, predominantly colour
tinge to vision) |
1.1 |
0.03 |
|
Cardiac disorders
Common |
Palpitation |
1.0 |
0.2 |
|
Vascular disorders
Very common |
Flushing |
10.9 |
1.4 |
|
Respiratory, thoracic and mediastinal disorders
Common |
Nasal congestion |
2.1 |
0.3 |
|
Gastrointestinal disorders
Common |
Dyspepsia |
3.0 |
0.4 |
There were reports of muscle aches when sildenafil was
administered more frequently than the recommended dosing regimen.
In postmarketing surveillance the following adverse
events have been uncommonly or rarely reported (Table 2):
|
Table 2 |
|
|
Immune system disorders |
Hypersensitivity reactions |
|
Eye disorders |
Eye pain, red eyes/ bloodshot eyes |
|
Cardiac disorders |
Tachycardia, ventricular arrhythmia, myocardial infarction,
unstable angina, sudden cardiac death (Section 4.4).
|
|
Vascular disorders |
Hypotension, (see Sections 4.4 and 4.5) ,
hypertension, epistaxis, syncope, cerebrovascular haemorrhage,
transient ischemic attack (see Section 4.4) |
|
Gastrointestinal disorders |
Vomiting |
|
Skin and subcutaneous tissue disorders |
Skin rash |
|
Reproductive system and breast
disorders |
Prolonged erection,
priapism |
In postmarketing surveillance, adverse events that have been
reported with an unknown frequency in patients taking VIAGRA
include:
Eye disorders: Non-arteritic anterior ischaemic optic
neuropathy (NAION), retinal vascular occlusion, visual field defect
|
|
|
4.9
Overdose |
|
|
In single dose volunteer studies of doses up to 800mg,
adverse reactions were similar to those seen at lower doses, but the
incidence rates and severities were increased. Doses of 200mg did
not result in increased efficacy but the incidence of adverse
reactions (headache, flushing, dizziness, dyspepsia, nasal
congestion, altered vision) was 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 not
eliminated in the urine.
|
|
| 5.
PHARMACOLOGICAL PROPERTIES |
|
|
5.1
Pharmacodynamic properties |
|
|
Pharmacotherapeutic group: Drugs used in erectile
dysfunction. ATC Code: G04B E03.
Sildenafil is an oral therapy for erectile dysfunction. In
the natural setting, i.e. with sexual stimulation, it restores
impaired erectile function by increasing blood flow to the penis.
The physiological mechanism responsible for erection of the
penis involves the release of nitric oxide (NO) in the corpus
cavernosum during sexual stimulation. Nitric oxide 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 is a potent and selective inhibitor of cGMP
specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum,
where PDE5 is responsible for degradation of cGMP. Sildenafil has a
peripheral site of action on erections. Sildenafil has no direct
relaxant effect on isolated human corpus cavernosum but potently
enhances the relaxant effect of NO on this tissue. When the NO/cGMP
pathway is activated, as occurs with sexual stimulation, inhibition
of PDE5 by sildenafil results in increased corpus cavernosum levels
of cGMP. Therefore sexual stimulation is required in order for
sildenafil to produce its intended beneficial pharmacological
effects.
Studies in vitro have shown that sildenafil is
selective for PDE5, which is involved in the erection process. Its
effect is more potent on PDE5 than on other known
phosphodiesterases. There is a 10-fold selectivity over PDE6 which
is involved in the phototransduction pathway in the retina. At
maximum recommended doses, there is an 80-fold selectivity over
PDE1, and over 700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. In
particular, sildenafil has greater than 4,000-fold selectivity for
PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved
in the control of cardiac contractility.
Two clinical studies were specifically designed to assess the
time window after dosing during which sildenafil could produce an
erection in response to sexual stimulation. In a penile
plethysmography (RigiScan) study of fasted patients, the median time
to onset for those who obtained erections of 60% rigidity
(sufficient for sexual intercourse) was 25 minutes (range 12-37
minutes) on sildenafil. In a separate RigiScan study, sildenafil was
still able to produce an erection in response to sexual stimulation
4-5 hours post-dose.
Sildenafil causes mild and transient decreases in blood
pressure which, in the majority of cases, do not translate into
clinical effects. The mean maximum decreases in supine systolic
blood pressure following 100mg oral dosing of sildenafil was 8.4
mmHg. The corresponding change in supine diastolic blood pressure
was 5.5 mmHg. These decreases in blood pressure are consistent with
the vasodilatory effects of sildenafil, probably due to increased
cGMP levels in vascular smooth muscle. Single oral doses of
sildenafil up to 100mg in healthy volunteers produced no clinically
relevant effects on ECG.
In a study of the hemodynamic effects of a single oral 100mg
dose of sildenafil in 14 patients with severe coronary artery
disease (CAD) >70% stenosis of at least one coronary artery), the
mean resting systolic and diastolic blood pressures decreased by 7%
and 6% respectively compared to baseline. Mean pulmonary systolic
blood pressure decreased by 9%. Sildenafil showed no effect on
cardiac output, and did not impair blood flow through the stenosed
coronary arteries.
No clinical relevant differences were demonstrated in time to
limiting angina for sildenafil when compared with placebo in a
double blind, placebo controlled exercise stress trial in 144
patients with erectile dysfunction and chronic stable angina, who
were taking on a regular basis anti-anginal medications (except
nitrates).
Mild and transient differences in colour discrimination
(blue/green) were detected in some subjects using the
Farnsworth-Munsell 100 hue test at 1 hour following a 100mg dose,
with no effects evident after 2 hours post-dose. The postulated
mechanism for this change in colour discrimination is related to
inhibition of PDE6, which is involved in the phototransduction
cascade of the retina. Sildenafil has no effect on visual acuity or
contrast sensitivity. In a small size placebo-controlled study of
patients with documented early age-related macular degeneration
(n=9), sildenafil (single dose, 100mg) demonstrated no significant
changes in visual tests conducted (visual acuity, Amsler grid,
colour discrimination simulated traffic light, Humphrey perimeter
and photostress).
There was no effect on sperm motility or morphology after
single 100mg oral doses of sildenafil in healthy volunteers.
Further information on
clinical trials
In clinical trials sildenafil was administered to more than
3000 patients aged 19-87. The following patient groups were
represented: elderly (21%), patients with hypertension (24%),
diabetes mellitus (16%), ischaemic heart disease and other
cardiovascular diseases (14%), hyperlipidaemia (14%), spinal cord
injury (6%), depression (5%), transurethral resection of the
prostate (5%), radical prostatectomy (4%). The following groups were
not well represented or excluded from clinical trials: patients with
pelvic surgery, patients post-radiotherapy, patients with severe
renal or hepatic impairment and patients with certain cardiovascular
conditions (see Section 4.3).
In fixed dose studies, the proportions of patients reporting
that treatment improved their erections were 62% (25mg), 74% (50mg)
and 82% (100mg) compared to 25% on placebo. In controlled clinical
trials, the discontinuation rate due to sildenafil was low and
similar to placebo.
Across all trials, the proportion of patients reporting
improvement on sildenafil were as follows: psychogenic erectile
dysfunction (84%), mixed erectile dysfunction (77%), organic
erectile dysfunction (68%), elderly (67%), diabetes mellitus (59%),
ischaemic heart disease (69%), hypertension (68%), TURP (61%),
radical prostatectomy (43%), spinal cord injury (83%), depression
(75%). The safety and efficacy of sildenafil was maintained in long
term studies.
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5.2
Pharmacokinetic properties |
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Absorption
Sildenafil is rapidly absorbed. Maximum observed plasma
concentrations are reached within 30 to 120 minutes (median 60
minutes) of oral dosing in the fasted state. The mean absolute oral
bioavailability is 41% (range 25-63%). After oral dosing of
sildenafil AUC and Cmax increase in proportion with dose
over the recommended dose range (25-100mg).
When sildenafil is taken with food, the rate of absorption is
reduced with a mean delay in Tmax of 60 minutes and a
mean reduction in Cmax of 29%.
Distribution
The mean steady state volume of distribution (Vd)
for sildenafil is 105 l, indicating distribution into the tissues.
After a single oral dose of 100 mg, the mean maximum total plasma
concentration of sildenafil is approximately 440 ng/ml (CV 40%).
Since sildenafil (and its major circulating N-desmethyl metabolite)
is 96% bound to plasma proteins, this results in the mean maximum
free plasma concentration for sildenafil of 18 ng/ml (38 nM).
Protein binding is independent of total drug concentrations.
In healthy volunteers receiving sildenafil (100mg single
dose), less than 0.0002% (average 188ng) of the administered dose
was present in ejaculate 90 minutes after dosing.
Metabolism
Sildenafil is cleared predominantly by the CYP3A4 (major
route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The
major circulating metabolite results from N-demethylation of
sildenafil. This metabolite has a phosphodiesterase selectivity
profile similar to sildenafil and an in vitro potency for
PDE5 approximately 50% that of the parent drug. Plasma
concentrations of this metabolite are approximately 40% of those
seen for sildenafil. The N-desmethyl metabolite is further
metabolised, with a terminal half life of approximately 4 h.
Elimination
The total body clearance of sildenafil is 41 l/h with a
resultant terminal phase half life of 3-5 h. After either oral or
intravenous administration, sildenafil is excreted as metabolites
predominantly in the faeces (approximately 80% of administered oral
dose) and to a lesser extent in the urine (approximately 13% of
administered oral dose).
Pharmacokinetics in special
patient groups
Elderly
Healthy elderly volunteers (65 years or over) had a reduced
clearance of sildenafil, resulting in approximately 90% higher
plasma concentrations of sildenafil and the active N-desmethyl
metabolite compared to those seen in healthy younger volunteers
(18-45 years). Due to age-differences in plasma protein binding, the
corresponding increase in free sildenafil plasma concentration was
approximately 40%.
Renal
insufficiency
In volunteers with mild to moderate renal impairment
(creatinine clearance = 30-80 ml/min), the pharmacokinetics of
sildenafil were not altered after receiving a 50mg single oral dose.
The mean AUC and Cmax of the N-desmethyl metabolite
increased 126% and 73% respectively, compared to age-matched
volunteers with no renal impairment. However, due to high
inter-subject variability, these differences were not statistically
significant. In volunteers with severe renal impairment (creatinine
clearance < 30 ml/min), sildenafil clearance was reduced,
resulting in mean increases in AUC and Cmax of 100% and
88% respectively compared to age-matched volunteers with no renal
impairment. In addition, N-desmethyl metabolite AUC and
Cmax values were significantly increased 79% and 200%
respectively.
Hepatic
insufficiency
In volunteers with mild to moderate 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. The
pharmacokinetics of sildenafil in patients with severely impaired
hepatic function have not been studied.
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5.3
Preclinical safety data |
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Non-clinical data revealed no special hazard for humans based
on conventional studies of safety pharmacology, repeated dose
toxicity, genotoxicity, carcinogenic potential, and toxicity to
reproduction.
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| 6. PHARMACEUTICAL
PARTICULARS |
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6.1 List of
excipients |
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Tablet core: microcrystalline cellulose, calcium hydrogen
phosphate (anhydrous), croscarmellose sodium, magnesium stearate.
Film coat: hypromellose, titanium dioxide (E171), lactose,
triacetin, indigo carmine aluminium lake (E132).
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6.2
Incompatibilities |
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6.3 Shelf
life |
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6.4 Special
precautions for storage |
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Do not store above 30oC.
Store in the original package, in order to protect from
moisture.
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6.5 Nature and
contents of container |
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PVC/Aluminium foil blisters in cartons of 1, 4, 8 or 12
tablets. Not all pack sizes may be marketed.
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6.6 Special
precautions for disposal and other handling |
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| 7. MARKETING
AUTHORISATION HOLDER |
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Pfizer Limited, Sandwich, Kent, CT13 9NJ, United Kingdom.
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| 8. MARKETING
AUTHORISATION NUMBER(S) |
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EU/1/98/077/001 - Viagra tablets 25 mg; pack size 1 tablet
EU/1/98/077/013 - Viagra tablets 25 mg; pack size 2 tablets
EU/1/98/077/002 - Viagra tablets 25 mg; pack size 4 tablets
EU/1/98/077/003 - Viagra tablets 25 mg; pack size 8 tablets
EU/1/98/077/004 - Viagra tablets 25 mg; pack size 12 tablets
EU/1/98/077/005 - Viagra tablets 50 mg; pack size 1 tablet
EU/1/98/077/014- Viagra tablets 50 mg; pack size 2 tablets
EU/1/98/077/006 - Viagra tablets 50 mg; pack size 4 tablets
EU/1/98/077/007 - Viagra tablets 50 mg; pack size 8 tablets
EU/1/98/077/008 - Viagra tablets 50 mg; pack size 12 tablets
EU/1/98/077/009 - Viagra tablets 100 mg; pack size 1 tablet
EU/1/98/077/015 - Viagra tablets 100 mg; pack size 2 tablets
EU/1/98/077/010 - Viagra tablets 100 mg; pack size 4 tablets
EU/1/98/077/011 - Viagra tablets 100 mg; pack size 8 tablets
EU/1/98/077/012 - Viagra tablets 100 mg; pack size 12 tablets
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| 9. DATE OF FIRST
AUTHORISATION/RENEWAL OF THE AUTHORISATION |
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Date of first authorisation: 14 September 1998
Date of last renewal: 14 September 2003
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| 10. DATE OF
REVISION OF THE TEXT |
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11. LEGAL
CATEGORY |
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POM
Detailed information on this medicinal product is available
on the website of the European Medicines Agency (EMEA)
http://www.emea.eu.int/
Ref: VI 14_0
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