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SILDENAFIL DR REDDYS 100 MG FILM-COATED TABLET

Active substance(s): SILDENAFIL CITRATE / SILDENAFIL CITRATE / SILDENAFIL CITRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Sildenafil Dr. Reddy’s 100 mg Film-Coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 140.48 mg sildenafil citrate equivalent to 100
mg sildenafil.
Excipient with known effect:
Each film-coated tablet contains 2.48 mg of lactose (as lactose monohydrate).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet

Blue coloured, round film-coated tablet debossed with ‘SC’ on one side and
‘100’ on other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Sildenafil is indicated in adult men with erectile dysfunction, which is the inability to
achieve or maintain a penile erection sufficient for satisfactory sexual performance.
In order for Sildenafil to be effective, sexual stimulation is required.

4.2

Posology and method of administration
Posology
Use in adults
The recommended dose is 50 mg taken as needed approximately one hour before
sexual activity. Based on efficacy and tolerability, the dose may be increased to 100
mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The
maximum recommended dosing frequency is once per day. If Sildenafil is taken with

food, the onset of activity may be delayed compared to the fasted state (see section
5.2).
Special populations
Elderly
Dosage adjustments are not required in elderly patients (≥ 65 years old).
Renal impairment
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 25 mg dose should be considered. Based on
efficacy and tolerability, the dose may be increased step-wise to 50 mg up to 100 mg
as necessary.
Hepatic impairment
Since sildenafil clearance is reduced in patients with hepatic impairment (e.g.
cirrhosis) a 25 mg dose should be considered. Based on efficacy and tolerability, the
dose may be increased step-wise to 50 mg up to 100 mg as necessary.
Paediatric population
Sildenafil is not indicated for individuals below 18 years of age.
Use in patients taking other medicinal products
With the exception of ritonavir for which co-administration with sildenafil is not
advised (see section 4.4) a starting dose of 25 mg should be considered in patients
receiving concomitant treatment with CYP3A4 inhibitors (see section 4.5).
In order to minimise the potential of developing postural hypotension in patients
receiving alpha-blocker treatment, patients should be stabilised 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).
Method of administration
For oral use.

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section
6.1.
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.
The co-administration of PDE5 inhibitors, including sildenafil, with guanylate
cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to
symptomatic hypotension (see section 4.5).
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).
Sildenafil 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).

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.
Cardiovascular risk factors
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.
Sildenafil 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 sildenafil. 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 sildenafil without sexual activity. It is not possible to determine whether these
events are related directly to these factors or to other factors.
Priapism
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).
Prolonged erections and priapism have been reported with sildenafil in postmarketing experience. In the event of an erection that persists longer than 4 hours, the
patient should seek immediate medical assistance. If priapism is not treated
immediately, penile tissue damage and permanent loss of potency could result.

Concomitant use with other PDE5 inhibitors or other treatments for erectile
dysfunction
The safety and efficacy of combinations of sildenafil with other PDE5 Inhibitors, or
other pulmonary arterial hypertension (PAH) treatments containing sildenafil, or
other treatments for erectile dysfunction have not been studied. Therefore the use of
such combinations is not recommended.

Effects on vision
Cases of visual defects have been reported spontaneously in connection with the
intake of sildenafil and other PDE5 inhibitors (see section 4.8). Cases of non-arteritic
anterior ischaemic optic neuropathy, a rare condition, have been reported
spontaneously and in an observational study in connection with the intake of
sildenafil and other PDE5 inhibitors (see section 4.8). Patients should be advised that
in the event of any sudden visual defect, they should stop taking Sildenafil and
consult a physician immediately (see section 4.3).

Concomitant use with ritonavir
Co-administration of sildenafil with ritonavir is not advised (see Section 4.5).

Concomitant use with alpha-blockers
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.

Effect on bleeding
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 tablet contains lactose. Sildenafil should not be administered
to men with rare hereditary problems of galactose intolerance, Lapp lactase
deficiency or glucose-galactose malabsorption.
Women
Sildenafil 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 and inducers of these isoenzymes may
increase 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 25 mg should be considered.
Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent
P450 inhibitor, at steady state (500 mg twice daily) with sildenafil (100 mg 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 200 ng/mL, compared to approximately 5 ng/mL when sildenafil
was administered alone. 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 25 mg within 48 hours.
Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at
steady state (1200 mg three times a day) with sildenafil (100 mg 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 100 mg dose of sildenafil was administered with erythromycin, a
moderate CYP3A4 inhibitor, at steady state (500 mg 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 (500 mg daily for 3
days) on the AUC, Cmax, tmax, elimination rate constant, or subsequent half-life of
sildenafil or its principal circulating metabolite. Cimetidine (800 mg), a cytochrome
P450 inhibitor and non-specific CYP3A4 inhibitor, caused a 56% increase in plasma
sildenafil concentrations when co-administered with sildenafil (50 mg) 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 treatment 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). In a study of healthy male volunteers, coadministration of the endothelin antagonist, bosentan, (an inducer of CYP3A4
[moderate], CYP2C9 and possibly of CYP2C19) at steady state (125 mg twice a day)
with sildenafil at steady state (80 mg three times a day) resulted in 62.6% and 55.4%
decrease in sildenafil AUC and Cmax, respectively. Therefore, concomitant
administration of strong CYP3A4 inducers, such as rifampin, is expected to cause
greater decreases in plasma concentrations of sildenafil
Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate
component it has the potential to result in a 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 Sildenafil 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 coadministration with nitric oxide donors or nitrates in any form is therefore
contraindicated (see section 4.3).
Riociguat: Preclinical studies showed additive systemic blood pressure lowering
effect when PDE5 inhibitors were combined with riociguat. In clinical studies,
riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors.
There was no evidence of favourable clinical effect of the combination in the
population studied. Concomitant use of riociguat with PDE5 inhibitors, including
sildenafil, is 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 (50 mg) was co-administered
with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by
CYP2C9.

Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl
salicylic acid (150 mg).
Sildenafil (50 mg) 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, betablockers, 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 (100 mg) 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 (100 mg) did not affect the steady state pharmacokinetics of the HIV
protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.
In healthy male volunteers, sildenafil at steady state (80 mg t.i.d.) resulted in a 49.8%
increase in bosentan AUC and a 42% increase in bosentan Cmax (125 mg b.i.d.).

4.6

Fertility, pregnancy and lactation
Sildenafil is not indicated for use by women.

There are no adequate and well-controlled studies in pregnant or breastfeeding
women.
No relevant adverse effects were found in reproduction studies in rats and rabbits
following oral administration of sildenafil.

There was no effect on sperm motility or morphology after single 100 mg
oral doses of sildenafil in healthy volunteers (see section 5.1).
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 Sildenafil before driving or operating
machinery.

4.8

Undesirable effects
Summary of the safety profile
The safety profile of sildenafil is based on 9,570 patients in 74 double-blind placebocontrolled clinical studies. The most commonly reported adverse reactions in clinical
studies among sildenafil treated patients were headache, flushing, dyspepsia, nasal

congestion, dizziness, nausea, hot flush, visual disturbance, cyanopsia and vision
blurred.
Adverse reactions from post-marketing surveillance has been gathered covering an
estimated period >10 years. Because not all adverse reactions are reported to the
Marketing Authorisation Holder and included in the safety database, the frequencies
of these reactions cannot be reliably determined.

Tabulated list of adverse reactions
In the table below all medically important adverse reactions, which occurred in
clinical trials at an incidence greater than placebo are listed by system organ class and
frequency (very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000
to <1/100), rare (≥1/10,000 to <1/1,000).
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
Table 1: Medically important adverse reactions reported at an incidence greater
than placebo in controlled clinical studies and medically important adverse
reactions reported through post-marketing surveillance
System Organ
Class

Very
common
(≥1/10)

Common
(≥1/100 and
<1/10)

Uncommon
(≥1/1,000 and
<1/100)

Infections and
infestations

Rhinitis

Immune
system
disorders

Hypersensitivity

Nervous
system
disorders

Headache

Dizziness

Somnolence,
Hypoaesthesia

Rare (≥1/10,000
and <1/1,000)

Cerebrovascular
accident,
Transient
ischaemic attack,
Seizure,*
Seizure
recurrence,*
Syncope

Eye disorders

Visual colour
distortions**,
Visual
disturbance,
Vision
blurred

Lacrimation
disorders***,
Eye pain,
Photophobia,
Photopsia,
Ocular
hyperaemia,
Visual
brightness,
Conjunctivitis

Non-arteritic
anterior
ischaemic optic
neuropathy
(NAION), *
Retinal
vascular
occlusion,*
Retinal
haemorrhage,
Arteriosclerotic
retinopathy,
Retinal
disorder,
Glaucoma,

Visual field
defect,
Diplopia,
Visual acuity
reduced,
Myopia,
Asthenopia,
Vitreous
floaters,
Iris disorder,
Mydriasis,
Halo vision,
Eye oedema,
Eye swelling,
Eye disorder,
Conjunctival
hyperaemia,
Eye irritation,
Abnormal
sensation in eye,
Eyelid oedema,
Scleral
discoloration

Ear and
labyrinth

Vertigo,

Deafness

Tinnitus

disorders

Cardiac
disorders

Vascular
disorders
Respiratory,
thoracic and
mediastinal
disorders
Gastrointestina
l disorders

Tachycardia,
Palpitations

Flushing,
Hot flush
Nasal
congestion

Nausea,
Dyspepsia

Hypertension,
Hypotension
Epistaxis,
Sinus
congestion
Gastro
oesophageal
reflux disease,
Vomiting,
Abdominal pain
upper,
Dry mouth

Sudden cardiac
death,*
Myocardial
infarction,
Ventricular
arrhythmia,*
Atrial
fibrillation,
Unstable
angina

Throat
tightness,
Nasal oedema,
Nasal dryness
Hypoaesthesia
oral

Skin and
subcutaneous
tissue
disorders

Rash

Musculoskelet
al
and connective
tissue
disorders
Renal and
urinary
disorders
Reproductive
system and
breast
disorders

Myalgia, Pain in
extremity

General
disorders and
administration
site conditions
Investigations

Chest pain,
Fatigue, Feeling
hot

StevensJohnson
Syndrome
(SJS),*
Toxic
Epidermal
Necrolysis
(TEN)*

Haematuria

Penile
haemorrhage,
Priapism*,
Haematospermi
a, Erection
increased
Irritability

Heart rate
increased

*Reported during post-marketing surveillance only
**Visual colour distortions: Chloropsia, Chromatopsia, Cyanopsia, Erythropsia and
Xanthopsia
***Lacrimation disorders: Dry eye, Lacrimal disorder and Lacrimation increased
Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme at
www.mhra.gov.uk/yellowcard
4.9

Overdose
In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar
to those seen at lower doses, but the incidence rates and severities were increased.
Doses of 200 mg 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: Urologicals; Drugs used in erectile dysfunction.
ATC Code: G04B E03.
Mechanism of action
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.
Pharmacodynamic 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 PDE2, 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.
Clinical efficacy and safety
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 100 mg 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 100 mg in healthy volunteers produced no clinically
relevant effects on ECG.
In a study of the hemodynamic effects of a single oral 100 mg 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.
A double-blind, placebo-controlled exercise stress trial evaluated 144 patients with
erectile dysfunction and chronic stable angina who regularly received anti-anginal
medicinal products (except nitrates). The results demonstrated no clinically relevant
differences between sildenafil and placebo in time to limiting angina.
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
100 mg 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, 100 mg) demonstrated no significant changes in the 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 100 mg oral doses
of sildenafil in healthy volunteers (see section 4.6).
Further information on clinical trials
In clinical trials sildenafil was administered to more than 8000 patients aged 19-87.
The following patient groups were represented: elderly (19.9%), patients with
hypertension (30.9%), diabetes mellitus (20.3%), ischaemic heart disease (5.8%),
hyperlipidaemia (19.8%), spinal cord injury (0.6%), depression (5.2%), transurethral
resection of the prostate (3.7%), radical prostatectomy (3.3%). 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% (25 mg), 74% (50 mg) and 82% (100 mg) 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.
Paediatric population

The European Medicines Agency has waived the obligation to submit the results of
studies with Sildenafil in all subsets of the paediatric population for the treatment of
erectile dysfunction. See 4.2 for information on paediatric use.

5.2

Pharmacokinetic properties
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 (25-100 mg).
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 (100 mg single dose), less than 0.0002%
(average 188 ng) of the administered dose was present in ejaculate 90 minutes after
dosing.
Biotransformation
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 50 mg
single oral dose. The mean AUC and Cmax of the N-desmethyl metabolite increased
up to 126% and up to 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 agematched volunteers with no renal impairment. In addition, N-desmethyl metabolite
AUC and Cmax values were significantly increased by 200% and 79% 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.

5.3

Preclinical safety data
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 and development.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Microcrystalline cellulose
Calcium hydrogen phosphate dihydrate
Croscarmellose sodium
Hydroxy Propyl Cellulose
Magnesium stearate
Film coat:
Hypromellose (E464)
Lactose Monohydrate
Triacetin (E1518)
Titanium Dioxide (E171)
Lake Indigo Carmine (E132)

6.2

Incompatibilities
None

6.3

Shelf life
2 years

6.4

Special precautions for storage
This medicinal product does not require any special storage precautions.

6.5

Nature and contents of container
PVC-PVdC/Aluminium blister packs
Pack sizes: 2, 4, 8, 12 or 24 film-coated tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Dr. Reddy’s Laboratories (UK) Ltd.
6 Riverview Road
Beverley
East Yorkshire
HU17 0LD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 08553/0470

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
14/08/2012

10

DATE OF REVISION OF THE TEXT
09/12/2016

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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