ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Sildenafil Teva 25 mg film-coated tablets
2.
Each tablet contains 25 mg of sildenafil (as citrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
White, oval-shaped film-coated tablets, engraved with ‘S 25’ on one side, and plain on the other side.
4.
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 Sildenafil Teva to be effective, sexual stimulation is required.
For oral use.
Use in adults:
The recommended dose is 50 mg taken as needed approximately one hour before sexual activity.
Based on efficacy and toleration, 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 Teva 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 25 mg dose should be considered. Based on efficacy and toleration, the dose may be
increased to 50 mg and 100 mg.
Use in patients with impaired hepatic function:
Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg dose
should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg and
100 mg.
Use in children and adolescents:
2
Sildenafil Teva is not indicated for individuals below 18 years of age.
Use in patients using 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 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).
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).
Sildenafil Teva 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)
.
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.
Sildenafil Teva 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
3
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.
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 Sildenafil Teva 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
alphablocker 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.
Sildenafil Teva is not indicated for use by women.
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 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 C
max
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.
4
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 C
max
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 specific 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, C
max
, t
max
, 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 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
(IC
50
> 150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM after
recommended doses, it is unlikely that Sildenafil Teva 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,
5
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, 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 (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.
Sildenafil Teva 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.
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 Teva, before driving or operating machinery.
The safety profile of sildenafil is based on 8,691 patients who received the recommended dosing
regimen in 67 placebo-controlled clinical studies. The most commonly reported adverse reactions in
clinical studies among sildenafil treated patients were headache, flushing, dyspepsia, visual disorders,
nasal congestion, dizziness and visual colour distortion.
Adverse reactions from post-marketing surveillance for other medicinal product containing sildenafil
has been gathered covering an estimated period >9 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.
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). In
6
addition, the frequency of medically important adverse reactions reported from post-marketing
experience is included as not known. 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
postmarketing surveillance
System Organ Class
Adverse Reactions
Immune system disorders
Rare
Hypersensitivity reactions
Nervous system disorders
Very common
Headache
Common
Dizziness
Uncommon
Somnolence, Hypoaesthesia
Rare
Cerebrovascular accident, Syncope
Not known
Transient ischaemic attack, Seizure, Seizure recurrence
Eye disorders
Common
Visual disorders, Visual colour distortion
Uncommon
Conjuncival disorders, Eye Disorders, Lacrimation Disorders, Other
Eye Disorders
Not known
Non-arteritic anterior ischaemic optic neuropathy (NAION), Retinal
vascular occlusion, Visual field defect
Ear and labyrinth disorders
Uncommon
Vertigo, Tinnitus
Rare
Deafness*
Vascular disorders
Common
Flushing
Rare
Hypertension, Hypotension
Cardiac disorders
Uncommon Palpitations, Tachycardia
Rare Myocardial infarction, Atrial fibrillation
Not known Ventricular arrhythmia, Unstable angina, Sudden cardiac death
Respiratory, thoracic and mediastinal disorders
Common Nasal congestion
Rare Epistaxis
Gastrointestinal disorders
Common Dyspepsia
Uncommon Vomiting, Nausea, Dry mouth
Skin, subcutaneous and soft tissue disorders
Uncommon Skin rash
Not known
Steven Johnson Syndrome (SJS), Toxic Epidermal Necrolysis
(TEN)
Muscoloskeletal and connective tissue disorders
Uncommon Myalgia
Reproductive system and breast disorders
Not known Priapism, Prolonged erection
General disorders and administration site conditions
Uncommon
Chest pain, Fatigue
Not known
Sudden cardiac death
Investigations
Uncommon
Heart rate increased
7
*Ear disorders: Sudden deafness. Sudden decrease or loss of hearing has been reported in a small
number of post-marketing and clinical trial cases with the use of all PDE5 inhibitors, including
sildenafil.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in erectile dysfunction. ATC Code: G04BE03.
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 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.
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
8
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.
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 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 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.
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.
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 C
max
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 t
max
of
60 minutes and a mean reduction in C
max
of 29 %.
9
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.
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 50 mg single oral dose. The mean
AUC and C
max
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 C
max
of 100 % and 88 % respectively compared to age-matched volunteers with no renal impairment. In
addition, N-desmethyl metabolite AUC and C
max
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 C
max
(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.
10
6.
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Calcium hydrogen phosphate anhydrous
Croscarmellose sodium
Magnesium stearate
Film-coat
Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol 3350
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package, in order to protect from moisture.
6.5
Nature and contents of container
PVC/Aluminium foil blisters in cartons of 2, 4, 8 or 12 tablets.
10 x 1 tablet in
PVC/Aluminium perforated unit dose blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
8.
EU/1/09/584/002
EU/1/09/584/003
EU/1/09/584/004
EU/1/09/584/005
EU/1/09/584/006
11
9.
30/11/2009
Detailed information on this product is available on the website of the European Medicines Agency
12
Sildenafil Teva 50 mg film-coated tablets
Each tablet contains 50 mg of sildenafil, (as citrate).
For a full list of excipients, see section 6.1.
Film-coated tablet.
White, oval-shaped film-coated tablets, engraved with ‘S 50’ on one side, and plain on the other side.
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 Sildenafil Teva to be effective, sexual stimulation is required.
For oral use.
Use in adults:
The recommended dose is 50 mg taken as needed approximately one hour before sexual activity.
Based on efficacy and toleration, 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 Teva 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 25 mg dose should be considered. Based on efficacy and toleration, the dose may be
increased to 50 mg and 100 mg.
Use in patients with impaired hepatic function:
Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg dose
should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg and
100 mg.
13
Use in children:
Sildenafil Teva is not indicated for individuals below 18 years of age. There is no relevant indication
for use in children.
Use in patients using 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 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).
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).
Sildenafil Teva 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)
.
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.
Sildenafil Teva 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
14
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.
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 Sildenafil Teva 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
alphablocker 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.
Sildenafil Teva is not indicated for use by women.
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 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 C
max
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
15
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 C
max
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 specific 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, C
max
, t
max
, 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 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
(IC
50
> 150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM after
recommended doses, it is unlikely that Sildenafil Teva 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.
16
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, 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 (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.
Sildenafil Teva 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.
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 Teva, before driving or operating machinery.
The safety profile of sildenafil is based on 8691 patients who received the recommended dosing
regimen in 67 placebo-controlled clinical studies. The most commonly reported adverse reactions in
clinical studies among sildenafil treated patients were headache, flushing, dyspepsia, visual disorders,
nasal congestion, dizziness and visual colour distortion.
Adverse reactions from post-marketing surveillance for other medicinal product containing sildenafil
has been gathered covering an estimated period >9 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.
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),
17
common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000). In
addition, the frequency of medically important adverse reactions reported from post-marketing
experience is included as not known. 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
postmarketing surveillance
System Organ Class
Adverse Reactions
Immune system disorders
Rare
Hypersensitivity reactions
Nervous system disorders
Very common
Headache
Common
Dizziness
Uncommon
Somnolence, Hypoaesthesia
Rare
Cerebrovascular accident, Syncope
Not known
Transient ischaemic attack, Seizure, Seizure recurrence
Eye disorders
Common
Visual disorders, Visual colour distortion
Uncommon
Conjuncival disorders, Eye Disorders, Lacrimation Disorders, Other
Eye Disorders
Not known
Non-arteritic anterior ischaemic optic neuropathy (NAION), Retinal
vascular occlusion, Visual field defect
Ear and labyrinth disorders
Uncommon
Vertigo, Tinnitus
Rare
Deafness*
Vascular disorders
Common
Flushing
Rare
Hypertension, Hypotension
Cardiac disorders
Uncommon Palpitations, Tachycardia
Rare Myocardial infarction, Atrial fibrillation
Not known Ventricular arrhythmia, Unstable angina, Sudden cardiac death
Respiratory, thoracic and mediastinal disorders
Common Nasal congestion
Rare Epistaxis
Gastrointestinal disorders
Common Dyspepsia
Uncommon Vomiting, Nausea, Dry mouth
Skin, subcutaneous and soft tissue disorders
Uncommon Skin rash
Not known
Steven Johnson Syndrome (SJS), Toxic Epidermal Necrolysis
(TEN)
Muscoloskeletal and connective tissue disorders
Uncommon Myalgia
Reproductive system and breast disorders
Not known Priapism, Prolonged erection
General disorders and administration site conditions
Uncommon
Chest pain, Fatigue
Not known
Sudden cardiac death
Investigations
Uncommon
Heart rate increased
18
* Ear disorders: Sudden deafness. Sudden decrease or loss of hearing has been reported in a small
number of post-marketing and clinical trial cases with the use of all PDE5 inhibitors, including
sildenafil.
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.
5.1 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 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.
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
19
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.
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 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 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.
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.
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 C
max
increase in
proportion with dose over the recommended dose range (25-100 mg).
20
When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in t
max
of
60 minutes and a mean reduction in C
max
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.
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 50 mg single oral dose. The mean
AUC and C
max
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 C
max
of 100 % and 88 % respectively compared to age-matched volunteers with no renal impairment. In
addition, N-desmethyl metabolite AUC and C
max
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 C
max
(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
21
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.
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Calcium hydrogen phosphate anhydrous
Croscarmellose sodium
Magnesium stearate
Film-coat
Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol 3350
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package, in order to protect from moisture.
6.5 Nature and contents of container
PVC/Aluminium foil blisters in cartons of 2, 4, 8 or 12 tablets.
10 x 1 tablet in
PVC/Aluminium perforated unit dose blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/09/584/008
22
EU/1/09/584/009
EU/1/09/584/010
EU/1/09/584/011
EU/1/09/584/012
30/11/2009
Detailed information on this product is available on the website of the European Medicines Agency
http: //www.ema.europa.eu
23
Sildenafil Teva 100 mg film-coated tablets
Each tablet contains 100 mg of sildenafil, (as citrate).
For a full list of excipients, see section 6.1.
Film-coated tablet.
White, oval-shaped film-coated tablets, engraved with ‘S 100’ on one side, and plain on the other side.
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 Sildenafil Teva to be effective, sexual stimulation is required.
For oral use.
Use in adults:
The recommended dose is 50 mg taken as needed approximately one hour before sexual activity.
Based on efficacy and toleration, 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 Teva 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 25 mg dose should be considered. Based on efficacy and toleration, the dose may be
increased to 50 mg and 100 mg.
Use in patients with impaired hepatic function:
Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg dose
should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg and
100 mg.
24
Use in children:
Sildenafil Teva is not indicated for individuals below 18 years of age. There is no relevant indication
for use in children.
Use in patients using 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 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).
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).
Sildenafil Teva 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)
.
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.
Sildenafil Teva 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
25
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.
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 Sildenafil Teva 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
alphablocker 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.
Sildenafil Teva is not indicated for use by women.
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 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 C
max
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
26
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 C
max
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 specific 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, C
max
, t
max
, 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 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
(IC
50
> 150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM after
recommended doses, it is unlikely that Sildenafil Teva 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.
27
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, 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 (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.
Sildenafil Teva 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.
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 Teva, before driving or operating machinery.
The safety profile of sildenafil is based on 8691 patients who received the recommended dosing
regimen in 67 placebo-controlled clinical studies. The most commonly reported adverse reactions in
clinical studies among sildenafil treated patients were headache, flushing, dyspepsia, visual disorders,
nasal congestion, dizziness and visual colour distortion.
Adverse reactions from post-marketing surveillance for other medicinal product containing sildenafil
has been gathered covering an estimated period >9 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.
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),
28
common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000). In
addition, the frequency of medically important adverse reactions reported from post-marketing
experience is included as not known. 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
postmarketing surveillance
System Organ Class
Adverse Reactions
Immune system disorders
Rare
Hypersensitivity reactions
Nervous system disorders
Very common
Headache
Common
Dizziness
Uncommon
Somnolence, Hypoaesthesia
Rare
Cerebrovascular accident, Syncope
Not known
Transient ischaemic attack, Seizure, Seizure recurrence
Eye disorders
Common
Visual disorders, Visual colour distortion
Uncommon
Conjuncival disorders, Eye Disorders, Lacrimation Disorders, Other
Eye Disorders
Not known
Non-arteritic anterior ischaemic optic neuropathy (NAION), Retinal
vascular occlusion, Visual field defect
Ear and labyrinth disorders
Uncommon
Vertigo, Tinnitus
Rare
Deafness*
Vascular disorders
Common
Flushing
Rare
Hypertension, Hypotension
Cardiac disorders
Uncommon Palpitations, Tachycardia
Rare Myocardial infarction, Atrial fibrillation
Not known Ventricular arrhythmia, Unstable angina, Sudden cardiac death
Respiratory, thoracic and mediastinal disorders
Common Nasal congestion
Rare Epistaxis
Gastrointestinal disorders
Common Dyspepsia
Uncommon Vomiting, Nausea, Dry mouth
Skin, subcutaneous and soft tissue disorders
Uncommon Skin rash
Not known
Steven Johnson Syndrome (SJS), Toxic Epidermal Necrolysis
(TEN)
Muscoloskeletal and connective tissue disorders
Uncommon Myalgia
Reproductive system and breast disorders
Not known Priapism, Prolonged erection
General disorders and administration site conditions
Uncommon
Chest pain, Fatigue
Not known
Sudden cardiac death
Investigations
Uncommon
Heart rate increased
29
* Ear disorders: Sudden deafness. Sudden decrease or loss of hearing has been reported in a small
number of post-marketing and clinical trial cases with the use of all PDE5 inhibitors, including
sildenafil.
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.
5.1 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 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.
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
30
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.
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 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 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.
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
were62% (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.
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 C
max
increase in
proportion with dose over the recommended dose range (25-100 mg).
31
When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in t
max
of
60 minutes and a mean reduction in C
max
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.
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 50 mg single oral dose. The mean
AUC and C
max
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 C
max
of 100 % and 88 % respectively compared to age-matched volunteers with no renal impairment. In
addition, N-desmethyl metabolite AUC and C
max
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 C
max
(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
32
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.
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Calcium hydrogen phosphate anhydrous
Croscarmellose sodium
Magnesium stearate
Film-coat
Poly(vinyl alcohol)
Titanium dioxide (E171)
Macrogol 3350
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package, in order to protect from moisture.
6.5 Nature and contents of container
PVC/Aluminium foil blisters in cartons of 2, 4, 8 or 12 tablets.
10 x 1 tablet in
PVC/Aluminium perforated unit dose blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/09/584/014
33
EU/1/09/584/015
EU/1/09/584/016
EU/1/09/584/017
EU/1/09/584/018
30/11/2009
Detailed information on this product is available on the website of the European Medicines Agency:
http://www.ema.europa.eu
34
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
35
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
4042 Debrecen
Hungary
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
2100 Gödöllő
Hungary
TEVA UK Ltd
Brampton Road, Hampden Park, Eastbourne
East Sussex, BN22 9AG
United Kingdom
Pharmachemie B.V.
Swensweg 5
2031 GAHaarlem
The Netherlands
TEVA Santé SA
Rue Bellocier,
89107 Sens
France
Teva Pharma,S.L.U.
Polígono Industrial Malpìca, calle C,no.4
50016 Zaragoza
Spain
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
36
The MAH must ensure that the system of pharmacovigilance, as described in version 5 (May 2008)
presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning
before and whilst the product is on the market.
PSURs
The PSUR submission schedule for Sildenafil Teva film-coated tablets should follow the PSURs
submission schedule for the reference medicinal product.
37
ANNEX III
LABELLING AND PACKAGE LEAFLET
38
A. LABELLING
39
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON – Sildenafil Teva 25 mg Film-coated tablets
1.
Sildenafil Teva 25 mg film-coated tablets
sildenafil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 25 mg sildenafil (as citrate)
3.
LIST OF EXCIPIENTS
4.
2 film-coated tablets
4 film-coated tablets
8 film-coated tablets
10 x 1 film-coated tablet
12 film-coated-tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture.
40
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
12.
EU/1/09/584/002
EU/1/09/584/003
EU/1/09/584/004
EU/1/09/584/005
EU/1/09/584/006
13.
BATCH NUMBER
BN
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Sildenafil Teva 25 mg
41
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER – Sildenafil Teva 25 mg Film-coated tablets
1.
Sildenafil Teva 25 mg film-coated tablets
sildenafil
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
42
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON – Sildenafil Teva 50
mg Film-coated tablets
1.
Sildenafil Teva 50 mg film-coated tablets
sildenafil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg sildenafil (as citrate)
3.
LIST OF EXCIPIENTS
4.
2 film-coated tablets
4 film-coated tablets
8 film-coated tablets
10 x 1 film-coated tablet
12 film-coated-tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture
43
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
12.
EU/1/09/584/008
EU/1/09/584/009
EU/1/09/584/010
EU/1/09/584/011
EU/1/09/584/012
13.
BATCH NUMBER
BN
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Sildenafil Teva 50 mg
44
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER – Sildenafil Teva 50
mg Film-coated tablets
1.
Sildenafil Teva 50 mg film-coated tablets
sildenafil
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
45
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON – Sildenafil Teva 100 mg Film-coated tablets
1.
Sildenafil Teva 100 mg film-coated tablets
sildenafil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 100 mg sildenafil (as citrate)
3.
LIST OF EXCIPIENTS
4.
2 film-coated tablets
4 film-coated tablets
8 film-coated tablets
10 x 1 film-coated tablet
12 film-coated-tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture
46
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
12.
EU/1/09/584/014
EU/1/09/584/015
EU/1/09/584/016
EU/1/09/584/017
EU/1/09/584/018
13.
BATCH NUMBER
BN
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Sildenafil Teva 100 mg
47
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER – Sildenafil Teva 100 mg Film-coated tablets
1.
Sildenafil Teva 100 mg film-coated tablets
sildenafil
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
48
B. PACKAGE LEAFLET
49
PACKAGE LEAFLET: INFORMATION FOR THE USER
Sildenafil Teva 25
mg film-coated tablets
Sildenafil
Read all of this leaflet carefully before you start taking this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
•
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Sildenafil Teva is and what it is used for
2. Before you take Sildenafil Teva
3. How to take Sildenafil Teva
4. Possible side effects
5.
How to store Sildenafil Teva
6. Furtherinformation
1.
WHAT SILDENAFIL TEVA IS AND WHAT IT IS USED FOR
Sildenafil Teva belongs to a group of medicines called phosphodiesterase type 5 inhibitors. It works
by helping to relax the blood vessels in your penis, allowing blood to flow into your penis when you
get sexually excited. Sildenafil Teva will only help you to get an erection if you are sexually
stimulated. You should not take Sildenafil Teva if you do not have erectile dysfunction. You should
not take Sildenafil Teva if you are a woman.
Sildenafil Teva is a treatment for men with erectile dysfunction, sometimes known as impotence. This
is when a man cannot get, or keep a hard, erect penis suitable for sexual activity.
2. BEFORE YOU TAKE SILDENAFIL TEVA
Do not take Sildenafil Teva
•
If you are taking medicines containing nitrates, as the combination may cause a potentially
dangerous decrease in your blood pressure. Tell your doctor if you are taking any of these
medicines which are often given for relief of angina pectoris (“chest pain”). If you are not
certain, ask your doctor or pharmacist.
•
If you are using any of the drugs known as nitric oxide donors such as amyl nitrite (“poppers”),
as the combination may also lead to potentially dangerous decrease in your blood pressure.
•
If you are allergic (hypersensitive) to sildenafil or any of the other ingredients of Sildenafil
Teva.
•
If you have a severe heart or liver problem.
•
If you have recently had a stroke or a heart attack, or if you have low blood pressure.
•
If you have certain rare inherited eye diseases (such as
retinitis pigmentosa
).
50
•
If you have ever had loss of vision because of non-arteritic anterior ischaemic optic neuropathy
(NAION).
Take special care with Sildenafil Teva
Tell your doctor
•
If you have sickle cell anaemia (an abnormality of red blood cells), leukaemia (cancer of blood
cells), multiple myeloma (cancer of bone marrow) or
•
If you have a deformity of your penis or Peyronie’s Disease.
•
If you have problems with your heart. Your doctor should in that case carefully check whether
your heart can take the additional strain of having sex.
•
If you currently have a stomach ulcer, or a bleeding disorder (such as haemophilia).
•
If you experience sudden decrease or loss of vision, stop taking Sildenafil Teva and contact
your doctor immediately.
You should not use Sildenafil Teva with any other treatment for erectile dysfunction.
Special considerations for children
and adolescents
Sildenafil Teva should not be given to individuals under the age of 18.
Special considerations for patients with kidney or liver problems
You should tell your doctor if you have kidney or liver problems. Your doctor may decide on a lower
dose for you.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken other medicines,
including medicines obtained without prescription.
Sildenafil Teva tablets may interfere with some medicines, especially those used to treat chest pain. In
the event of a medical emergency, you should tell any health care professional treating your condition
that you have taken Sildenafil Teva and when you did. Do not take Sildenafil Teva with other
medicines unless your doctor tells you that you can.
You should not take Sildenafil Teva if you are taking medicines called nitrates, as the combination of
these products may cause a potentially dangerous decrease in your blood pressure. Always tell your
doctor or pharmacist if you are taking any of these medicines that are often used for the relief of
angina pectoris (or “chest pain”).
You should not take Sildenafil Teva if you are using any of the drugs known as nitric oxide donors
such as amyl nitrite (“poppers”) as the combination may also lead to potentially dangerous decrease in
your blood pressure.
If you are taking medicines known as protease inhibitors, such as for the treatment of HIV, your
doctor may start you on the lowest dose (25 mg) of Sildenafil Teva.
Some patients who take alpha-blocker therapy for the treatment of high blood pressure or prostate
enlargement may experience dizziness or light-headedness, which may be caused by low blood
pressure upon sitting or standing up too quickly. Certain patients have experienced these symptoms
when taking Sildenafil Teva with alpha-blockers. This is most likely to occur within 4 hours after
taking Sildenafil Teva. In order to reduce the likelihood that these symptoms occur, you should be on
a regular daily dose of your alpha-blocker before you start Sildenafil Teva. Your doctor may start you
on a lower (25 mg) dose of Sildenafil Teva.
Taking Sildenafil Teva
with food and drink
Sildenafil Teva can be taken with or without food. However, you may find that Sildenafil Teva takes
longer to start working if you take it with a heavy meal.
51
Drinking alcohol can temporarily impair your ability to get an erection. To get the maximum benefit
from your medicine you are advised not to drink excessive amounts of alcohol before taking Sildenafil
Teva.
Pregnancy and breast-feeding
Sildenafil Teva is not indicated for use by women.
Driving and using machines
Sildenafil Teva can cause dizziness and can affect vision. You should be aware of how you react to
Sildenafil Teva before you drive or use machinery.
3. HOW TO TAKE SILDENAFIL TEVA
Always take Sildenafil Teva exactly as your doctor has told you. You should check with your doctor
or pharmacist if you are not sure. The usual dose is 50 mg.
You should not use Sildenafil Teva more than once a day.
You should take Sildenafil Teva about one hour before you plan to have sex. Swallow the tablet whole
with a glass of water.
If you have the impression that the effect of Sildenafil Teva is too strong or too weak, talk to your
doctor or pharmacist.
Sildenafil Teva will only help you to get an erection if you are sexually stimulated. The amount of
time Sildenafil Teva takes to work varies from person to person, but it normally takes between half an
hour and one hour. You may find that Sildenafil Teva takes longer to work if you take it with a heavy
meal.
If Sildenafil Teva does not help you to get an erection, or if your erection does not last long enough
for you to complete sexual intercourse you should tell your doctor.
If you take more Sildenafil Teva
than you should:
You may experience an increase in side effects and their severity. Doses above 100 mg do not increase
the efficacy.
You should not take more tablets than your doctor tells you to.
Contact your doctor if you take more tablets than you should.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Sildenafil Teva can cause side effects although not everybody gets them. The side
effects reported in association with the use of Sildenafil Teva are usually mild to moderate and of a
short duration.
If you have chest pains during or after intercourse:
-
Get in a semi-sitting position and try to relax
-
Do not use nitrates
to treat your chest pain
-
Contact your doctor immediately
52
All medicines, including Sildenafil Teva can cause allergic reactions. You should contact your doctor
immediately if you experience any of the following symptoms after taking Sildenafil Teva: sudden
wheeziness, difficulty in breathing or dizziness, swelling of the eyelids, face, lips or throat.
Prolonged and sometimes painful erections have been reported after taking Sildenafil Teva. If you
have an erection which lasts for more than 4 hours, you should contact a doctor immediately.
The following side effects have been reported at the approximate frequencies shown:
Very common:
affects more than 1 user in 10
Common:
affects 1 to 10 users in 100
Uncommon:
affects 1 to 10 users in 1,000
Rare:
affects 1 to 10 users in 10,000
Very Rare:
affects less than 1 user in 10,000
Not known:
frequency cannot be estimated from the available data
Very common:
•
Headache
Common:
•
facial flushing
•
indigestion
•
effects on vision (including colour tinge to vision, light sensitivity, blurred vision or reduced
sharpness of vision)
•
stuffy nose
•
dizziness.
Uncommon:
•
vomiting
•
skin rash
•
bleeding at the back of the eye
•
eye irritation
•
bloodshot eyes/red eyes
•
eye pain
•
double vision
•
abnormal sensation in the eye
•
irregular or rapid heartbeat
•
muscle pain
•
feeling sleepy
•
reduced sense of touch
•
vertigo
•
ringing in the ears
•
nausea
•
dry mouth
•
chest pain
•
feeling tired.
Rare:
•
high blood pressure
•
low blood pressure
•
fainting
•
stroke
•
nosebleed
•
sudden decrease or loss of hearing
53
Additional side effects reported from post-marketing experience include: pounding heartbeat, chest
pain, sudden death, heart attack or temporary decreased blood flow to parts of the brain. Most, but not
all, of these men had heart problems before taking this medicine. It is not possible to determine
whether these events were directly related to sildenafil.
Cases of convulsions or seizures and serious
skin reactions characterised by rash, blisters, peeling skin and pain which require immediate medical
attention have also been reported.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet please tell
your doctor.
5. HOW TO STORE SILDENAFIL TEVA
Keep out of the reach and sight of children.
Do not use Sildenafil Teva after the expiry date which is stated on the blister and carton. The expiry
date refers to the last day of that month.
Store in the original package, in order to protect from moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What Sildenafil Teva contains
The active substance is sildenafil. Each tablet contains 25 mg of sildenafil (as citrate).
The other ingredients are:
Tablet core: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose
sodium, magnesium stearate.
Film coat: poly(vinyl alcohol), titanium dioxide (E171), macrogol 3350, talc.
What Sildenafil Teva looks like and contents of the pack
Sildenafil Teva 25 mg are white, oval-shaped film-coated tablets, engraved with ‘S 25’ on one side,
and plain on the other side.
Sildenafil Teva is available in blister packs of 2, 4, 8 and 12 tablets, and perforated unit dose blisters
containing 10 x 1 tablet.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
Manufacturer:
TEVA Pharmaceutical Works Private Limited Company
Pallagi út 13
4042 Debrecen
Hungary
TEVA Pharmaceutical Works Private Limited Company
54
Táncsics Mihály út 82
2100 Gödöllő
Hungary
TEVA UK Ltd
Brampton Road, Hampden Park, Eastbourne
East Sussex
BN22 9AG
United Kingdom
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé Sa
Rue Bellocier
89107 Sens
France
Teva Pharma, S.L.U.
Polígono Industrial Malpìca, calle C,no.4
50016 Zaragoza
Spain
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
55
España
Teva Pharma, S.L.U.
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 230 65 24
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
56
PACKAGE LEAFLET: INFORMATION FOR THE USER
Sildenafil Teva 50
mg film-coated tablets
Sildenafil
Read all of this leaflet carefully before you start taking this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
•
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Sildenafil Teva is and what it is used for
2. Before you take Sildenafil Teva
3. How to take Sildenafil Teva
4. Possible side effects
6.
How to store Sildenafil Teva
6. Furtherinformation
1.
WHAT SILDENAFIL TEVA IS AND WHAT IT IS USED FOR
Sildenafil Teva belongs to a group of medicines called phosphodiesterase type 5 inhibitors. It works
by helping to relax the blood vessels in your penis, allowing blood to flow into your penis when you
get sexually excited. Sildenafil Teva will only help you to get an erection if you are sexually
stimulated. You should not take Sildenafil Teva if you do not have erectile dysfunction. You should
not take Sildenafil Teva if you are a woman.
Sildenafil Teva is a treatment for men with erectile dysfunction, sometimes known as impotence. This
is when a man cannot get, or keep a hard, erect penis suitable for sexual activity.
2. BEFORE YOU TAKE SILDENAFIL TEVA
Do not take Sildenafil Teva
•
If you are taking medicines containing nitrates, as the combination may cause a potentially
dangerous decrease in your blood pressure. Tell your doctor if you are taking any of these
medicines which are often given for relief of angina pectoris (“chest pain”). If you are not
certain, ask your doctor or pharmacist.
•
If you are using any of the drugs known as nitric oxide donors such as amyl nitrite (“poppers”),
as the combination may also lead to potentially dangerous decrease in your blood pressure.
•
If you are allergic (hypersensitive) to sildenafil or any of the other ingredients of Sildenafil
Teva.
•
If you have a severe heart or liver problem.
•
If you have recently had a stroke or a heart attack, or if you have low blood pressure.
•
If you have certain rare inherited eye diseases (such as
retinitis pigmentosa
).
57
•
If you have ever had loss of vision because of non-arteritic anterior ischaemic optic neuropathy
(NAION).
Take special care with Sildenafil Teva
Tell your doctor
•
If you have sickle cell anaemia (an abnormality of red blood cells), leukaemia (cancer of blood
cells), multiple myeloma (cancer of bone marrow) or
•
If you have a deformity of your penis or Peyronie’s Disease.
•
If you have problems with your heart. Your doctor should in that case carefully check whether
your heart can take the additional strain of having sex.
•
If you currently have a stomach ulcer, or a bleeding disorder (such as haemophilia).
•
If you experience sudden decrease or loss of vision, stop taking Sildenafil Teva and contact
your doctor immediately.
You should not use Sildenafil Teva with any other treatment for erectile dysfunction.
Special considerations for children and adolescents
Sildenafil Teva should not be given to individuals under the age of 18.
Special considerations for patients with kidney or liver problems
You should tell your doctor if you have kidney or liver problems. Your doctor may decide on a lower
dose for you.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken other medicines,
including medicines obtained without prescription.
Sildenafil Teva tablets may interfere with some medicines, especially those used to treat chest pain. In
the event of a medical emergency, you should tell any health care professional treating your condition
that you have taken Sildenafil Teva and when you did. Do not take Sildenafil Teva with other
medicines unless your doctor tells you that you can.
You should not take Sildenafil Teva if you are taking medicines called nitrates, as the combination of
these products may cause a potentially dangerous decrease in your blood pressure. Always tell your
doctor or pharmacist if you are taking any of these medicines that are often used for the relief of
angina pectoris (or “chest pain”).
You should not take Sildenafil Teva is you are using any of the drugs known as nitric oxide donors
such as amyl nitrite (“poppers”) as the combination may also lead to potentially dangerous decrease in
your blood pressure.
If you are taking medicines known as protease inhibitors, such as for the treatment of HIV, your
doctor may start you on the lowest dose (25 mg) of Sildenafil Teva.
Some patients who take alpha-blocker therapy for the treatment of high blood pressure or prostate
enlargement may experience dizziness or light-headedness, which may be caused by low blood
pressure upon sitting or standing up too quickly. Certain patients have experienced these symptoms
when taking Sildenafil Teva with alpha-blockers. This is most likely to occur within 4 hours after
taking Sildenafil Teva. In order to reduce the likelihood that these symptoms occur, you should be on
a regular daily dose of your alpha-blocker before you start Sildenafil Teva. Your doctor may start you
on a lower (25 mg) dose of Sildenafil Teva.
Taking Sildenafil Teva
with food and drink
Sildenafil Teva can be taken with or without food. However, you may find that Sildenafil Teva takes
longer to start working if you take it with a heavy meal.
58
Drinking alcohol can temporarily impair your ability to get an erection. To get the maximum benefit
from your medicine you are advised not to drink excessive amounts of alcohol before taking Sildenafil
Teva.
Pregnancy and breast-feeding
Sildenafil Teva is not indicated for use by women.
Driving and using machines
Sildenafil Teva can cause dizziness and can affect vision. You should be aware of how you react to
Sildenafil Teva before you drive or use machinery.
3. HOW TO TAKE SILDENAFIL TEVA
Always take Sildenafil Teva exactly as your doctor has told you. You should check with your doctor
or pharmacist if you are not sure. The usual dose is 50 mg.
You should not use Sildenafil Teva more than once a day.
You should take Sildenafil Teva about one hour before you plan to have sex. Swallow the tablet whole
with a glass of water.
If you have the impression that the effect of Sildenafil Teva is too strong or too weak, talk to your
doctor or pharmacist.
Sildenafil Teva will only help you to get an erection if you are sexually stimulated. The amount of
time Sildenafil Teva takes to work varies from person to person, but it normally takes between half an
hour and one hour. You may find that Sildenafil Teva takes longer to work if you take it with a heavy
meal.
If Sildenafil Teva does not help you to get an erection, or if your erection does not last long enough
for you to complete sexual intercourse you should tell your doctor.
If you take more Sildenafil Teva
than you should:
You may experience an increase in side effects and their severity. Doses above 100 mg do not increase
the efficacy.
You should not take more tablets than your doctor tells you to.
Contact your doctor if you take more tablets than you should.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Sildenafil Teva can cause side effects although not everybody gets them. The side
effects reported in association with the use of Sildenafil Teva are usually mild to moderate and of a
short duration.
If you have chest pains during or after intercourse:
-
Get in a semi-sitting position and try to relax
-
Do not use nitrates
to treat your chest pain
-
Contact your doctor immediately
59
All medicines, including Sildenafil Teva can cause allergic reactions. You should contact your doctor
immediately if you experience any of the following symptoms after taking Sildenafil Teva: sudden
wheeziness, difficulty in breathing or dizziness, swelling of the eyelids, face, lips or throat.
Prolonged and sometimes painful erections have been reported after taking Sildenafil Teva. If you
have an erection which lasts for more than 4 hours, you should contact a doctor immediately.
The following side effects have been reported at the approximate frequencies shown:
Very common:
affects more than 1 user in 10
Common:
affects 1 to 10 users in 100
Uncommon:
affects 1 to 10 users in 1,000
Rare:
affects 1 to 10 users in 10,000
Very Rare:
affects less than 1 user in 10,000
Not known:
frequency cannot be estimated from the available data
Very common:
•
Headache
Common:
•
facial flushing
•
indigestion
•
effects on vision (including colour tinge to vision, light sensitivity, blurred vision or reduced
sharpness of vision)
•
stuffy nose
•
dizziness.
Uncommon:
•
vomiting
•
skin rash
•
bleeding at the back of the eye
•
eye irritation
•
bloodshot eyes/red eyes
•
eye pain
•
double vision
•
abnormal sensation in the eye
•
irregular or rapid heartbeat
•
muscle pain
•
feeling sleepy
•
reduced sense of touch
•
vertigo
•
ringing in the ears
•
nausea
•
dry mouth
•
chest pain
•
feeling tired.
Rare:
•
high blood pressure
•
low blood pressure
•
fainting
•
stroke
•
nosebleed
•
sudden decrease or loss of hearing
60
Additional side effects reported from post-marketing experience include: pounding heartbeat, chest
pain, sudden death, heart attack or temporary decreased blood flow to parts of the brain. Most, but not
all, of these men had heart problems before taking this medicine. It is not possible to determine
whether these events were directly related to sildenafil.
Cases of convulsions or seizures and serious
skin reactions characterised by rash, blisters, peeling skin and pain which require immediate medical
attention have also been reported.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet please tell
your doctor.
5. HOW TO STORE SILDENAFIL TEVA
Keep out of the reach and sight of children.
Do not use Sildenafil Teva after the expiry date which is stated on the blister and carton. The expiry
date refers to the last day of that month.
Store in the original package, in order to protect from moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What Sildenafil Teva contains
The active substance is sildenafil. Each tablet contains 50 mg of sildenafil (as citrate).
The other ingredients are:
Tablet core: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose
sodium, magnesium stearate.
Film coat: poly(vinyl alcohol), titanium dioxide (E171), macrogol 3350, talc.
What Sildenafil Teva looks like and contents of the pack
Sildenafil Teva 50 mg are white, oval-shaped film-coated tablets, engraved with ‘S 50’ on one side,
and plain on the other side.
Sildenafil Teva is available in blister packs of 2, 4, 8 and 12 tablets, and perforated unit dose blisters
containing 10 x 1 tablet.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
Manufacturer:
TEVA Pharmaceutical Works Private Limited Company
Pallagi út 13
4042 Debrecen
Hungary
TEVA Pharmaceutical Works Private Limited Company
61
Táncsics Mihály út 82
2100 Gödöllő
Hungary
TEVA UK Ltd
Brampton Road, Hampden Park, Eastbourne
East Sussex
BN22 9AG
United Kingdom
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé Sa
Rue Bellocier
89107 Sens
France
Teva Pharma, S.L.U.
Polígono Industrial Malpìca, calle C,no.4
50016 Zaragoza
Spain
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
62
España
Teva Pharma, S.L.U.
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 230 65 24
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
63
PACKAGE LEAFLET: INFORMATION FOR THE USER
Sildenafil Teva 100
mg film-coated tablets
Sildenafil
Read all of this leaflet carefully before you start taking this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
•
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Sildenafil Teva is and what it is used for
2. Before you take Sildenafil Teva
3. How to take Sildenafil Teva
4. Possible side effects
7.
How to store Sildenafil Teva
6. Furtherinformation
1.
WHAT SILDENAFIL TEVA IS AND WHAT IT IS USED FOR
Sildenafil Teva belongs to a group of medicines called phosphodiesterase type 5 inhibitors. It works
by helping to relax the blood vessels in your penis, allowing blood to flow into your penis when you
get sexually excited. Sildenafil Teva will only help you to get an erection if you are sexually
stimulated. You should not take Sildenafil Teva if you do not have erectile dysfunction. You should
not take Sildenafil Teva if you are a woman.
Sildenafil Teva is a treatment for men with erectile dysfunction, sometimes known as impotence. This
is when a man cannot get, or keep a hard, erect penis suitable for sexual activity.
2. BEFORE YOU TAKE SILDENAFIL TEVA
Do not take Sildenafil Teva
•
If you are taking medicines containing nitrates, as the combination may cause a potentially
dangerous decrease in your blood pressure. Tell your doctor if you are taking any of these
medicines which are often given for relief of angina pectoris (“chest pain”). If you are not
certain, ask your doctor or pharmacist.
•
If you are using any of the drugs known as nitric oxide donors such as amyl nitrite (“poppers”),
as the combination may also lead to potentially dangerous decrease in your blood pressure.
•
If you are allergic (hypersensitive) to sildenafil or any of the other ingredients of Sildenafil
Teva.
•
If you have a severe heart or liver problem.
•
If you have recently had a stroke or a heart attack, or if you have low blood pressure.
•
If you have certain rare inherited eye diseases (such as
retinitis pigmentosa
).
•
If you have ever had loss of vision because of non-arteritic anterior ischaemic optic neuropathy
(NAION).
64
Take special care with Sildenafil Teva
Tell your doctor
•
If you have sickle cell anaemia (an abnormality of red blood cells), leukaemia (cancer of blood
cells), multiple myeloma (cancer of bone marrow) or
•
If you have a deformity of your penis or Peyronie’s Disease.
•
If you have problems with your heart. Your doctor should in that case carefully check whether
your heart can take the additional strain of having sex.
•
If you currently have a stomach ulcer, or a bleeding disorder (such as haemophilia).
•
If you experience sudden decrease or loss of vision, stop taking Sildenafil Teva and contact
your doctor immediately.
You should not use Sildenafil Teva with any other treatment for erectile dysfunction.
Special considerations for children
and adolescents
Sildenafil Teva should not be given to individuals under the age of 18.
Special considerations for patients with kidney or liver problems
You should tell your doctor if you have kidney or liver problems. Your doctor may decide on a lower
dose for you.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken other medicines,
including medicines obtained without prescription.
Sildenafil Teva tablets may interfere with some medicines, especially those used to treat chest pain. In
the event of a medical emergency, you should tell any health care professional treating your condition
that you have taken Sildenafil Teva and when you did. Do not take Sildenafil Teva with other
medicines unless your doctor tells you that you can.
You should not take Sildenafil Teva if you are taking medicines called nitrates, as the combination of
these products may cause a potentially dangerous decrease in your blood pressure. Always tell your
doctor or pharmacist if you are taking any of these medicines that are often used for the relief of
angina pectoris (or “chest pain”).
You should not take Sildenafil Teva is you are using any of the drugs known as nitric oxide donors
such as amyl nitrite (“poppers”) as the combination may also lead to potentially dangerous decrease in
your blood pressure.
If you are taking medicines known as protease inhibitors, such as for the treatment of HIV, your
doctor may start you on the lowest dose (25 mg) of Sildenafil Teva.
Some patients who take alpha-blocker therapy for the treatment of high blood pressure or prostate
enlargement may experience dizziness or light-headedness, which may be caused by low blood
pressure upon sitting or standing up too quickly. Certain patients have experienced these symptoms
when taking Sildenafil Teva with alpha-blockers. This is most likely to occur within 4 hours after
taking Sildenafil Teva. In order to reduce the likelihood that these symptoms occur, you should be on
a regular daily dose of your alpha-blocker before you start Sildenafil Teva. Your doctor may start you
on a lower (25 mg) dose of Sildenafil Teva.
Taking Sildenafil Teva
with food and drink
Sildenafil Teva can be taken with or without food. However, you may find that Sildenafil Teva takes
longer to start working if you take it with a heavy meal.
Drinking alcohol can temporarily impair your ability to get an erection. To get the maximum benefit
from your medicine you are advised not to drink excessive amounts of alcohol before taking Sildenafil
Teva.
65
Pregnancy and breast-feeding
Sildenafil Teva is not indicated for use by women.
Driving and using machines
Sildenafil Teva can cause dizziness and can affect vision. You should be aware of how you react to
Sildenafil Teva before you drive or use machinery.
3. HOW TO TAKE SILDENAFIL TEVA
Always take Sildenafil Teva exactly as your doctor has told you. You should check with your doctor
or pharmacist if you are not sure. The usual dose is 50 mg.
You should not use Sildenafil Teva more than once a day.
You should take Sildenafil Teva about one hour before you plan to have sex. Swallow the tablet whole
with a glass of water.
If you have the impression that the effect of Sildenafil Teva is too strong or too weak, talk to your
doctor or pharmacist.
Sildenafil Teva will only help you to get an erection if you are sexually stimulated. The amount of
time Sildenafil Teva takes to work varies from person to person, but it normally takes between half an
hour and one hour. You may find that Sildenafil Teva takes longer to work if you take it with a heavy
meal.
If Sildenafil Teva does not help you to get an erection, or if your erection does not last long enough
for you to complete sexual intercourse you should tell your doctor.
If you take more Sildenafil Teva
than you should:
You may experience an increase in side effects and their severity. Doses above 100 mg do not increase
the efficacy.
You should not take more tablets than your doctor tells you to.
Contact your doctor if you take more tablets than you should.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Sildenafil Teva can cause side effects although not everybody gets them. The side
effects reported in association with the use of Sildenafil Teva are usually mild to moderate and of a
short duration.
If you have chest pains during or after intercourse:
-
Get in a semi-sitting position and try to relax
-
Do not use nitrates
to treat your chest pain
-
Contact your doctor immediately
All medicines, including Sildenafil Teva can cause allergic reactions. You should contact your doctor
immediately if you experience any of the following symptoms after taking Sildenafil Teva: sudden
wheeziness, difficulty in breathing or dizziness, swelling of the eyelids, face, lips or throat.
66
Prolonged and sometimes painful erections have been reported after taking Sildenafil Teva. If you
have an erection which lasts for more than 4 hours, you should contact a doctor immediately.
The following side effects have been reported at the approximate frequencies shown:
Very common:
affects more than 1 user in 10
Common:
affects 1 to 10 users in 100
Uncommon:
affects 1 to 10 users in 1,000
Rare:
affects 1 to 10 users in 10,000
Very Rare:
affects less than 1 user in 10,000
Not known:
frequency cannot be estimated from the available data
Very common:
•
Headache
Common:
•
facial flushing
•
indigestion
•
effects on vision (including colour tinge to vision, light sensitivity, blurred vision or reduced
sharpness of vision)
•
stuffy nose
•
dizziness.
Uncommon:
•
vomiting
•
skin rash
•
bleeding at the back of the eye
•
eye irritation
•
bloodshot eyes/red eyes
•
eye pain
•
double vision
•
abnormal sensation in the eye
•
irregular or rapid heartbeat
•
muscle pain
•
feeling sleepy
•
reduced sense of touch
•
vertigo
•
ringing in the ears
•
nausea
•
dry mouth
•
chest pain
•
feeling tired.
Rare:
•
high blood pressure
•
low blood pressure
•
fainting
•
stroke
•
nosebleed
•
sudden decrease or loss of hearing
Additional side effects reported from post-marketing experience include: pounding heartbeat, chest
pain, sudden death, heart attack or temporary decreased blood flow to parts of the brain. Most, but not
all, of these men had heart problems before taking this medicine. It is not possible to determine
whether these events were directly related to sildenafil.
Cases of convulsions or seizures and serious
67
skin reactions characterised by rash, blisters, peeling skin and pain which require immediate medical
attention have also been reported.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet please tell
your doctor.
5. HOW TO STORE SILDENAFIL TEVA
Keep out of the reach and sight of children.
Do not use Sildenafil Teva after the expiry date which is stated on the blister and carton. The expiry
date refers to the last day of that month.
Store in the original package, in order to protect from moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What Sildenafil Teva contains
The active substance is sildenafil. Each tablet contains 100 mg of sildenafil (as citrate).
The other ingredients are:
Tablet core: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose
sodium, magnesium stearate.
Film coat: poly(vinyl alcohol), titanium dioxide (E171), macrogol 3350, talc.
What Sildenafil Teva looks like and contents of the pack
Sildenafil Teva 100 mg are white, oval-shaped film-coated tablets, engraved with ‘S 100’ on one side,
and plain on the other side.
Sildenafil Teva is available in blister packs of 2, 4, 8 and 12 tablets, and perforated unit dose blisters
containing 10 x 1 tablet.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
Manufacturer:
TEVA Pharmaceutical Works Private Limited Company
Pallagi út 13
4042 Debrecen
Hungary
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
2100 Gödöllő
Hungary
68
TEVA UK Ltd
Brampton Road, Hampden Park, Eastbourne
East Sussex
BN22 9AG
United Kingdom
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé Sa
Rue Bellocier
89107 Sens
France
Teva Pharma, S.L.U.
Polígono Industrial Malpìca, calle C,no.4
50016 Zaragoza
Spain
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Pharma, S.L.U.
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
69
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 230 65 24
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
70
Source: European Medicines Agency
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