ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Sildenafil ratiopharm 25 mg film-coated tablets
2.
Each film-coated tablet contains 25 mg of sildenafil (as citrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Blue, oval film-coated tablet with edge
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 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 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.
2
Use in children and adolescents:
Sildenafil ratiopharm is not indicated for individuals below 18 years of age.
Use in patients using other medicines:
With the exception of ritonavir for which co-administration with sildenafil is not advised (see section
4.4) a starting dose of 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 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 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 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 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 haemodynamically stable on alpha-
blocker therapy prior to initiating sildenafil treatment. Initiation of sildenafil at a dose of 25 mg should
be considered (see section 4.2). In addition, physicians should advise patients what to do in the event
of postural hypotensive symptoms.
Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium
nitroprusside
in vitro
. There is no safety information on the administration of sildenafil to patients with
bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these
patients only after careful benefit-risk assessment.
Sildenafil ratiopharm 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 will alter the clearance of substrates of these
isoenzymes.
There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as
theophylline or dipyridamole.
In vivo
studies
Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was
shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide
donors or nitrates in any form is therefore contraindicated (see section 4.3).
Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to
symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hours
post sildenafil dosing (see sections 4.2 and 4.4). In three specific drug-drug interaction studies, the
alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered
simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In
these study populations, mean additional reductions of supine blood pressure of 7/7 mmHg,
9/5 mmHg, and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg,
11/4 mmHg, and 4/5 mmHg, respectively, were observed. When sildenafil and doxazosin were
administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports
5
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 ratiopharm 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, 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 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
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.
6
Table 1: Medically important adverse reactions reported at an incidence greater than placebo in
controlled clinical studies and medically important adverse reactions reported through post-
marketing surveillance
System Organ Class
Immune system disorders
Rare
Hypersensitivity reactions
Nervous system disorders
Very common
Headache
Common
Dizziness
Uncommon
Cerebrovascular accident, Syncope
Not known
Transient ischaemic attack, Seizure, Seizure recurrence
Eye disorders
Common
Uncommon
Conjunctival 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
Rare
Nasal congestion
Gastrointestinal disorders
Common Dyspepsia
Uncommon Vomiting, Nausea, Dry mouth
Skin, subcutaneous and soft tissue disorders
Uncommon Skin rash
Not known Stevens-Johnson syndrome (SJS), Toxic epidermal
necrolysis (TEN)
Musculoskeletal 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
Investigations
Uncommon Heart rate increased
* Ear disorders: Sudden deafness. Sudden decrease or loss of hearing has been reported in a small
number of post-marketing and clinical trials cases with the use of all PDE5 inhibitors, including
sildenafil.
7
Rare
Somnolence, Hypoaesthesia
Visual disorders, Visual colour distortion
Epistaxis
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
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.
8
In a study of the haemodynamic 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 8,000 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%.
Distribution:
The mean steady state volume of distribution (V
d
) 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
9
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
agematched 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.
6.
10
6.1 List of excipients
Microcrystalline cellulose
Hypromellose
Croscarmellose sodium
Magnesium stearate
Calcium hydrogen phosphate, anhydrous
Talc
Macrogol 6000
Titanium dioxide
Iron oxide red
Indigo carmine aluminium lake
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVdC/PVC/Aluminium blisters.
Pack sizes of 1, 2, 4, 8, or 12 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
ratiopharm GmbH
Graf-Arco-Straße 3
89079 Ulm
Germany
info@ratiopharm.de
8.
EU/1/09/603/001
EU/1/09/603/002
EU/1/09/603/003
EU/1/09/603/004
EU/1/09/603/013
11
9.
Date of first authorisation: 23 December 2009.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
12
1.
Sildenafil ratiopharm 50 mg film-coated tablets
2.
Each film-coated tablet contains 50 mg of sildenafil (as citrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Blue, oblong film-coated tablet with edge
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 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 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 and adolescents:
Sildenafil ratiopharm is not indicated for individuals below 18 years of age.
Use in patients using other medicines:
With the exception of ritonavir for which co-administration with sildenafil is not advised (see section
4.4) a starting dose of 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 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 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
14
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 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 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 haemodynamically stable on alpha-
blocker therapy prior to initiating sildenafil treatment. Initiation of sildenafil at a dose of 25 mg should
be considered (see section 4.2). In addition, physicians should advise patients what to do in the event
of postural hypotensive symptoms.
Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium
nitroprusside
in vitro
. There is no safety information on the administration of sildenafil to patients with
bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these
patients only after careful benefit-risk assessment.
Sildenafil ratiopharm 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.
15
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 will alter the clearance of substrates of these
isoenzymes.
There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as
theophylline or dipyridamole.
In vivo
studies
Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was
shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide
donors or nitrates in any form is therefore contraindicated (see section 4.3).
Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to
symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hours
post sildenafil dosing (see sections 4.2 and 4.4). In three specific drug-drug interaction studies, the
alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered
simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In
these study populations, mean additional reductions of supine blood pressure of 7/7 mmHg,
9/5 mmHg, and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg,
11/4 mmHg, and 4/5 mmHg, respectively, were observed. When sildenafil and doxazosin were
administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports
16
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 ratiopharm 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, 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 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
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.
17
Table 1: Medically important adverse reactions reported at an incidence greater than placebo in
controlled clinical studies and medically important adverse reactions reported through post-
marketing surveillance
System Organ Class
Immune system disorders
Rare
Hypersensitivity reactions
Nervous system disorders
Very common
Headache
Common
Dizziness
Uncommon
Cerebrovascular accident, Syncope
Not known
Transient ischaemic attack, Seizure, Seizure recurrence
Eye disorders
Common
Uncommon
Conjunctival 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
Rare
Nasal congestion
Gastrointestinal disorders
Common Dyspepsia
Uncommon Vomiting, Nausea, Dry mouth
Skin, subcutaneous and soft tissue disorders
Uncommon Skin rash
Not known Stevens-Johnson syndrome (SJS), Toxic epidermal
necrolysis (TEN)
Musculoskeletal 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
Investigations
Uncommon Heart rate increased
* Ear disorders: Sudden deafness. Sudden decrease or loss of hearing has been reported in a small
number of post-marketing and clinical trials cases with the use of all PDE5 inhibitors, including
sildenafil.
18
Rare
Somnolence, Hypoaesthesia
Visual disorders, Visual colour distortion
Epistaxis
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
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.
19
In a study of the haemodynamic 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 8,000 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%.
Distribution:
The mean steady state volume of distribution (V
d
) 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
20
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
agematched 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.
6.
21
6.1 List of excipients
Microcrystalline cellulose
Hypromellose
Croscarmellose sodium
Magnesium stearate
Calcium hydrogen phosphate, anhydrous
Talc
Macrogol 6000
Titanium dioxide
Iron oxide red
Indigo carmine aluminium lake
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVdC/PVC/Aluminium blisters.
Pack sizes of 1, 2, 4, 8, or 12 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
ratiopharm GmbH
Graf-Arco-Straße 3
89079 Ulm
Germany
info@ratiopharm.de
8.
EU/1/09/603/005
EU/1/09/603/006
EU/1/09/603/007
EU/1/09/603/008
EU/1/09/603/014
22
9.
Date of first authorisation: 23 December 2009.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
23
1.
Sildenafil ratiopharm 100 mg film-coated tablets
2.
Each film-coated tablet contains 100 mg of sildenafil (as citrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Blue, oblong film-coated tablet with edge
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 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 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 and adolescents:
Sildenafil ratiopharm is not indicated for individuals below 18 years of age.
Use in patients using other medicines:
With the exception of ritonavir for which co-administration with sildenafil is not advised (see section
4.4) a starting dose of 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 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 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
25
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 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 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 haemodynamically stable on alpha-
blocker therapy prior to initiating sildenafil treatment. Initiation of sildenafil at a dose of 25 mg should
be considered (see section 4.2). In addition, physicians should advise patients what to do in the event
of postural hypotensive symptoms.
Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium
nitroprusside
in vitro
. There is no safety information on the administration of sildenafil to patients with
bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these
patients only after careful benefit-risk assessment.
Sildenafil ratiopharm 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.
26
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 will alter the clearance of substrates of these
isoenzymes.
There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as
theophylline or dipyridamole.
In vivo
studies
Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was
shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide
donors or nitrates in any form is therefore contraindicated (see section 4.3).
Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to
symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hours
post sildenafil dosing (see sections 4.2 and 4.4). In three specific drug-drug interaction studies, the
alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered
simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In
these study populations, mean additional reductions of supine blood pressure of 7/7 mmHg,
9/5 mmHg, and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg,
11/4 mmHg, and 4/5 mmHg, respectively, were observed. When sildenafil and doxazosin were
administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports
27
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 ratiopharm 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, 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 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
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.
28
Table 1: Medically important adverse reactions reported at an incidence greater than placebo in
controlled clinical studies and medically important adverse reactions reported through post-
marketing surveillance
System Organ Class
Immune system disorders
Rare
Hypersensitivity reactions
Nervous system disorders
Very common
Headache
Common
Dizziness
Uncommon
Cerebrovascular accident, Syncope
Not known
Transient ischaemic attack, Seizure, Seizure recurrence
Eye disorders
Common
Uncommon
Conjunctival 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
Rare
Nasal congestion
Gastrointestinal disorders
Common Dyspepsia
Uncommon Vomiting, Nausea, Dry mouth
Skin, subcutaneous and soft tissue disorders
Uncommon Skin rash
Not known Stevens-Johnson syndrome (SJS), Toxic epidermal
necrolysis (TEN)
Musculoskeletal 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
Investigations
Uncommon Heart rate increased
* Ear disorders: Sudden deafness. Sudden decrease or loss of hearing has been reported in a small
number of post-marketing and clinical trials cases with the use of all PDE5 inhibitors, including
sildenafil.
29
Rare
Somnolence, Hypoaesthesia
Visual disorders, Visual colour distortion
Epistaxis
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
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.
30
In a study of the haemodynamic 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 8,000 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%.
Distribution:
The mean steady state volume of distribution (V
d
) 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
31
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
agematched 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.
6.
32
6.1 List of excipients
Microcrystalline cellulose
Hypromellose
Croscarmellose sodium
Magnesium stearate
Calcium hydrogen phosphate, anhydrous
Talc
Macrogol 6000
Titanium dioxide
Iron oxide red
Indigo carmine aluminium lake
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVdC/PVC/Aluminium blisters.
Pack sizes of 1, 2, 4, 8, or 12 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
ratiopharm GmbH
Graf-Arco-Straße 3
89079 Ulm
Germany
info@ratiopharm.de
8.
EU/1/09/603/009
EU/1/09/603/010
EU/1/09/603/011
EU/1/09/603/012
EU/1/09/603/015
33
9.
Date of first authorisation: 23 December 2009.
Detailed information on this medicinal 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
Merckle GmbH
Ludwig-Merckle-Strasse 3
89143 Blaubeuren
Germany
HBM Pharma s.r.o.
Sklabinská 30
036 80 Martin
Slovak Republic
Medicamentos Internacionales, S.A.
c/ Solana, n°26
28850 Torrejón de Ardoz (Madrid)
Spain
Famar S.A.
7, Anthousas Avenue
15344 Anthousa, Attiki
Greece
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
The MAH must ensure that the system of pharmacovigilance, as described in version 2.2 dated
October 2007 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.
PSUR cycle
The PSUR submission schedule should follow the PSUR schedule for the reference product.
36
ANNEX III
LABELLING AND PACKAGE LEAFLET
37
A. LABELLING
38
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Sildenafil ratiopharm 25 mg film-coated tablets
Sildenafil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 25 mg of sildenafil (as citrate).
3.
LIST OF EXCIPIENTS
4.
1 film-coated tablet
2 film-coated tablets
4 film-coated tablets
8 film-coated tablets
12 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
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
39
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ratiopharm GmbH
Graf-Arco-Straße 3
89079 Ulm
Germany
info@ratiopharm.de
EU/1/09/603/001 1 film-coated tablet
EU/1/09/603/002 4 film-coated tablets
EU/1/09/603/003 8 film-coated tablets
EU/1/09/603/004 12 film-coated tablets
EU/1/09/603/013 2 film-coated tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Sildenafil ratiopharm 25 mg
40
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Sildenafil ratiopharm 50 mg film-coated tablets
Sildenafil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 50 mg of sildenafil (as citrate).
3.
LIST OF EXCIPIENTS
4.
1 film-coated tablet
2 film-coated tablets
4 film-coated tablets
8 film-coated tablets
12 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
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
41
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ratiopharm GmbH
Graf-Arco-Straße 3
89079 Ulm
Germany
info@ratiopharm.de
EU/1/09/603/005 1 film-coated tablet
EU/1/09/603/006 4 film-coated tablets
EU/1/09/603/007 8 film-coated tablets
EU/1/09/603/008 12 film-coated tablets
EU/1/09/603/014 2 film-coated tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Sildenafil ratiopharm 50 mg
42
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Sildenafil ratiopharm 100 mg film-coated tablets
Sildenafil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 100 mg of sildenafil (as citrate).
3.
LIST OF EXCIPIENTS
4.
1 film-coated tablet
2 film-coated tablets
4 film-coated tablets
8 film-coated tablets
12 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
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
43
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ratiopharm GmbH
Graf-Arco-Straße 3
89079 Ulm
Germany
info@ratiopharm.de
EU/1/09/603/009 1 film-coated tablet
EU/1/09/603/010 4 film-coated tablets
EU/1/09/603/011 8 film-coated tablets
EU/1/09/603/012 12 film-coated tablets
EU/1/09/603/015 2 film-coated tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Sildenafil ratiopharm 100 mg
44
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Sildenafil ratiopharm 25 mg film-coated tablets
Sildenafil
2.
ratiopharm
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
45
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Sildenafil ratiopharm 50 mg film-coated tablets
Sildenafil
2.
ratiopharm
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
46
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Sildenafil ratiopharm 100 mg film-coated tablets
Sildenafil
2.
ratiopharm
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
47
B. PACKAGE LEAFLET
48
PACKAGE LEAFLET: INFORMATION FOR THE USER
Sildenafil ratiopharm 25 mg film-coated tablets
Sildenafil
Read all of this leaflet carefully before you start taking this medicine.
-
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 gets 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 ratiopharm is and what it is used for
2. Before you take Sildenafil ratiopharm
3. How to take Sildenafil ratiopharm
4. Possible side effects
5.
How to store Sildenafil ratiopharm
6.
Further information
1.
WHAT Sildenafil ratiopharm IS AND WHAT IT IS USED FOR
What Sildenafil ratiopharm is
Sildenafil ratiopharm belongs to a group of medicines called phosphodiesterase type 5 inhibitors.
Sildenafil ratiopharm allows an erection to last long enough for you to satisfactorily complete sexual
activity. It reduces the action of the natural chemical in your body, which makes erections go away.
Sildenafil ratiopharm will only work when you are sexually stimulated.
What Sildenafil ratiopharm is used for
Sildenafil ratiopharm 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 ratiopharm
Do
NOT
take Sildenafil ratiopharm
-
if you are allergic (hypersensitive) to sildenafil or any of the other ingredients of Sildenafil
ratiopharm.
-
if you are taking medicines that contain nitrates (e.g. glycerol trinitrate) or nitric oxide donors
(e.g. amyl nitrite, also called “poppers”). These medicines are often used to relieve the
symptoms of chest pain (angina pectoris). Taking these medicines with Sildenafil ratiopharm
could seriously affect your blood pressure. Tell your doctor if you are taking any of these
medicines. If you are not certain, ask your doctor or pharmacist.
-
if you have recently had a stroke or a heart attack.
-
if you have low blood pressure.
-
if you have a severe liver problem.
-
if you have certain rare inherited eye diseases (such as retinitis pigmentosa).
-
if you have ever suffered from loss of vision due to an eye condition known as “stroke of the
eye” (non-arteritic anterior ischaemic optic neuropathy, NAION).
49
-
Keep this leaflet. You may need to read it again.
-
if you have a severe heart problem.
Take special care with Sildenafil ratiopharm
-
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 suffer from any of the following disorders or symptoms, as you may experience more
side effects:
•
an abnormality of the red blood cells (sickle cell anaemia);
•
cancer of the blood (leukaemia);
•
a cancer of the bone marrow (multiple myeloma);
•
any disease or deformity of the penis.
-
if you suffer from any of the following disorders, please tell your doctor who will check
carefully whether this medicine is suitable for you:
•
•
if you have a blood-clotting disorder (e.g. haemophilia).
-
if you suffer from kidney or liver problems. Please tell your doctor about this. In this case,
he/she may decide to give you a lower dose.
You should
NOT
take Sildenafil ratiopharm
-
if you are already undergoing other treatments for erectile dysfunction.
-
if you are a woman.
Sildenafil ratiopharm should
NOT
be given to children and adolescents under the age of 18.
If you experience sudden decrease or loss of vision, stop taking Sildenafil ratiopharm and contact your
doctor
IMMEDIATELY
.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
In a medical emergency, you must tell anyone treating you that you have taken Sildenafil ratiopharm.
Do
NOT
take Sildenafil ratiopharm if you are taking medicines that contain nitrates (e.g. glycerol
trinitrate) or nitric oxide donors (e.g. amyl nitrite, also called “poppers”). These medicines are often
used to relieve the symptoms of chest pain (angina pectoris). Simultaneous intake of nitrates or nitric
oxide donors with Sildenafil ratiopharm can have severe effects on your blood pressure.
Taking Sildenafil ratiopharm together with some medicines may lead to problems. Therefore, tell your
doctor if you are taking any of the following medicines:
- ritonavir or saquinavir (medicines for the treatment of HIV infections);
- ketoconazole or itraconazole (medicines for the treatment of fungal infections);
- erythromycin (an antibiotic);
- cimetidine (medicine for the treatment of heartburn and peptic ulcers);
- alpha blockers (group of medicines for the treatment of high blood pressure or an enlarged
prostate [benign prostatic hyperplasia]).
Some patients taking alpha blockers may experience dizziness or light-headedness when getting
up. These are symptoms of a fall in blood pressure upon rising quickly from sitting or lying
(postural hypotension). These symptoms usually occur within 4 hours of taking Sildenafil
ratiopharm. In order to reduce the probability of these symptoms occurring, you should start
taking Sildenafil ratiopharm only when you are already well controlled on a regular daily dose
of your alpha blocker.
If you are taking one of these medicines, your doctor may start you on the lowest dose (25 mg) of
Sildenafil ratiopharm. If you are taking ritonavir, you may not exceed a maximum dose of 25 mg
sildenafil within a period of 48 hours.
50
if you currently have a stomach ulcer;
-
if you do not have erectile dysfunction.
Using
Sildenafil ratiopharm with food and drink
When Sildenafil ratiopharm is taken with food, it may take a little longer for Sildenafil ratiopharm to
work.
Alcoholic drink can make erection difficulties worse. In order to get the maximum benefit from your
medicine, it is recommended that you avoid alcohol before intake of Sildenafil ratiopharm.
Driving and using machines
Sildenafil ratiopharm might make some people feel dizzy or affect their vision or hearing. If you feel
dizzy, or if your vision or hearing is affected after taking Sildenafil ratiopharm, do not drive or operate
any tools or machines.
3.
HOW TO TAKE Sildenafil ratiopharm
Always take Sildenafil ratiopharm exactly as your doctor has told you. You should check with your
doctor or pharmacist if you are not sure.
The usual dose is
Take 1 film-coated tablet of Sildenafil ratiopharm about 1 hour before sexual activity. Swallow the
film-coated tablet whole with a glass of water.
You should not take more film-coated tablets than your doctor tells you to.
You should not take Sildenafil ratiopharm more than once a day.
Sildenafil ratiopharm will only help you to get an erection if you are sexually stimulated. The amount
of time Sildenafil ratiopharm takes to work varies from person to person, but it normally takes
between half an hour and one hour. You may find that Sildenafil ratiopharm takes longer to work if
you take it with a heavy meal.
If Sildenafil ratiopharm 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 ratiopharm than you should
Men who take too much Sildenafil ratiopharm may experience more side effects or may get severe
muscle pain. If you take more Sildenafil ratiopharm than you should, tell your doctor.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Sildenafil ratiopharm can cause side effects although not everybody gets them.
The following frequency conventions are used in the evaluation of side effects:
very common:
affects more than 1 user in 10
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.
Important side effects:
51
common:
affects 1 to 10 users in 100
-
Chest pain:
If you experience chest pain (uncommon) during or after sexual activity, you should
NOT
take
any medicines that contain nitrates (e.g. glycerol trinitrate). Please contact a doctor
IMMEDIATELY
.
-
Allergic reactions:
Allergic reactions such as skin rash, raised areas of the skin that itch and severe allergic
reactions with weakness, drop in blood pressure, difficulty breathing and swelling of the
eyelids, face, lips or throat have been reported rarely. If you think you are having this type of
reaction, you must stop taking Sildenafil ratiopharm and get medical help
IMMEDIATELY
.
-
Visual disturbances:
If you experience a sudden impairment or loss of vision (frequency not known), stop taking
Sildenafil ratiopharm and contact your doctor
IMMEDIATELY
.
-
Prolonged erections:
Prolonged and sometimes painful erections have been reported after taking Sildenafil
ratiopharm (frequency not known). If you have such an erection, which lasts continuously for
more than 4 hours, you should contact a doctor
IMMEDIATELY
.
You may experience the following additional side effects:
-
very common: headache;
-
common: dizziness, altered vision (increased brightness of light or blurred vision), colour tinge
to vision, flushing, stuffy nose, indigestion;
-
uncommon: feeling sleepy, reduced sense of touch, bloodshot eyes, eye pain, watery eyes,
abnormal sensation in the eye, vertigo, ringing in the ears, pounding heartbeat, faster heartbeat,
vomiting, nausea, dry mouth, skin rash, muscle pain, feeling tired, measurement of faster
heartbeat;
-
rare: stroke, fainting, sudden impairment or loss of hearing, high blood pressure, low blood
pressure, heart attack, irregular heartbeat, nosebleed;
-
not known: temporary decreased blood flow to parts of the brain, seizure, recurrence of seizures,
occlusion of blood vessels inside the eye, partial, sudden, temporary, or permanent impairment
or loss of vision in one or both eyes, abnormal heartbeat, unstable angina (chest pain), sudden
death, serious skin reactions characterised by rash, blisters, peeling skin and pain, which require
immediate medical attention.
Most, but not all, of the men who experienced cardiovascular side effects already had cardiovascular
problems before taking this medicine. It is not possible to determine whether these events were
directly related to Sildenafil ratiopharm.
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.
5.
HOW TO STORE Sildenafil ratiopharm
Keep out of the reach and sight of children.
Do not use Sildenafil ratiopharm after the expiry date which is stated on the outer carton and blister
after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
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.
52
6.
FURTHER INFORMATION
What Sildenafil ratiopharm contains
-
The active substance is sildenafil.
Each film-coated tablet contains 25 mg of sildenafil (as citrate).
-
The other ingredients are: microcrystalline cellulose,
hypromellose, croscarmellose sodium,
magnesium stearate, calcium hydrogen phosphate anhydrous, talc, macrogol 6000, titanium
dioxide, iron oxide red, indigo carmine aluminium lake.
What Sildenafil ratiopharm looks like and contents of the pack
Sildenafil ratiopharm are blue, oval film-coated tablets with edge.
Sildenafil ratiopharm are supplied in packs of 1, 2, 4, 8 or 12 film-coated tablets in blisters. Not all
pack sizes may be marketed.
Marketing Authorisation Holder
ratiopharm GmbH
Graf-Arco-Straße 3
89079 Ulm
Germany
info@ratiopharm.de
Manufacturer
Merckle GmbH
Ludwig-Merckle-Straße 3
89143 Blaubeuren
Germany
HBM Pharma s.r.o.
Sklabinská 30
036 80 Martin
Slovak Republic
Medicamentos Internacionales, S.A.
c/ Solana, n°26
28850 Torrejón de Ardoz (Madrid)
Spain
Famar S.A.
7, Anthousas Avenue
15344 Anthousa, Attiki
Greece
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
ratiopharm Belgium S.A.
Tél/Tel: +32 2 761 10 11
Luxembourg/Luxemburg
ratiopharm S.A. Luxemburg
Tél/Tel: +35 2 40 37 27
България
ratiopharm GmbH, Германия
Teл: +49 731 402 02
Magyarország
ratiopharm Hungária Kft.
Tel: +36 1 273 2730
Česká republika
ratiopharm CZ s.r.o.
Malta
ratiopharm GmbH, Il Ġermanja
53
Tel: +420 2 510 21 122
Tel: +49 731 402 02
Danmark
ratiopharm A/S
Tlf: +45 45 46 06 60
Nederland
ratiopharm Nederland bv
Tel: +31 23 7070 840
Deutschland
ratiopharm GmbH
Tel: +49 731 402 02
Norge
ratiopharm AS
Tlf: +47 66 77 55 90
Eesti
ratiopharm Eesti büroo
Tel: +372 6838 006
Österreich
ratiopharm Arzneimittel Vertriebs-GmbH
Tel: +43 1 97 007
Ελλάδα
ratiopharm GmbH, Γερμανία
Τηλ: +49 731 402 02
Polska
ratiopharm Polska Sp.z.o.o
Tel: +48 22 335 39 20
España
ratiopharm España, S.A.
Tel: +34 91 567 29 70
Portugal
ratiopharm, Comércio e Indústria de Produtos
farmacêuticos Lda
Tel: +351 21 424 80 00
France
Laboratoire ratiopharm S.A.
Tél: +33 1 42 07 97 04
România
ratiopharm GmbH, Germania
Tel: +49 731 402 02
Ireland
ratiopharm UK Ltd, United Kingdom
Tel: +44 239 238 6330
Slovenija
ratiopharm GmbH, Nemčija
Tel: +49 731 402 02
Ísland
ratiopharm GmbH, Þýskaland
Sími: +49 731 402 02
Slovenská republika
ratiopharm Slovensko s.r.o.
Tel: +421 2 57 200 300
Italia
ratiopharm Italia s.r.l.
Tel: +39 02 28 87 71
Suomi/Finland
ratiopharm Oy
Puh/Tel: +358 20 180 5900
Κύπρος
ratiopharm GmbH, Γερμανία
Τηλ: +49 731 402 02
Sverige
ratiopharm AB
Tel: +46 42 37 0740
Latvija
ratiopharm Latvijas pārstāvniecība
Tel: +371 67499110
United Kingdom
ratiopharm UK Ltd
Tel: +44 239 238 6330
Lietuva
ratiopharm atstovas Lietuvoje
Tel: + 370 5 212 3295
This leaflet was last approved in {MM/YYYY}.
54
PACKAGE LEAFLET: INFORMATION FOR THE USER
Sildenafil ratiopharm 50 mg film-coated tablets
Sildenafil
Read all of this leaflet carefully before you start taking this medicine.
-
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 gets 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 ratiopharm is and what it is used for
2.
Before you take Sildenafil ratiopharm
3.
How to take Sildenafil ratiopharm
4.
How to store Sildenafil ratiopharm
6.
Further information
1.
WHAT Sildenafil ratiopharm IS AND WHAT IT IS USED FOR
What Sildenafil ratiopharm is
Sildenafil ratiopharm belongs to a group of medicines called phosphodiesterase type 5 inhibitors.
Sildenafil ratiopharm allows an erection to last long enough for you to satisfactorily complete sexual
activity. It reduces the action of the natural chemical in your body, which makes erections go away.
Sildenafil ratiopharm will only work when you are sexually stimulated.
What Sildenafil ratiopharm is used for
Sildenafil ratiopharm 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 ratiopharm
Do
NOT
take Sildenafil ratiopharm
-
if you are allergic (hypersensitive) to sildenafil or any of the other ingredients of Sildenafil
ratiopharm.
-
if you are taking medicines that contain nitrates (e.g. glycerol trinitrate) or nitric oxide donors
(e.g. amyl nitrite, also called “poppers”). These medicines are often used to relieve the
symptoms of chest pain (angina pectoris). Taking these medicines with Sildenafil ratiopharm
could seriously affect your blood pressure. Tell your doctor if you are taking any of these
medicines. If you are not certain, ask your doctor or pharmacist.
-
if you have recently had a stroke or a heart attack.
-
if you have low blood pressure.
-
if you have a severe liver problem.
-
if you have certain rare inherited eye diseases (such as retinitis pigmentosa).
-
if you have ever suffered from loss of vision due to an eye condition known as “stroke of the
eye” (non-arteritic anterior ischaemic optic neuropathy, NAION).
55
-
Keep this leaflet. You may need to read it again.
5.
Possible side effects
-
if you have a severe heart problem.
Take special care with Sildenafil ratiopharm
-
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 suffer from any of the following disorders or symptoms, as you may experience more
side effects:
•
an abnormality of the red blood cells (sickle cell anaemia);
•
cancer of the blood (leukaemia);
•
a cancer of the bone marrow (multiple myeloma);
•
any disease or deformity of the penis.
-
if you suffer from any of the following disorders, please tell your doctor who will check
carefully whether this medicine is suitable for you:
•
•
if you have a blood-clotting disorder (e.g. haemophilia).
-
if you suffer from kidney or liver problems. Please tell your doctor about this. In this case,
he/she may decide to give you a lower dose.
You should
NOT
take Sildenafil ratiopharm
-
if you are already undergoing other treatments for erectile dysfunction.
-
if you are a woman.
Sildenafil ratiopharm should
NOT
be given to children and adolescents under the age of 18.
If you experience sudden decrease or loss of vision, stop taking Sildenafil ratiopharm and contact your
doctor
IMMEDIATELY
.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
In a medical emergency, you must tell anyone treating you that you have taken Sildenafil ratiopharm.
Do
NOT
take Sildenafil ratiopharm if you are taking medicines that contain nitrates (e.g. glycerol
trinitrate) or nitric oxide donors (e.g. amyl nitrite, also called “poppers”). These medicines are often
used to relieve the symptoms of chest pain (angina pectoris). Simultaneous intake of nitrates or nitric
oxide donors with Sildenafil ratiopharm can have severe effects on your blood pressure.
Taking Sildenafil ratiopharm together with some medicines may lead to problems. Therefore, tell your
doctor if you are taking any of the following medicines:
- ritonavir or saquinavir (medicines for the treatment of HIV infections);
- ketoconazole or itraconazole (medicines for the treatment of fungal infections);
- erythromycin (an antibiotic);
- cimetidine (medicine for the treatment of heartburn and peptic ulcers);
- alpha blockers (group of medicines for the treatment of high blood pressure or an enlarged
prostate [benign prostatic hyperplasia]).
Some patients taking alpha blockers may experience dizziness or light-headedness when getting
up. These are symptoms of a fall in blood pressure upon rising quickly from sitting or lying
(postural hypotension). These symptoms usually occur within 4 hours of taking Sildenafil
ratiopharm. In order to reduce the probability of these symptoms occurring, you should start
taking Sildenafil ratiopharm only when you are already well controlled on a regular daily dose
of your alpha blocker.
If you are taking one of these medicines, your doctor may start you on the lowest dose (25 mg) of
Sildenafil ratiopharm. If you are taking ritonavir, you may not exceed a maximum dose of 25 mg
sildenafil within a period of 48 hours.
56
if you currently have a stomach ulcer;
-
if you do not have erectile dysfunction.
Using
Sildenafil ratiopharm with food and drink
When Sildenafil ratiopharm is taken with food, it may take a little longer for Sildenafil ratiopharm to
work.
Alcoholic drink can make erection difficulties worse. In order to get the maximum benefit from your
medicine, it is recommended that you avoid alcohol before intake of Sildenafil ratiopharm.
Driving and using machines
Sildenafil ratiopharm might make some people feel dizzy or affect their vision or hearing. If you feel
dizzy, or if your vision or hearing is affected after taking Sildenafil ratiopharm, do not drive or operate
any tools or machines.
3.
HOW TO TAKE Sildenafil ratiopharm
Always take Sildenafil ratiopharm exactly as your doctor has told you. You should check with your
doctor or pharmacist if you are not sure.
The usual dose is
Take 1 film-coated tablet of Sildenafil ratiopharm about 1 hour before sexual activity. Swallow the
film-coated tablet whole with a glass of water.
You should not take more film-coated tablets than your doctor tells you to.
You should not take Sildenafil ratiopharm more than once a day.
Sildenafil ratiopharm will only help you to get an erection if you are sexually stimulated. The amount
of time Sildenafil ratiopharm takes to work varies from person to person, but it normally takes
between half an hour and one hour. You may find that Sildenafil ratiopharm takes longer to work if
you take it with a heavy meal.
If Sildenafil ratiopharm 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 ratiopharm than you should
Men who take too much Sildenafil ratiopharm may experience more side effects or may get severe
muscle pain. If you take more Sildenafil ratiopharm than you should, tell your doctor.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Sildenafil ratiopharm can cause side effects although not everybody gets them.
The following frequency conventions are used in the evaluation of side effects:
very common:
affects more than 1 user in 10
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.
Important side effects:
57
common:
affects 1 to 10 users in 100
-
Chest pain:
If you experience chest pain (uncommon) during or after sexual activity, you should
NOT
take
any medicines that contain nitrates (e.g. glycerol trinitrate). Please contact a doctor
IMMEDIATELY
.
-
Allergic reactions:
Allergic reactions such as skin rash, raised areas of the skin that itch and severe allergic
reactions with weakness, drop in blood pressure, difficulty breathing and swelling of the
eyelids, face, lips or throat have been reported rarely. If you think you are having this type of
reaction, you must stop taking Sildenafil ratiopharm and get medical help
IMMEDIATELY
.
-
Visual disturbances:
If you experience a sudden impairment or loss of vision (frequency not known), stop taking
Sildenafil ratiopharm and contact your doctor
IMMEDIATELY
.
-
Prolonged erections:
Prolonged and sometimes painful erections have been reported after taking Sildenafil
ratiopharm (frequency not known). If you have such an erection, which lasts continuously for
more than 4 hours, you should contact a doctor
IMMEDIATELY
.
You may experience the following additional side effects:
-
very common: headache;
-
common: dizziness, altered vision (increased brightness of light or blurred vision), colour tinge
to vision, flushing, stuffy nose, indigestion;
-
uncommon: feeling sleepy, reduced sense of touch, bloodshot eyes, eye pain, watery eyes,
abnormal sensation in the eye, vertigo, ringing in the ears, pounding heartbeat, faster heartbeat,
vomiting, nausea, dry mouth, skin rash, muscle pain, feeling tired, measurement of faster
heartbeat;
-
rare: stroke, fainting, sudden impairment or loss of hearing, high blood pressure, low blood
pressure, heart attack, irregular heartbeat, nosebleed;
-
not known: temporary decreased blood flow to parts of the brain, seizure, recurrence of seizures,
occlusion of blood vessels inside the eye, partial, sudden, temporary, or permanent impairment
or loss of vision in one or both eyes, abnormal heartbeat, unstable angina (chest pain), sudden
death, serious skin reactions characterised by rash, blisters, peeling skin and pain, which require
immediate medical attention.
Most, but not all, of the men who experienced cardiovascular side effects already had cardiovascular
problems before taking this medicine. It is not possible to determine whether these events were
directly related to Sildenafil ratiopharm.
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.
5.
HOW TO STORE Sildenafil ratiopharm
Keep out of the reach and sight of children.
Do not use Sildenafil ratiopharm after the expiry date which is stated on the outer carton and blister
after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
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.
58
6.
FURTHER INFORMATION
What Sildenafil ratiopharm contains
-
The active substance is sildenafil.
Each film-coated tablet contains 50 mg of sildenafil (as citrate).
-
The other ingredients are: microcrystalline cellulose,
hypromellose, croscarmellose sodium,
magnesium stearate, calcium hydrogen phosphate anhydrous, talc, macrogol 6000, titanium
dioxide, iron oxide red, indigo carmine aluminium lake.
What Sildenafil ratiopharm looks like and contents of the pack
Sildenafil ratiopharm are blue, oblong film-coated tablets with edge.
Sildenafil ratiopharm are supplied in packs of 1, 2, 4, 8 or 12 film-coated tablets in blisters. Not all
pack sizes may be marketed.
Marketing Authorisation Holder
ratiopharm GmbH
Graf-Arco-Straße 3
89079 Ulm
Germany
info@ratiopharm.de
Manufacturer
Merckle GmbH
Ludwig-Merckle-Straße 3
89143 Blaubeuren
Germany
HBM Pharma s.r.o.
Sklabinská 30
036 80 Martin
Slovak Republic
Medicamentos Internacionales, S.A.
c/ Solana, n°26
28850 Torrejón de Ardoz (Madrid)
Spain
Famar S.A.
7, Anthousas Avenue
15344 Anthousa, Attiki
Greece
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
ratiopharm Belgium S.A.
Tél/Tel: +32 2 761 10 11
Luxembourg/Luxemburg
ratiopharm S.A. Luxemburg
Tél/Tel: +35 2 40 37 27
България
ratiopharm GmbH, Германия
Teл: +49 731 402 02
Magyarország
ratiopharm Hungária Kft.
Tel: +36 1 273 2730
Česká republika
ratiopharm CZ s.r.o.
Malta
ratiopharm GmbH, Il Ġermanja
59
Tel: +420 2 510 21 122
Tel: +49 731 402 02
Danmark
ratiopharm A/S
Tlf: +45 45 46 06 60
Nederland
ratiopharm Nederland bv
Tel: +31 23 7070 840
Deutschland
ratiopharm GmbH
Tel: +49 731 402 02
Norge
ratiopharm AS
Tlf: +47 66 77 55 90
Eesti
ratiopharm Eesti büroo
Tel: +372 6838 006
Österreich
ratiopharm Arzneimittel Vertriebs-GmbH
Tel: +43 1 97 007
Ελλάδα
ratiopharm GmbH, Γερμανία
Τηλ: +49 731 402 02
Polska
ratiopharm Polska Sp.z.o.o
Tel: +48 22 335 39 20
España
ratiopharm España, S.A.
Tel: +34 91 567 29 70
Portugal
ratiopharm, Comércio e Indústria de Produtos
farmacêuticos Lda
Tel: +351 21 424 80 00
France
Laboratoire ratiopharm S.A.
Tél: +33 1 42 07 97 04
România
ratiopharm GmbH, Germania
Tel: +49 731 402 02
Ireland
ratiopharm UK Ltd, United Kingdom
Tel: +44 239 238 6330
Slovenija
ratiopharm GmbH, Nemčija
Tel: +49 731 402 02
Ísland
ratiopharm GmbH, Þýskaland
Sími: +49 731 402 02
Slovenská republika
ratiopharm Slovensko s.r.o.
Tel: +421 2 57 200 300
Italia
ratiopharm Italia s.r.l.
Tel: +39 02 28 87 71
Suomi/Finland
ratiopharm Oy
Puh/Tel: +358 20 180 5900
Κύπρος
ratiopharm GmbH, Γερμανία
Τηλ: +49 731 402 02
Sverige
ratiopharm AB
Tel: +46 42 37 0740
Latvija
ratiopharm Latvijas pārstāvniecība
Tel: +371 67499110
United Kingdom
ratiopharm UK Ltd
Tel: +44 239 238 6330
Lietuva
ratiopharm atstovas Lietuvoje
Tel: + 370 5 212 3295
This leaflet was last approved in {MM/YYYY}.
60
PACKAGE LEAFLET: INFORMATION FOR THE USER
Sildenafil ratiopharm 100 mg film-coated tablets
Sildenafil
Read all of this leaflet carefully before you start taking this medicine.
-
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 gets 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 ratiopharm is and what it is used for
2.
Before you take Sildenafil ratiopharm
3.
How to take Sildenafil ratiopharm
4.
How to store Sildenafil ratiopharm
6.
Further information
1.
WHAT Sildenafil ratiopharm IS AND WHAT IT IS USED FOR
What Sildenafil ratiopharm is
Sildenafil ratiopharm belongs to a group of medicines called phosphodiesterase type 5 inhibitors.
Sildenafil ratiopharm allows an erection to last long enough for you to satisfactorily complete sexual
activity. It reduces the action of the natural chemical in your body, which makes erections go away.
Sildenafil ratiopharm will only work when you are sexually stimulated.
What Sildenafil ratiopharm is used for
Sildenafil ratiopharm 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 ratiopharm
Do
NOT
take Sildenafil ratiopharm
-
if you are allergic (hypersensitive) to sildenafil or any of the other ingredients of Sildenafil
ratiopharm.
-
if you are taking medicines that contain nitrates (e.g. glycerol trinitrate) or nitric oxide donors
(e.g. amyl nitrite, also called “poppers”). These medicines are often used to relieve the
symptoms of chest pain (angina pectoris). Taking these medicines with Sildenafil ratiopharm
could seriously affect your blood pressure. Tell your doctor if you are taking any of these
medicines. If you are not certain, ask your doctor or pharmacist.
-
if you have recently had a stroke or a heart attack.
-
if you have low blood pressure.
-
if you have a severe liver problem.
-
if you have certain rare inherited eye diseases (such as retinitis pigmentosa).
-
if you have ever suffered from loss of vision due to an eye condition known as “stroke of the
eye” (non-arteritic anterior ischaemic optic neuropathy, NAION).
61
-
Keep this leaflet. You may need to read it again.
5.
Possible side effects
-
if you have a severe heart problem.
Take special care with Sildenafil ratiopharm
-
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 suffer from any of the following disorders or symptoms, as you may experience more
side effects:
•
an abnormality of the red blood cells (sickle cell anaemia);
•
cancer of the blood (leukaemia);
•
a cancer of the bone marrow (multiple myeloma);
•
any disease or deformity of the penis.
-
if you suffer from any of the following disorders, please tell your doctor who will check
carefully whether this medicine is suitable for you:
•
•
if you have a blood-clotting disorder (e.g. haemophilia).
-
if you suffer from kidney or liver problems. Please tell your doctor about this. In this case,
he/she may decide to give you a lower dose.
You should
NOT
take Sildenafil ratiopharm
-
if you are already undergoing other treatments for erectile dysfunction.
-
if you are a woman.
Sildenafil ratiopharm should
NOT
be given to children and adolescents under the age of 18.
If you experience sudden decrease or loss of vision, stop taking Sildenafil ratiopharm and contact your
doctor
IMMEDIATELY
.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
In a medical emergency, you must tell anyone treating you that you have taken Sildenafil ratiopharm.
Do
NOT
take Sildenafil ratiopharm if you are taking medicines that contain nitrates (e.g. glycerol
trinitrate) or nitric oxide donors (e.g. amyl nitrite, also called “poppers”). These medicines are often
used to relieve the symptoms of chest pain (angina pectoris). Simultaneous intake of nitrates or nitric
oxide donors with Sildenafil ratiopharm can have severe effects on your blood pressure.
Taking Sildenafil ratiopharm together with some medicines may lead to problems. Therefore, tell your
doctor if you are taking any of the following medicines:
- ritonavir or saquinavir (medicines for the treatment of HIV infections);
- ketoconazole or itraconazole (medicines for the treatment of fungal infections);
- erythromycin (an antibiotic);
- cimetidine (medicine for the treatment of heartburn and peptic ulcers);
- alpha blockers (group of medicines for the treatment of high blood pressure or an enlarged
prostate [benign prostatic hyperplasia]).
Some patients taking alpha blockers may experience dizziness or light-headedness when getting
up. These are symptoms of a fall in blood pressure upon rising quickly from sitting or lying
(postural hypotension). These symptoms usually occur within 4 hours of taking Sildenafil
ratiopharm. In order to reduce the probability of these symptoms occurring, you should start
taking Sildenafil ratiopharm only when you are already well controlled on a regular daily dose
of your alpha blocker.
If you are taking one of these medicines, your doctor may start you on the lowest dose (25 mg) of
Sildenafil ratiopharm. If you are taking ritonavir, you may not exceed a maximum dose of 25 mg
sildenafil within a period of 48 hours.
62
if you currently have a stomach ulcer;
-
if you do not have erectile dysfunction.
Using
Sildenafil ratiopharm with food and drink
When Sildenafil ratiopharm is taken with food, it may take a little longer for Sildenafil ratiopharm to
work.
Alcoholic drink can make erection difficulties worse. In order to get the maximum benefit from your
medicine, it is recommended that you avoid alcohol before intake of Sildenafil ratiopharm.
Driving and using machines
Sildenafil ratiopharm might make some people feel dizzy or affect their vision or hearing. If you feel
dizzy, or if your vision or hearing is affected after taking Sildenafil ratiopharm, do not drive or operate
any tools or machines.
3.
HOW TO TAKE Sildenafil ratiopharm
Always take Sildenafil ratiopharm exactly as your doctor has told you. You should check with your
doctor or pharmacist if you are not sure.
The usual dose is
Take 1 film-coated tablet of Sildenafil ratiopharm about 1 hour before sexual activity. Swallow the
film-coated tablet whole with a glass of water.
You should not take more film-coated tablets than your doctor tells you to.
You should not take Sildenafil ratiopharm more than once a day.
Sildenafil ratiopharm will only help you to get an erection if you are sexually stimulated. The amount
of time Sildenafil ratiopharm takes to work varies from person to person, but it normally takes
between half an hour and one hour. You may find that Sildenafil ratiopharm takes longer to work if
you take it with a heavy meal.
If Sildenafil ratiopharm 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 ratiopharm than you should
Men who take too much Sildenafil ratiopharm may experience more side effects or may get severe
muscle pain. If you take more Sildenafil ratiopharm than you should, tell your doctor.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Sildenafil ratiopharm can cause side effects although not everybody gets them.
The following frequency conventions are used in the evaluation of side effects:
very common:
affects more than 1 user in 10
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.
Important side effects:
63
common:
affects 1 to 10 users in 100
-
Chest pain:
If you experience chest pain (uncommon) during or after sexual activity, you should
NOT
take
any medicines that contain nitrates (e.g. glycerol trinitrate). Please contact a doctor
IMMEDIATELY
.
-
Allergic reactions:
Allergic reactions such as skin rash, raised areas of the skin that itch and severe allergic
reactions with weakness, drop in blood pressure, difficulty breathing and swelling of the
eyelids, face, lips or throat have been reported rarely. If you think you are having this type of
reaction, you must stop taking Sildenafil ratiopharm and get medical help
IMMEDIATELY
.
-
Visual disturbances:
If you experience a sudden impairment or loss of vision (frequency not known), stop taking
Sildenafil ratiopharm and contact your doctor
IMMEDIATELY
.
-
Prolonged erections:
Prolonged and sometimes painful erections have been reported after taking Sildenafil
ratiopharm (frequency not known). If you have such an erection, which lasts continuously for
more than 4 hours, you should contact a doctor
IMMEDIATELY
.
You may experience the following additional side effects:
-
very common: headache;
-
common: dizziness, altered vision (increased brightness of light or blurred vision), colour tinge
to vision, flushing, stuffy nose, indigestion;
-
uncommon: feeling sleepy, reduced sense of touch, bloodshot eyes, eye pain, watery eyes,
abnormal sensation in the eye, vertigo, ringing in the ears, pounding heartbeat, faster heartbeat,
vomiting, nausea, dry mouth, skin rash, muscle pain, feeling tired, measurement of faster
heartbeat;
-
rare: stroke, fainting, sudden impairment or loss of hearing, high blood pressure, low blood
pressure, heart attack, irregular heartbeat, nosebleed;
-
not known: temporary decreased blood flow to parts of the brain, seizure, recurrence of seizures,
occlusion of blood vessels inside the eye, partial, sudden, temporary, or permanent impairment
or loss of vision in one or both eyes, abnormal heartbeat, unstable angina (chest pain), sudden
death, serious skin reactions characterised by rash, blisters, peeling skin and pain, which require
immediate medical attention.
Most, but not all, of the men who experienced cardiovascular side effects already had cardiovascular
problems before taking this medicine. It is not possible to determine whether these events were
directly related to Sildenafil ratiopharm.
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.
5.
HOW TO STORE Sildenafil ratiopharm
Keep out of the reach and sight of children.
Do not use Sildenafil ratiopharm after the expiry date which is stated on the outer carton and blister
after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
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.
64
6.
FURTHER INFORMATION
What Sildenafil ratiopharm contains
-
The active substance is sildenafil.
Each film-coated tablet contains 100 mg of sildenafil (as citrate).
-
The other ingredients are: microcrystalline cellulose,
hypromellose, croscarmellose sodium,
magnesium stearate, calcium hydrogen phosphate anhydrous, talc, macrogol 6000, titanium
dioxide, iron oxide red, indigo carmine aluminium lake.
What Sildenafil ratiopharm looks like and contents of the pack
Sildenafil ratiopharm are blue, oblong film-coated tablets with edge.
Sildenafil ratiopharm are supplied in packs of 1, 2, 4, 8 or 12 film-coated tablets in blisters. Not all
pack sizes may be marketed.
Marketing Authorisation Holder
ratiopharm GmbH
Graf-Arco-Straße 3
89079 Ulm
Germany
info@ratiopharm.de
Manufacturer
Merckle GmbH
Ludwig-Merckle-Straße 3
89143 Blaubeuren
Germany
HBM Pharma s.r.o.
Sklabinská 30
036 80 Martin
Slovak Republic
Medicamentos Internacionales, S.A.
c/ Solana, n°26
28850 Torrejón de Ardoz (Madrid)
Spain
Famar S.A.
7, Anthousas Avenue
15344 Anthousa, Attiki
Greece
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
ratiopharm Belgium S.A.
Tél/Tel: +32 2 761 10 11
Luxembourg/Luxemburg
ratiopharm S.A. Luxemburg
Tél/Tel: +35 2 40 37 27
България
ratiopharm GmbH, Германия
Teл: +49 731 402 02
Magyarország
ratiopharm Hungária Kft.
Tel: +36 1 273 2730
Česká republika
ratiopharm CZ s.r.o.
Malta
ratiopharm GmbH, Il Ġermanja
65
Tel: +420 2 510 21 122
Tel: +49 731 402 02
Danmark
ratiopharm A/S
Tlf: +45 45 46 06 60
Nederland
ratiopharm Nederland bv
Tel: +31 23 7070 840
Deutschland
ratiopharm GmbH
Tel: +49 731 402 02
Norge
ratiopharm AS
Tlf: +47 66 77 55 90
Eesti
ratiopharm Eesti büroo
Tel: +372 6838 006
Österreich
ratiopharm Arzneimittel Vertriebs-GmbH
Tel: +43 1 97 007
Ελλάδα
ratiopharm GmbH, Γερμανία
Τηλ: +49 731 402 02
Polska
ratiopharm Polska Sp.z.o.o
Tel: +48 22 335 39 20
España
ratiopharm España, S.A.
Tel: +34 91 567 29 70
Portugal
ratiopharm, Comércio e Indústria de Produtos
farmacêuticos Lda
Tel: +351 21 424 80 00
France
Laboratoire ratiopharm S.A.
Tél: +33 1 42 07 97 04
România
ratiopharm GmbH, Germania
Tel: +49 731 402 02
Ireland
ratiopharm UK Ltd, United Kingdom
Tel: +44 239 238 6330
Slovenija
ratiopharm GmbH, Nemčija
Tel: +49 731 402 02
Ísland
ratiopharm GmbH, Þýskaland
Sími: +49 731 402 02
Slovenská republika
ratiopharm Slovensko s.r.o.
Tel: +421 2 57 200 300
Italia
ratiopharm Italia s.r.l.
Tel: +39 02 28 87 71
Suomi/Finland
ratiopharm Oy
Puh/Tel: +358 20 180 5900
Κύπρος
ratiopharm GmbH, Γερμανία
Τηλ: +49 731 402 02
Sverige
ratiopharm AB
Tel: +46 42 37 0740
Latvija
ratiopharm Latvijas pārstāvniecība
Tel: +371 67499110
United Kingdom
ratiopharm UK Ltd
Tel: +44 239 238 6330
Lietuva
ratiopharm atstovas Lietuvoje
Tel: + 370 5 212 3295
This leaflet was last approved in {MM/YYYY}.
66
Source: European Medicines Agency
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