ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
RILUTEK 50 mg film-coated tablets
2.
Each film-coated tablet contains 50 mg of riluzole
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
The tablets are capsule-shaped, white and engraved with “RPR 202” on one side.
4.
RILUTEK is indicated to extend life or the time to mechanical ventilation for patients with
amyotrophic lateral sclerosis (ALS).
Clinical trials have demonstrated that RILUTEK extends survival for patients with ALS (see section
5.1). Survival was defined as patients who were alive, not intubated for mechanical ventilation and
tracheotomy-free.
There is no evidence that RILUTEK exerts a therapeutic effect on motor function, lung function,
fasciculations, muscle strength and motor symptoms. RILUTEK has not been shown to be effective in
the late stages of ALS.
Safety and efficacy of RILUTEK has only been studied in ALS. Therefore, RILUTEK should not be
used in patients with any other form of motor neurone disease.
Treatment with RILUTEK should only be initiated by specialist physicians with experience in the
management of motor neurone diseases.
The recommended daily dose in adults or elderly is 100 mg (50 mg every 12 hours).
No significant increased benefit can be expected from higher daily doses.
Special populations
Children
: RILUTEK is not recommended for use in children, due to a lack of data on the safety and
efficacy of riluzole in any neurodegenerative diseases occurring in children or adolescents.
Patients with impaired renal function
: RILUTEK is not recommended for use in patients with impaired
renal function, as studies at repeated doses have not been conducted in this population (see section
4.4).
Elderly
: based on pharmacokinetic data, there are no special instructions for the use of RILUTEK in
this population.
Patients with impaired hepatic function
: (see section 4.3, section 4.4, and section 5.2).
2
Hypersensitivity to the active substance or to any of the excipients.
Hepatic disease or baseline transaminases greater than 3 times the upper limit of normal.
Patients who are pregnant or breast-feeding.
Liver impairment
:
Riluzole should be prescribed with care in patients with a history of abnormal liver function, or in
patients with slightly elevated serum transaminases (ALT/SGPT; AST/SGOT up to 3 times the upper
limit of the normal range (ULN)), bilirubin and/or gamma-glutamyl transferase (GGT) levels. Baseline
elevations of several liver function tests (especially elevated bilirubin) should preclude the use of
riluzole (see section 4.8).
Because of the risk of hepatitis, serum transaminases, including ALT, should be measured before and
during therapy with riluzole. ALT should be measured every month during the first 3 months of
treatment, every 3 months during the remainder of the first year, and periodically thereafter. ALT
levels should be measured more frequently in patients who develop elevated ALT levels.
Riluzole should be discontinued if the ALT levels increase to 5 times the ULN. There is no experience
with dose reduction or rechallenge in patients who have developed an increase of ALT to 5 times
ULN. Readministration of riluzole to patients in this situation cannot be recommended.
Neutropenia
:
Patients should be warned to report any febrile illness to their physicians. The report of a febrile illness
should prompt physicians to check white blood cell counts and to discontinue riluzole in case of
neutropenia (see section 4.8).
Interstitial lung disease
Cases of interstitial lung disease have been reported in patients treated with riluzole, some of them
were severe (see section 4.8). If respiratory symptoms develop such as dry cough and/or dyspnea,
chest radiography should be performed, and in case of findings suggestive of interstitial lung disease
(e.g. bilateral diffuse lung opacities), riluzole should be discontinued immediately. In the majority of
the reported cases, symptoms resolved after drug discontinuation and symptomatic treatment.
Renal impairment
:
Studies at repeated doses have not been conducted in patients with impaired renal function (see section
4.2).
There have been no clinical studies to evaluate the interactions of riluzole with other medicinal
products.
In vitro
studies using human liver microsomal preparations suggest that CYP 1A2 is the principal
isozyme involved in the initial oxidative metabolism of riluzole. Inhibitors of CYP 1A2 (e.g. caffeine,
diclofenac, diazepam, nicergoline, clomipramine, imipramine, fluvoxamine, phenacetin, theophylline,
amitriptyline and quinolones) could potentially decrease the rate of riluzole elimination, while
inducers of CYP 1A2 (e.g. cigarette smoke, charcoal-broiled food, rifampicin and omeprazole) could
increase the rate of riluzole elimination.
3
RILUTEK is contraindicated (see section 4.3) in pregnancy (see section 5.3).
Clinical experience with riluzole in pregnant women is lacking.
RILUTEK is contraindicated (see section 4.3) in breast-feeding women (see section 5.3).
It is not known whether riluzole is excreted in human milk.
Patients should be warned about the potential for dizziness or vertigo, and advised not to drive or
operate machinery if these symptoms occur.
No studies on the effects on the ability to drive and use machines have been performed.
In phase III clinical studies conducted in ALS patients treated with riluzole, the most commonly
reported adverse reactions were asthenia, nausea and abnormal liver function tests.
convention: 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), very rare (<1/10,000), not known (cannot be estimated from the available
data).
Blood and lymphatic system disorders
Uncommon:
anaemia
Not known:
severe neutropenia (see section 4.4)
Immune system disorders
Uncommon:
anaphylactoid reaction, angioedema
Nervous system disorders
Common:
headache, dizziness, oral paraesthesia and somnolence
Cardiac disorders
Common:
tachycardia
Respiratory, thoracic and mediastinal disorders
Uncommon:
interstitial lung disease (see section 4.4)
Gastrointestinal disorders
Very common:
nausea
Common:
diarrhoea, abdominal pain, vomiting
Uncommon:
pancreatitis
Hepato-biliary disorders
Very common:
abnormal liver function tests*. Increased alanine aminotransferase usually appeared
within 3 months after the start of therapy with riluzole; they were usually transient and levels returned
to below twice the ULN after 2 to 6 months while treatment was continued. These increases could be
associated with jaundice. In patients (n=20) from clinical studies with increases in ALT to more than 5
times the ULN, treatment was discontinued and the levels returned to less than 2 times the ULN within
2 to 4 months in most cases (see section 4.4)
Not known:
hepatitis
4
General disorders and administration site conditions
Very common:
asthenia
Common:
pain
* study data indicate that Asian patients may be more susceptible to liver function test abnormalities -
3.2% (194/5995) of Asian patients and 1.8% (100/5641) of Caucasian patients.
Neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma, and
methemoglobinemia have been observed in isolated cases.
In case of overdose, treatment is symptomatic and supportive.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other nervous system drugs, ATC code: N07XX02.
Although the pathogenesis of ALS is not completely elucidated, it is suggested that glutamate (the
primary excitatory neurotransmitter in the central nervous system) plays a role for cell death in the
disease.
Riluzole is proposed to act by inhibiting glutamate processes. The mode of action is unclear.
Clinical trials
In a trial, 155 patients were randomised to riluzole 100 mg/day (50 mg twice daily) or placebo and
were followed-up for 12 to 21 months. Survival, as defined in the second paragraph of section 4.1, was
significantly extended for patients who received riluzole as compared to patients who received
placebo. The median survival time was 17.7 months versus 14.9 months for riluzole and placebo,
respectively.
In a dose-ranging trial, 959 patients with ALS were randomised to one of four treatment groups:
riluzole 50, 100, 200 mg/day, or placebo and were followed-up for 18 months. In patients treated with
riluzole 100 mg/day, survival was significantly higher compared to patients who received placebo. The
effect of riluzole 50 mg/day was not statistically significant compared to placebo and the effect of
200 mg/day was essentially comparable to that of 100 mg/day. The median survival time approached
16.5 months versus 13.5 months for riluzole 100 mg/day and placebo, respectively.
In a parallel group study designed to assess the efficacy and safety of riluzole in patients at a late stage
of the disease, survival time and motor function under riluzole did not differ significantly from that of
placebo. In this study the majority of patients had a vital capacity less than 60%.
In a double-blind placebo-controlled trial designed to assess the efficacy and safety of riluzole in
Japanese patients, 204 patients were randomised to riluzole 100 mg/day (50 mg twice daily) or
placebo and were followed-up for 18 months. In this study, the efficacy was assessed on inability to
walk alone, loss of upper limb function, tracheostomy, need for artificial ventilation, gastric tube
feeding or death. Tracheostomy-free survival in patients treated with riluzole did not differ
significantly from placebo. However, the power of this study to detect differences between treatment
groups was low. Meta-analysis including this study and those described above showed a less striking
effect on survival for riluzole as compared to placebo although the differences remained statistically
significant.
5
5.2 Pharmacokinetic properties
The pharmacokinetics of riluzole have been evaluated in healthy male volunteers after single oral
administration of 25 to 300 mg and after multiple-dose oral administration of 25 to 100 mg bid.
Plasma levels increase linearly with the dose and the pharmacokinetic profile is dose-independent.
With multiple dose administration (10 day-treatment at 50 mg riluzole bid), unchanged riluzole
accumulates in plasma by about 2 fold and steady-state is reached in less than 5 days.
Absorption
Riluzole is rapidly absorbed after oral administration with maximal plasma concentrations occurring
within 60 to 90 minutes (C
max
= 173 ± 72 (sd) ng/ml). About 90% of the dose is absorbed and the
absolute bioavailability is 60 ± 18%.
The rate and extent of absorption is reduced when riluzole is administered with high-fat meals
(decrease in C
max
of 44%, decrease in AUC of 17%).
Distribution
Riluzole is extensively distributed throughout the body and has been shown to cross the blood brain
barrier. The volume of distribution of riluzole is about 245 ± 69 l (3.4 l/kg). Riluzole is about 97%
protein bound and it binds mainly to serum albumin and to lipoproteins.
Metabolism
Unchanged riluzole is the main component in plasma and is extensively metabolised by cytochrome
P450 and subsequent glucuronidation. In vitro studies using human liver preparations demonstrated
that cytochrome P450 1A2 is the principal isoenzyme involved in the metabolism of riluzole. The
metabolites identified in urine are three phenolic derivatives, one ureido-derivative and unchanged
riluzole.
The primary metabolic pathway for riluzole is initial oxidation by cytochrome P450 1A2 producing N-
hydroxy-riluzole (RPR112512), the major active metabolite of riluzole. This metabolite is rapidly
glucuronoconjugated to O- and N-glucuronides.
Elimination
The elimination half-life ranges from 9 to 15 hours. Riluzole is eliminated mainly in the urine.
The overall urinary excretion accounts for about 90% of the dose. Glucuronides accounted for more
than 85% of the metabolites in the urine. Only 2% of a riluzole dose was recovered unchanged in the
urine.
Special populations
Patients with impaired renal function
: there is no significant difference in pharmacokinetic parameters
between patients with moderate or severe chronic renal insufficiency (creatinine clearance between 10
and 50 ml.min
-1
) and healthy volunteers after a single oral dose of 50 mg riluzole.
Elderly
: the pharmacokinetic parameters of riluzole after multiple dose administration (4.5 days of
treatment at 50 mg riluzole bid) are not affected in the elderly (> 70 years).
Patients with impaired hepatic function
: the AUC of riluzole after a single oral dose of 50 mg
increases by about 1.7 fold in patients with mild chronic liver insufficiency and by about 3 fold in
patients with moderate chronic liver insufficiency.
6
Race
: a clinical study conducted to evaluate the pharmacokinetics of riluzole and its metabolite N-
hydroxyriluzole following repeated oral administration twice daily for 8 days in 16
healthy Japanese
and 16 Caucasian adult males showed in the Japanese group a lower exposure of riluzole (
C
max
0.85
[90% CI 0.68-1.08] and AUC
inf.
0.88 [90% CI 0.69-1.13])
and similar exposure to the metabolite. The
clinical significance of these results is not known.
5.3 Preclinical safety data
Riluzole did not show any carcinogenicity potential in either rats or mice.
Standard tests for genotoxicity performed with riluzole were negative. Tests on the major active
metabolite of riluzole gave positive results in two in vitro tests. Intensive testing in seven other
standard
in vitro
or
in vivo
assays did not show any genotoxic potential of the metabolite. On the basis
of these data, and taking into consideration the negative studies on the carcinogenesis of riluzole in the
mouse and rat, the genotoxic effect of this metabolite is not considered to be of relevance in humans.
Reductions in red blood cell parameters and/or alterations in liver parameters were noted
inconsistently in subacute and chronic toxicity studies in rats and monkeys. In dogs, haemolytic
anaemia was observed.
In a single toxicity study, the absence of corpora lutea was noted at a higher incidence in the ovary of
treated compared to control female rats. This isolated finding was not noted in any other study or
species.
All these findings were noted at doses which were 2-10 times higher than the human dose of
100 mg/day.
Fertility studies in rats revealed slight impairment of reproductive performance and fertility at doses of
15 mg/kg/day (which is higher than the therapeutic dose), probably due to sedation and lethargy.
In the pregnant rat, the transfer of
14
C- riluzole across the placenta to the foetus has been detected. In
rats, riluzole decreased the pregnancy rate and the number of implantations at exposure levels at least
twice the systemic exposure of humans given clinical therapy. No malformations were seen in animal
reproductive studies.
In lactating rats,
14
C-riluzole was detected in milk.
6.
6.1 List of excipients
Core
:
Dibasic calcium phosphate, anhydrous
Micro crystalline cellulose
Colloidal silica, anhydrous
Magnesium stearate
Croscarmellose sodium
Coating
:
Hypromellose
Macrogol 6000
Titanium dioxide (E171)
7
6.2 Incompatibilities
Not applicable.
6.3 Shelf-life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Tablets are packaged in opaque pvc/aluminium blister cards.
Each package contains 56 tablets (4 blister cards of 14 tablets each).
6.6 Special precautions for disposal
No special requirements.
7.
Aventis Pharma S.A.
20 avenue Raymond Aron
F-92165 Antony Cedex
France
8.
EU/1/96/010/001
9.
date of first authorisation: 10 June 1996
date of last renewal: 10 June 2006
8
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
9
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Sanofi Winthrop Industrie, 56, Route de Choisy au Bac, F-60205 Compiègne, France.
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
OTHER CONDITIONS
The Marketing Authorisation Holder will provide Periodic Safety Update Report every two years until
otherwise decided by the Committee for Medicinal Products for Human Use (CHMP).
10
ANNEX III
LABELLING AND PACKAGE LEAFLET
11
A. LABELLING
12
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
RILUTEK 50 mg film-coated tablets
riluzole
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 50 mg of riluzole
3.
LIST OF EXCIPIENTS
4.
56 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
Oral 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
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
13
Aventis Pharma S.A., 20 avenue Raymond Aron, F-92165 Antony Cedex, France
EU/1/96/010/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
RILUTEK
14
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
PVC/ALUMINIUM BLISTER
1.
RILUTEK 50 mg film-coated tablets
riluzole
2.
Aventis Pharma
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
15
B. PACKAGE LEAFLET
16
PACKAGE LEAFLET: INFORMATION FOR THE USER
RILUTEK 50 mg film-coated tablets
Riluzole
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects 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 RILUTEK is and what it is used for
2.
Before you take RILUTEK
3.
How to take RILUTEK
4.
Possible side effects
5.
How to store RILUTEK
6.
Further information
1. WHAT RILUTEK IS AND WHAT IT IS USED FOR
What RILUTEK is
The active substance in RILUTEK is riluzole which acts on the nervous system.
What RILUTEK is used for
RILUTEK is used in patients with amyotrophic lateral sclerosis (ALS).
ALS is a form of motor neurone disease where attacks of the nerve cells responsible for sending
instructions to the muscles lead to weakness, muscle waste and paralysis.
The destruction of nerve cells in motor neurone disease may be caused by too much glutamate (a
chemical messenger) in the brain and spinal cord. RILUTEK stops the release of glutamate and this
may help in preventing the nerve cells being damaged.
Please consult your doctor for more information about ALS and the reason why this medicine has been
prescribed for you.
2. BEFORE YOU TAKE RILUTEK
Do not take RILUTEK
-
if you are
allergic
(hypersensitive) to riluzole or any of the other ingredients of RILUTEK,
if you have any
liver disease
or increased blood levels of some enzymes of the liver
(transaminases),
-
if you are
pregnant or breast-feeding
.
-
17
Take special care with RILUTEK
Tell your doctor;
-
if you have any
liver problems:
yellowing of your skin or the white of your eyes (jaundice),
itching all over, feeling sick, being sick
-
if your
kidneys
are not working very well
-
if you have any
fever
: it may be due to a low number of white blood cells which can cause an
increased risk of infection
-
if you are less than 18 years of age. The use of RILUTEK is not recommended in children
because there is no information available in this population.
If any of the above applies to you, or if you are not sure, tell your doctor who will decide what to
do.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
Pregnancy and breast-feeding
You MUST NOT take RILUTEK if you are or think you may be pregnant, or if you are breast feeding.
If you think you may be pregnant, or if you intend to breast-feed, ask your doctor for advice before
taking RILUTEK.
Driving and using machines
You can drive or use any tools or machines, unless you feel dizzy or light headed after taking this
medicine.
3. HOW TO TAKE RILUTEK
The recommended dose is one tablet, twice a day.
The tablets should be taken by mouth, every 12 hours, at the same time of the day each day (e.g. in the
morning and evening).
If you take more RILUTEK than you should
If you take too many tablets, contact your doctor or the nearest hospital emergency department
immediately.
If you forget to take RILUTEK
If you forget to take your tablet, leave out that dose completely and take the next tablet at the usual
time.
Do not take a double dose to make up for a forgotten tablet.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, RILUTEK can cause side effects, although not everybody gets them.
18
IMPORTANT
Tell your doctor immediately
-
if you experience any
fever
(increase in temperature) because RILUTEK may cause a decrease
in the number of white blood cells. Your doctor may want to take a blood sample to check the
number of white blood cells, which are important in fighting infections.
-
if you experience any of the following symptoms: yellowing of your skin or the white of your
eyes (jaundice), itching all over, feeling sick, being sick, as this may be signs of
liver disease
(hepatitis).Your doctor may do regular blood tests while you are taking RILUTEK to make sure
that this does not occur.
-
if you experience cough or difficulties in breathing, as this may be a sign of lung disease (called
interstitial lung disease).
Very common side effects
(affecting more than 1 in 10 patients) of RILUTEK are:
-
tiredness
feeling sick
-
increased blood levels of some enzymes of the liver (transaminases).
-
Common side effects
(affecting between 1 in 10 and 1 in 100 patients) of RILUTEK are:
-
dizziness
-
numbness or tingling of the mouth
-
vomiting
sleepiness
increase in heart beat
diarrhoea
-
-
-
headache
abdominal pain
pain
-
-
-
Uncommon side effects
(affecting between 1 in 100 and 1 in 1000 patients) of RILUTEK are:
-
anaemia
allergic reactions
-
inflammation of the pancreas (pancreatitis).
-
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.
5.
HOW TO STORE RILUTEK
Keep
out of the reach and sight of children.
Do not use RILUTEK after the expiry date which is stated on the carton and the blister.
6.
FURTHER INFORMATION
What RILUTEK contains
-
The active substance is riluzole.
-
The other ingredients are:
Core
: anhydrous dibasic calcium phosphate, micro crystalline cellulose, anhydrous colloidal silica,
magnesium stearate, croscarmellose sodium;
Coating
: hypromellose, macrogol 6000, titanium dioxide (E171).
19
What RILUTEK looks like and content of the pack
The tablets are film-coated, capsule-shaped and white. Each tablet contains 50 mg of riluzole and is
engraved with “RPR 202” on one side.
RILUTEK is available in a pack of 56 tablets (4 blister cards of 14 tablets each) to be taken orally.
Marketing Authorisation Holder
Aventis Pharma S.A., 20 avenue Raymond Aron, F-92165 Antony Cedex, France
Manufacturer
Sanofi Winthrop Industrie, 56, Route de Choisy au Bac, F-60205 Compiègne, France.
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/ Belgien
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00
Luxembourg/Luxemburg
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)
България
sanofi-aventis Bulgaria EOOD
Тел.: +359 (0)2 970 53 00
Magyarország
sanofi-aventis zrt., Magyarország
Tel.: +36 1 505 0050
Česká republika
sanofi-aventis, s.r.o.
Tel: +420 233 086 111
Malta
sanofi-aventis Malta Ltd.
Tel: +356 21493022
Danmark
sanofi-aventis Denmark A/S
Tlf: +45 45 16 70 00
Nederland
sanofi-aventis Netherlands B.V.
Tel: +31 (0)182 557 755
Deutschland
Sanofi-Aventis Deutschland GmbH
Tel: +49 (0)180 2 222010
Norge
sanofi-aventis Norge AS
Tlf: +47 67 10 71 00
Eesti
sanofi-aventis Estonia OÜ
Tel: +372 627 34 88
Österreich
sanofi-aventis GmbH
Tel: +43 1 80 185 – 0
Ελλάδα
sanofi-aventis AEBE
Τηλ: +30 210 900 16 00
Polska
sanofi-aventis Sp. z o.o.
Tel.: +48 22 280 00 00
España
sanofi-aventis, S.A.
Tel: +34 93 485 94 00
Portugal
sanofi-aventis - Produtos Farmacêuticos, Lda
Tel: +351 21 35 89 400
France
sanofi-aventis France
Tél : 0 800 222 555
Appel depuis l’étranger : +33 1 57 63 23 23
România
sanofi-aventis România S.R.L.
Tel: +40 (0) 21 317 31 36
Ireland
sanofi-aventis Ireland Ltd.
Tel: +353 (0) 1 403 56 00
Slovenija
sanofi-aventis d.o.o.
Tel: +386 1 560 48 00
20
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
sanofi-aventis Pharma Slovakia s.r.o.
Tel: +421 2 33 100 100
Italia
sanofi-aventis S.p.A.
Tel: +39 02 393 91
Suomi/Finland
sanofi-aventis Oy
Puh/Tel: +358 (0) 201 200 300
Κύπρος
sanofi-aventis Cyprus Ltd.
Τηλ: +357 22 871600
Sverige
sanofi-aventis AB
Tel: +46 (0)8 634 50 00
Latvija
sanofi-aventis Latvia SIA
Tel: +371 67 33 24 51
United Kingdom
sanofi-aventis
Tel: +44 (0) 1483 505 515
Lietuva
UAB sanofi-aventis Lietuva
Tel: +370 5 2755224
This leaflet was last approved in {MM/YYYY}.
21
Source: European Medicines Agency
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