Clopidogrel Qualimed

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

Clopidogrel Qualimed 75 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride).

Excipient:
Each film-coated tablet contains 13 mg hydrogenated castor oil. 

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.
Pink, round and slightly convex film-coated tablets.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prevention of atherothrombotic events

Clopidogrel is indicated in:  
• Adults patients suffering from myocardial infarction (from a few days until less than 35 days), 

ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial 
disease.

For further information please refer to section 5.1.

4.2 Posology and method of administration

Posology

• Adults and elderly
Clopidogrel should be given as a single daily dose of 75 mg. 

If a dose is missed:
- Within less than 12 hours after regular scheduled time: patients should take the dose 

immediately and then take the next dose at the regular scheduled time.
- For more than 12 hours: patients should take the next dose at the regular scheduled time 

and should not double the dose.

• Paediatric population 
Clopidogrel should not be used in children because of efficacy concerns (see section 5.1).

• Renal impairment
Therapeutic experience is limited in patients with renal impairment (see section 4.4).

• Hepatic impairment
Therapeutic experience is limited in patients with moderate hepatic disease who may have 
bleeding diatheses (see section 4.4).

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Method of administration
For oral use
It may be given with or without food.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Severe hepatic impairment.
• Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

4.4 Special warnings and precautions for use

Bleeding and haematological disorders
Due to the risk of bleeding and haematologicaladverse reactions, blood cell count determination and/or 
other appropriate testing should be promptly considered whenever clinical symptoms suggestive of 
bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet agents, 
clopidogrel should be used with caution in patients who may be at risk of increased bleeding from 
trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, 
heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including 
Cox-2 inhibitors. Patients should be followed carefully for any signs of bleeding including occult 
bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or 
surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended 
since it may increase the intensity of bleedings (see section 4.5).

If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, 
clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and 
dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal 
product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who 
have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel 
(alone or in combination with ASA), and that they should report any unusual bleeding (site or 
duration) to their physician.

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of 
clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and 
microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction 
or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Recent ischaemic stroke
In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute 
ischaemic stroke.

Cytochrome P450 2C19 (CYP2C19)
Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended 
doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. 
Tests are available to identify a patient's CYP2C19 genotype. 

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal 
products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of 
the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a 

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precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see 
section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2). 

Renal impairment
Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore 
clopidogrel should be used with caution in these patients (see section 4.2).

Hepatic impairment
Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. 
Clopidogrel should therefore be used with caution in this population (see section 4.2).

Excipients
This medicinal product contains hydrogenated castor oil which may cause stomach upset and 
diarrhoea.

4.5 Interaction with other medicinal products and other forms of interaction

Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is not 
recommended since it may increase the intensity of bleedings (see section 4.4). Although the 
administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or 
International Normalised Ratio (INR) in patients receiving long-term warfarin therapy, 
coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent 
effects on hemostasis.

Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients receive 
concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4).

Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced 
platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet 
aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not 
significantly increase the prolongation of bleeding time induced by clopidogrel intake. A 
pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to 
increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see 
section 4.4). However, clopidogrel and ASA have been administered together for up to one year (see 
section 5.1).

Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification 
of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no 
effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic 
interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. 
Therefore, concomitant use should be undertaken with caution (see section 4.4).

Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin 
specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. 
The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents 
and heparin are co-administered with ASA (see section 4.8).

NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of 
clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of 
interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of 
gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and 
clopidogrel should be co-administered with caution (see section 4.4).

Other concomitant therapy: 
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal 
products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of 
the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a 

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precaution concomitant use of strong or moderateCYP2C19 inhibitors should be discouraged (see 
sections 4.4 and 5.2).

Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, 
fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, 
carbamazepine, oxcarbazepine and chloramphenicol.

Proton Pump Inhibitors (PPI): 
Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours 
between the administrations of the two drugs decreased the exposure of the active metabolite by 45% 
(loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) 
and 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected 
to give a similar interaction with clopidogrel.

Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) 
interaction in terms of major cardiovascular events have been reported from both observational and 
clinical studies. As a precaution, concomitant use of omeprazole or esomeprozole should be 
discouraged (see section 4.4). 

Less pronounced reductions of metabolite exposure has been observed with pantoprazole or 
lansoprazole.
The plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced 
(maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was 
associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, 
respectively. These results indicate that clopidogrel can be administered with pantoprazole.

There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers 
(except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with antiplatelet activity of 
clopidogrel.

Other medicinal products: A number of other clinical studies have been conducted with clopidogrel 
and other concomitant medicinal products to investigate the potential for pharmacodynamic and 
pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed 
when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. 
Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the 
coadministration of phenobarbital, or oestrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of 
clopidogrel. Antacids did not modify the extent of clopidogrel absorption.

Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by 
CYP2C9 can be safely co-administered with clopidogrel.

Apart from the specific medicinal product interaction information described above, interaction studies 
with clopidogrel and some medicinal products commonly administered in patients with 
atherothrombotic disease have not been performed. However, patients entered into clinical trials with 
clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, 
ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents 
(including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically 
significant adverse interactions.

4.6 Fertility, pregnancy and lactation

Pregnancy
As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to 
use clopidogrel during pregnancy as a precautionary measure. 

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Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/
foetal development, parturition or postnatal development (see section 5.3).

Breastfeeding
It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown 
excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be 
continued during treatment with Clopidogrel Qualimed.

Fertility
Clopidogrel was not shown to alter fertility in animal studies.

4.7 Effects on ability to drive and use machines

Clopidogrel has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Clopidogrel has been evaluated for safety in more than 42,000 patients, who have participated in 
clinical studies, including over 9,000 patients treated for 1 year or more. The clinically relevant 
adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed 
below. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of 
age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE, 
CLARITY, COMMIT studies are discussed below. In addition to clinical studies experience, adverse 
reactions have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing 
experience where it was mostly reported during the first month of treatment.

In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding 
was 9.3%. The incidence of severe cases was similar for clopidogrel and ASA. 

In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary 
bypass graft surgery in patients who stopped therapy more than five days prior to surgery . In patients 
who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for 
clopidogrel plus ASA, and 6.3% for placebo plus ASA.

In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the 
placebo plus ASA group. The incidence of major bleeding was similar between groups. This was 
consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or 
heparin therapy. 

In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar 
in both groups 

Adverse reactions that occurred either during clinical studies or that were spontaneously reported are 
presented in the table below. Their frequency is defined using the following conventions: 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). Within each system organ class, adverse reactions are presented in order of decreasing 
seriousness.

System Organ
Class

Common Uncommon Rare Very rare

Blood and the 
lymphatic system 
disorders

Thrombocytopenia
, leucopenia, 
eosinophilia

Neutropenia, 
including severe 
neutropenia

Thrombotic 
thrombocytopenic 
purpura (TTP) (see 
section 4.4), 

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System Organ
Class

Common Uncommon Rare Very rare

aplastic anaemia, 
pancytopenia, 
agranulocytosis, 
severe 
thrombocytopenia, 
granulocytopenia, 
anaemia

Immune system 
disorders

Serum sickness, 
anaphylactoid 
reactions

Psychiatric 
disorders

Hallucinations, 
confusion

Nervous system 
disorders

Intracranial 
bleeding (some 
cases were 
reported with fatal 
outcome), 
headache, 
paraesthesia, 
dizziness

Taste disturbances

Eye disorders Eye bleeding 
(conjunctival, 
ocular, retinal)

Ear and labyrinth 
disorders

Vertigo

Vascular 
disorders

Haematoma Serious 
haemorrhage, 
haemorrhage of 
operative wound, 
vasculitis, 
hypotension

Respiratory, 
thoracic and 
mediastinal 
disorders

Epistaxis Respiratory tract 
bleeding 
(haemoptysis, 
pulmonary 
haemorrhage), 
bronchospasm, 
interstitial 
pneumonitis

Gastrointestinal 
disorders

Gastrointestinal 
haemorrhage, 
diarrhoea, 
abdominal pain, 
dyspepsia

Gastric ulcer and 
duodenal ulcer, 
gastritis, vomiting, 
nausea, 
constipation, 
flatulence

Retroperitoneal 
haemorrhage

Gastrointestinal and 
retroperitoneal 
haemorrhage with 
fatal outcome, 
pancreatitis, colitis 
(including 
ulcerative or 
lymphocytic 
colitis), stomatitis

Hepato-biliary 
disorders

Acute liver failure, 
hepatitis, abnormal 
liver function test

Skin and 
subcutaneous 
tissue disorders

Bruising Rash, pruritus, skin 
bleeding (purpura)

Bullous dermatitis 
(toxic epidermal 
necrolysis, Stevens 
Johnson Syndrome, 

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System Organ
Class

Common Uncommon Rare Very rare

erythema 
multiforme), 
angioedema, rash 
erythematous, 
urticaria, eczema, 
lichen planus

Musculoskeletal, 
connective tissue 
and bone 
disorders

Musculo-skeletal 
bleeding 
(haemarthrosis), 
arthritis, arthralgia, 
myalgia

Renal and urinary 
disorders

Haematuria Glomerulonephritis, 
blood creatinine 
increased

General disorders 
and 
administration 
site conditions

Bleeding at 
puncture site

Fever

Investigations Bleeding time 
prolonged, 
neutrophil count 
decreased, platelet 
count decreased

4.9 Overdose

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent 
bleeding complications. Appropriate therapy should be considered if bleedings are observed. No 
antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of 
prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin, ATC code: B01AC-04. 

Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel 
must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet 
aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine 
diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the 
glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible 
binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) 
and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet 
aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of 
platelet activation by released ADP.

Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or 
subject to inhibition by medicinal products, not all patients will have adequate platelet inhibition.

Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation 
from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At 
steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 

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60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 
5 days after treatment was discontinued.

The safety and efficacy of clopidogrel have been evaluated in 4 double-blind studies involving over 
80,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY 
and COMMIT studies comparing clopidogrel to placebo, both medicinal products given in 
combination with ASA and other standard therapy. 

Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease

The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent 
myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or 
established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or 
ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of 
the patients received ASA for the first few days following the acute myocardial infarction.
Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of 
myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention 
to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA 
(relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p = 0.045), which corresponds, for every 
1000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from 
experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show 
any significant difference between clopidogrel (5.8%) and ASA (6.0%).
In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the 
benefit appeared to be strongest (achieving statistical significance at p = 0.003) in patients enrolled 
due to PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 
to 36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to 
18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial 
infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR = 
-4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the benefit 
of clopidogrel in patients over 75 years was less than that observed in patients ≤75 years.
Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear 
whether the differences in relative risk reduction across qualifying conditions are real, or a result of 
chance.

Paediatric population

In a dose escalation study of 86 neonates or infants up to 24 months of age at risk for thrombosis 
(PICOLO), clopidogrel was evaluated at consecutive doses of 0.01, 0.1 and 0.2 mg/kg in neonates and 
infants and 0.15 mg/kg only in neonates. The dose of 0.2 mg/kg achieved the mean percent inhibition 
of 49.3% (5 µM ADP-induced platelet aggregation) which was comparable to that of adults taking 
Plavix 75 mg/day.

In a randomised, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonates 
and infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial 
shunt were randomised to receive clopidogrel 0.2 mg/kg (n=467) or placebo (n=439) along with 
concomitant background therapy up to the time of second stage surgery. The mean time between shunt 
palliation and first administration of study medicinal product was 20 days. Approximately 88% of 
patients received concomitant ASA (range of 1 to 23 mg/kg/day). There was no significant difference 
between groups in the primary composite endpoint of death, shunt thrombosis or cardiac-related 
intervention prior to 120 days of age following an event considered of thrombotic nature (89 [19.1%] 
for the clopidogrel group and 90 [20.5%] for the placebo group) (see section 4.2). Bleeding was the 
most frequently reported adverse reaction in both clopidogrel and placebo groups; however, there was 
no significant difference in the bleeding rate between groups. In the long-term safety follow-up of this 
study, 26 patients with the shunt still in place at one year of age received clopidogrel up to 18 months 
of age. No new safety concerns were noted during this long-term follow-up.

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The CLARINET and the PICOLO trials were conducted using a constituted solution of clopidogrel. In 
a relative bioavailability study in adults, the constituted solution of clopidogrel showed a similar extent 
and slightly higher rate of absorption of the main circulating (inactive) metabolite compared to the 
authorised tablet.

5.2 Pharmacokinetic properties

Absorption
After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak 
plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after a single 75 mg oral dose) 
occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary 
excretion of clopidogrel metabolites. 

Distribution
Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma 
proteins (98% and 94% respectively). The binding is non-saturable in vitro over a wide concentration 
range. 

Metabolism
Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised 
according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into 
its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple 
cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. 
Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the 
active metabolite, a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by 
CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite which has been isolated 
in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.

The Cmax of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose 
as it is after four days of 75-mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after 
dosing. 

Elimination
Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the 
urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral 
dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination halflife of the 
main circulating (inactive) metabolite was 8 hours after single and repeated administration.

Pharmacogenetics
CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel 
intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as 
measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. 

The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and 
CYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the 
majority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other 
alleles associated with absent or reduced metabolism are less frequent and include CYP2C19*4, *5, 
*6, *7, and *8. A patient with poor metaboliser status will possess two loss-of-function alleles as 
defined above. Published frequencies for the poor CYP2C19 metaboliser  genotypes are 
approximately 2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to 
determine a patient’s CYP2C19 genotype. 

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, 
extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg 
followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). 
No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation 

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(IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor 
metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive 
metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor 
metabolisers with mean IPA (5 μM ADP) of 24% (24 hours) and 37% (Day 5) as compared to IPA of 
39% (24 hours) and 58% (Day 5) in the extensive metabolisers and 37% (24 hours) and 60% (Day 5) 
in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active 
metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% 
(24 hours) and 61% (Day 5), which were greater than in the poor metabolisers receiving the 
300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the 
300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been 
established in clinical outcome trials.

Consistent with the above results, in a meta-analysis including 6 studies of 335 clopidogrel-treated 
subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for 
intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 μM 
ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to 
extensive metabolisers.

The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not 
been evaluated in prospective, randomised, controlled trials. There have been a number of 
retrospective analyses, however, to evaluate this effect in patients treated with clopidogrel for whom 
there are genotyping results: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227), 
TRITON-TIMI 38 (n=1477), and ACTIVE-A (n=601), as well as a number of published cohort 
studies.

In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of 
patients with either intermediate or poor metaboliser status had a higher rate of cardiovascular events 
(death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers.

In CHARISMA and one cohort study (Simon), an increased event rate was observed only in poor 
metabolisers when compared to extensive metabolisers.

In CURE, CLARITY and one of the cohort studies (Trenk), no increased event rate was observed 
based on metaboliser status.

None of these analyses were adequately sized to detect differences in outcome in poor metabolisers.

Special populations

The pharmacokinetics of the active metabolite of clopidogrel is not known in these special 
populations.

Renal impairment
After repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease (creatinine 
clearance from 5 to 15 ml/min) inhibition of ADP-induced platelet aggregation was lower (25%) than 
that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen 
in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in 
all patients.

Hepatic impairment
After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic 
impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy 
subjects. The mean bleeding time prolongation was also similar in the two groups. 

Race

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The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs 
according to race/ethnicity (see Pharmacogenetics). From literature, limited data in Asian populations 
are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.

5.3 Preclinical safety data

During non clinical studies in rat and baboon, the most frequently observed effects were liver changes. 
These occurred at doses representing at least 25 times the exposure seen in humans receiving the 
clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No 
effect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the 
therapeutic dose.

At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of 
clopidogrel was also reported in rat and baboon. 

There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to 
mice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times 
the exposure seen in humans receiving the clinical dose of 75 mg/day).

Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed no 
genotoxic activity. 

Clopidogrel was found to have no effect on the fertility of male and female rats and was not 
teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in 
the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled 
clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. 
Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be 
excluded.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:
Cellulose, microcrystalline
Colloidal anhydrous silica
Crospovidone (type A)
Macrogol 6000
Hydrogenated castor oil

Film coating:
Hydroxypropylcellulose (E463)
Titanium dioxide (E171)
Red iron oxide (E172)
Talc
Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

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6.4 Special precautions for storage

Store in the original package in order to protect from moisture and light.

6.5 Nature and contents of container

Blister of OPA/Al/PVC-Al containing 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in the 
box.
Calendar Blister of OPA/Al/PVC-Al containing 7, 14, 28, 56, 84 film-coated tablets in the box.
Perforated unit dose blister of OPA/Al/PVC-Al containing 30x1 and 50x1 film-coated tablets in the 
box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal 

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Qualimed, 117 allee des Parcs, 69 800 Saint Priest, France

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/09/559/001-016

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 September 2009

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency  http://www.ema.europa.eu/

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ANNEX II

A. THE MANUFACTURING AUTHORISATION HOLDER(S) 
RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

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A. THE MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR 
BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

KRKA, d.d., Novo mesto
Šmarješka cesta 6
8501 Novo mesto
Slovenia

TAD Pharma GmbH
Heinz-Lohmann-Straße 5
27472 Cuxhaven
Germany

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

• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 
THE MARKETING AUTHORISATION HOLDER

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, presented in Module 1.8.1. of the 
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.

Risk Management plan

Risk Management Plan was not submitted. The application is based on a reference medicinal product 
for which no safety concerns requiring additional risk minimization activities have been identified.

PSURs

The PSUR submission schedule for Clopidogrel Qualimed film coated tablets should follow PSURs 
submission schedule for the reference medicinal product.

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ANNEX III

LABELLING AND PACKAGE LEAFLET

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A. LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Clopidogrel Qualimed 75 mg film-coated tablets

Clopidogrel

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride).

3. LIST OF EXCIPIENTS

It also contains hydrogenated castor oil.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

7 film-coated tablets
7 film-coated tablets - calendar blister
14 film-coated tablets
14 film-coated tablets - calendar blister
28 film-coated tablets
28 film-coated tablets - calendar blister
30 film-coated tablets
30x1 film-coated tablets
50 film-coated tablets
50x1 film-coated tablets
56 film-coated tablets
56 film-coated tablets - calendar blister
84 film-coated tablets
84 film-coated tablets - calendar blister
90 film-coated tablets
100 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.

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7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP:

9. SPECIAL STORAGE CONDITIONS

Store in the original package in order to protect from moisture and light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Qualimed, 117 allee des Parcs, 69 800 Saint Priest, France

12. MARKETING AUTHORISATION NUMBER(S) 

7 film-coated tablets: EU/1/09/559/001
14 film-coated tablets: EU/1/09/559/002
28 film-coated tablets: EU/1/09/559/003
30 film-coated tablets: EU/1/09/559/004
50 film-coated tablets: EU/1/09/559/005
56 film-coated tablets: EU/1/09/559/006
84 film-coated tablets: EU/1/09/559/007
90 film-coated tablets: EU/1/09/559/008
100 film-coated tablets: EU/1/09/559/009
30x1 film-coated tablets EU/1/09/559/010
50x1 film-coated tablets EU/1/09/559/011
7 film-coated tablets - calendar blister: EU/1/09/559/012
14 film-coated tablets - calendar blister: EU/1/09/559/013
28 film-coated tablets - calendar blister: EU/1/09/559/014
56 film-coated tablets - calendar blister: EU/1/09/559/015
84 film-coated tablets - calendar blister: EU/1/09/559/016

13. BATCH NUMBER

Batch:

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

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16. INFORMATION IN BRAILLE

Clopidogrel Qualimed 75 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER (Boxes of 7, 14, 28, 30, 30x1, 50, 50x1, 56, 84, 90 and 100)

1. NAME OF THE MEDICINAL PRODUCT

Clopidogrel Qualimed 75 mg film-coated tablets

Clopidogrel

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Qualimed

3. EXPIRY DATE

EXP:

4. BATCH NUMBER

Batch:

5. OTHER

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

CALENDAR BLISTER (boxes of 7, 14, 28, 56 or 84 tablets)

1. NAME OF THE MEDICINAL PRODUCT

Clopidogrel Qualimed 75 mg film-coated tablets

Clopidogrel

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Qualimed

3. EXPIRY DATE

EXP:

4. BATCH NUMBER

Batch:

5. OTHER

Calendar days
Mon
Tue
Wed
Thu
Fri
Sat
Sun

Week 1
Week 2 (for boxes of 14, 28, 56, 84)
Week 3 (for boxes of 28, 56, 84)
Week 4 (for boxes of 28, 56, 84)

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B. PACKAGE LEAFLET

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Clopidogrel Qualimed 75 mg film-coated tablets
Clopidogrel

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 Clopidogrel Qualimed is and what it is used for
2. Before you take Clopidogrel Qualimed 
3. How to take Clopidogrel Qualimed 
4. Possible side effects
5. How to store Clopidogrel Qualimed 
6. Further information

1. WHAT CLOPIDOGREL QUALIMED IS AND WHAT IT IS USED FOR

Clopidogrel Qualimed belongs to a group of medicines called antiplatelet medicinal products. Platelets 
are very small structures in the blood, which clump together during blood clotting. By preventing this 
clumping, antiplatelet medicinal products reduce the chances of blood clots forming (a process called 
thrombosis).

Clopidogrel Qualimed is taken to prevent blood clots (thrombi) forming in hardened blood vessels 
(arteries), a process known as atherothrombosis, which can lead to atherothrombotic events (such as 
stroke, heart attack, or death).

You have been prescribed Clopidogrel Qualimed to help prevent blood clots and reduce the risk of 
these severe events because:
- You have a condition of hardening of arteries (also known as atherosclerosis), and
- You have previously experienced a heart attack, stroke or have a condition known as peripheral 

arterial disease.

2. BEFORE YOU TAKE CLOPIDOGREL QUALIMED 

Do not take Clopidogrel Qualimed 
• if you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of Clopidogrel 

Qualimed;
• if you have a medical condition that is currently causing bleeding such as a stomach ulcer or 

bleeding within the brain;
• if you suffer from severe liver disease;

If you think any of these apply to you, or if you are in any doubt at all, consult your doctor before 
taking Clopidogrel Qualimed.

Take special care with Clopidogrel Qualimed 
If any of the situations mentioned below apply to you, you should tell your doctor before taking 
Clopidogrel Qualimed:
• if you have a risk of bleeding such as

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- a medical condition that puts you at risk of internal bleeding (such as a stomach ulcer)
- a blood disorder that makes you prone to internal bleeding (bleeding inside any tissues, organs 
or joints of your body).
- a recent serious injury
- a recent surgery (including dental)
- a planned surgery (including dental) in the next seven days

• if you have had a clot in an artery of your brain (ischaemic stroke) which occurred within the 
last seven days

• if you have kidney or liver disease.

While you are taking Clopidogrel Qualimed:
• You should tell your doctor if a surgery (including dental) is planned.
• You should also tell your doctor immediately if you develop a medical condition (also known as 

Thrombotic Thrombocytopenic Purpura or TTP) that includes fever and bruising under the skin 
that may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, 
yellowing of the skin or eyes (jaundice) (see section 4 ‘Possible side effects’).

• If you cut or injure yourself, it may take longer than usual for bleeding to stop. This is linked to 
the way your medicine works as it prevents the ability of blood clots to form. For minor cuts 
and injuries e.g., cutting yourself, shaving, this is usually of no concern. However, if you are 
concerned by your bleeding, you should contact your doctor straightaway (see section 4 
‘Possible side effects’).

• Your doctor may order blood tests.

Clopidogrel Qualimed is not intended for use in children or adolescents.

Taking 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.
Some other medicines may influence the use of Clopidogrel Qualimed or vice versa.

You should specifically tell your doctor if you take
- oral anticoagulants, medicines used to reduce blood clotting,
- a non-steroidal anti-inflammatory medicine, usually used to treat painful and/or inflammatory 
conditions of muscle or joints, 
- heparin, or any other injectable medicine used to reduce blood clotting,
-omeprazole, esomeprazole or cimetidine, medicines to treat for upset stomach,

- fluconazole, voriconazole, ciprofloxacin, or chloramphenicol, medicines to treat bacterial and 
fungal infections,
- fluoxetine, fluvoxamine, or moclobemide, medicines to treat depression,
- carbamazepine, or oxcarbazepine, medicines to treat some forms of epilepsy,
- ticlopidine, other antiplatelet agent.

An occasional use of acetylsalicylic acid (no more than 1000 mg in any 24 hour period), a substance 
present in many medicines used to relieve pain and lower fever, should generally not cause a problem, 
but prolonged use in other circumstances should be discussed with your doctor.

Taking Clopidogrel Qualimed with food and drink
Clopidogrel Qualimed may be taken with or without food.

Pregnancy and breast-feeding
It is preferable not to take this product during pregnancy..

If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist 
before taking Clopidogrel Qualimed. If you become pregnant while taking Clopidogrel Qualimed, 
consult your doctor immediately as it is recommended not to take clopidogrel while you are pregnant.

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You should not breastfeed while taking this medicine.
If you are breastfeeding or planning to breastfeed, talk to your doctor before taking this medicine.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
Clopidogrel Qualimed is unlikely to affect your ability to drive or to use machines.

Important information about some of the ingredients of Clopidogrel Qualimed 
Clopidogrel Qualimed contains hydrogenated castor oil which may cause stomach upset and 
diarrhoea.

3. HOW TO TAKE CLOPIDOGREL QUALIMED 

Always take Clopidogrel Qualimed exactly as your doctor has told you. You should check with your 
doctor or pharmacist if you are not sure. 

The usual dose is one 75 mg tablet of Clopidogrel Qualimed per day to be taken orally with or without 
food, and at the same time each day.

You should take Clopidogrel Qualimed for as long as your doctor continues to prescribe it.

If you take more Clopidogrel Qualimed than you should:
Contact your doctor or the nearest hospital emergency department because of the increased risk of 
bleeding.

If you forget to take Clopidogrel Qualimed: 
If you forget to take a dose of Clopidogrel Qualimed, but remember within 12 hours of your usual 
time, take your tablet straightaway and then take your next tablet at the usual time.
If you forget for more than 12 hours, simply take the next single dose at the usual time. Do not take a 
double dose to make up for a forgotten tablet dose.

For the 7, 14, 28, 56, 84 tablets (calendar blister) pack sizes, you can check the day on which you last 
took a tablet of Clopidogrel Qualimed by referring to the calendar printed on the blister.

If you stop taking Clopidogrel Qualimed: 
Do not stop the treatment unless your doctor tells you so. Contact your doctor or pharmacist before 
stopping.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Clopidogrel Qualimed can cause side effects, although not everybody gets them.

The frequency of possible side effects listed below is defined using the following convention:
• very common (affects more than 1 user  in 10)
• common (affects 1 to 10 users in 100)
• uncommon (affects 1 to 10 users in 1,000)
• rare (affects 1 to 10 users in 10,000)
• very rare (affects less than 1 user in 10,000)
• not known (frequency cannot be estimated from the available data)

Contact your doctor immediately if you experience:

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- fever, signs of infection or extreme tiredness. These may be due to rare decrease of some blood 
cells.

- signs of liver problems such as yellowing of the skin and/or the eyes (jaundice), whether or not 
associated with bleeding which appears under the skin as red pinpoint dots and/or confusion 
(see section 2 ‘Take special care with Clopidogrel Qualimed’).

- swelling in the mouth or skin disorders such as rashes and itching, blisters of the skin. These 
may be the signs of an allergic reaction.

The most common side effect is bleeding.
Bleeding may occur as bleeding in the stomach or bowels, bruising, haematoma (unusual bleeding or 
bruising under the skin), nose bleed, blood in the urine. In a small number of cases, bleeding in the 
eye, inside the head, the lung or the joints has also been reported.

If you experience prolonged bleeding when taking Clopidogrel Qualimed
If you cut or injure yourself, it may take longer than usual for bleeding to stop. This is linked to the 
way your medicine works as it prevents the ability of blood clots to form. For minor cuts and injuries 
e.g., cutting yourself, shaving, this is of no concern. However, if you are concerned by your bleeding, 
you should contact your doctor straightaway (see section 2 ‘Take special care with Clopidogrel 
Qualimed’).

Other side effects reported are
Common side effects: Diarrhoea, abdominal pain, indigestion or heartburn.

Uncommon side effects: Headache, stomach ulcer, vomiting, nausea, constipation, excessive gas in 
stomach or intestines, rashes, itching, dizziness, sensation of tingling and numbness.

Rare side effect: Vertigo.

Very rare side effects: Jaundice; severe abdominal pain with or without back pain; fever, breathing 
difficulties sometimes associated with cough; generalised allergic reactions; swelling in the mouth; 
blisters of the skin; skin allergy; inflammation of the mouth (stomatitis); decrease in blood pressure; 
confusion; hallucinations; joint pain; muscular pain; changes in the way things taste..

In addition, your doctor may identify changes in your blood or urine test results.

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 CLOPIDOGREL QUALIMED

Keep out of the reach and sight of children.
Do not use Clopidogrel Qualimed after the expiry date which is stated on the carton and blister after 
EXP. The expiry date refers to the last day of that month.

Store in the original package in order to protect from moisture and light.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

What Clopidogrel Qualimed contains
The active substance is clopidogrel. Each film-coated tablet contains 75 mg of clopidogrel (as 
hydrochloride).
The other ingredients are:

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- Tablet core: microcrystalline cellulose, colloidal anhydrous silica, crospovidone (type A), 
macrogol 6000, hydrogenated castor oil 

- Film-coating: hydroxypropylcellulose (E463), titanium dioxide (E171), red iron oxide (E172), 
talc and propylene glycol.

What Clopidogrel Qualimed looks like and contents of the pack
The film-coated tablets are pink, round and slightly convex.
Boxes of 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in blisters are available.
Boxes of 7, 14, 28, 56, 84 film-coated tablets in calendar blisters are available.
Boxes of 30x1 and 50x1 film-coated tablets in perforated unit dose blisters are available.

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Qualimed, 117 allee des Parcs, 69 800 Saint Priest, France

Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Mylan bvba/sprl
Tél/Tel: + 0032 2 658 61 00 

Luxembourg/Luxemburg
Mylan bvba/sprl
Tél/Tel: + 0032 2 658 61 00 (Belgium)

Bulgaria
Mylan SAS
Tel: +33 4 37 25 75 00 (France)

Hungary
Mylan Kft
Tel: 36 1 8026993

Ceská republika
MylanPharmaceuticals s.r.o.
Tel: +420 274 770 201

Malta
George Borg Barthet Ltd
Tel: +356 21244205

Danmark
Mylan ApS 
Tlf: + 45 3694 4568 

Nederland
Mylan B.V
Tel: + 31 (0)33 2997080

Deutschland
Mylan dura GmbH 
Tel: + 49-(0) 6151 9512 0

Norge
Mylan AB
Tlf: + 46 8-555 227 50 (Sverige)

Eesti
Mylan SAS
Tel: +33 4 37 25 75 00 (France)

Österreich
Arcana Arzneimittel GmbH
Tel: +43 1 416 24 18

Greece
Generics Pharma Hellas ΕΠΕ 
Τηλ:  +30 210 9936410

Polska
Mylan Sp.z.o.o
Tel: +48 22 5466400

España
Mylan Pharmaceuticals, S.L
tel: +  34 93 3786400

Portugal
Mylan, Lda.
Phone: + 00351 21 412 7200

France
Qualimed

România
Mylan SAS

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Tel: +33 4 37 25 75 00 Tel: +33 4 37 25 75 00 (France)

Ireland
Mc Dermott Laboratories Ltd 
Tel: + 1800 272 272 
Allphar +353 1 4041600

Slovenija
Mylan SAS
Tel: +33 4 37 25 75 00 (France)

Ísland
Actavis Group PTC ehf
Sími: + 354 5503300

Slovenská republika
Mylan sr.o
Tel: +421 2 32 604 901

Italia
Mylan S.p.A
Tel: + +39/02-61246921

Suomi/Finland
Mylan OY
Puh/Tel: + 358 9-46 60 03 

Cyprus
Pharmaceutical Trading Co Ltd
Τηλ: +35 7 24656165

Sverige
Mylan AB 
Tel: + 46 8-555 227 50

Latvija
Mylan SAS
Tel: +33 4 37 25 75 00 (France)

United Kingdom
Generics [UK] Ltd trading as Mylan
Tel: +44 1707 853000

Lietuva
Mylan SAS
Tel: +33 4 37 25 75 00 (France)

This leaflet was last approved in MM/YYYY.

Detailed information is available on the European Medicines Agency  website:
http://www.ema.europa.eu/

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A.	THE MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH RELEASE
	B.	CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET