Clopidogrel ratiopharm GmbH

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel ratiopharm GmbH 75 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 75 mg of clopidogrel (as besilate). 
Excipients with known effect: 
Each film-coated tablet contains 3.80 mg of hydrogenated castor oil. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
White to off-white, marbled, round and biconvex film-coated tablets.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Clopidogrel is indicated in adults for the secondary prevention of atherothrombotic events in: 
 

• Adult 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. 

 
• Adult patients suffering from acute coronary syndrome: 

- Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave 
myocardial infarction), including patients undergoing a stent placement following 
percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). 

- ST segment elevation acute myocardial infarction, in combination with ASA in 
medically treated patients eligible for thrombolytic therapy. 

 
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. 
 
In patients suffering from acute coronary syndrome: 
-  Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave 

myocardial infarction): clopidogrel treatment should be initiated with a single 300 mg loading 
dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg 
daily). Since higher doses of ASA were associated with higher bleeding risk it is recommended 
that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has 
not been formally established. Clinical trial data support use up to 12 months, and the 
maximum benefit was seen at 3 months (see section 5.1). 

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-  ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily 
dose of 75 mg initiated with a 300 mg loading dose in combination with ASA and with or 
without thrombolytics. For patients over 75 years of age clopidogrel should be initiated without 
a loading dose. Combined therapy should be started as early as possible after symptoms start 
and continued for at least four weeks. The benefit of the combination of clopidogrel with ASA 
beyond four weeks has not been studied in this setting (see section 5.1). 

 
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). 
 
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 listed in section 2 or section 

6.1. 
• 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 haematological adverse 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, or selective serotonin reuptake inhibitors (SSRIs), or other medicinal products 
associated with bleeding risk such as pentoxifylline (see section 4.5). 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 

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(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.  
 
Acquired haemophilia 
Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated 
activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired 
haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should 
be managed and treated by specialists, and clopidogrel should be discontinued. 
 
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 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).  
 
CYP2C8 substrates 
Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate 
medicinal products (see section 4.5). 
 
Cross-reactions among thienopyridines 
Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, 
ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see section 
4.8). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or 
haematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who had 
developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have 
an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for 
signs of hypersensitivity in patients with a known allergy to thienopyridines is advised. 
 
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). 
 
Excipient(s)  
 
Castor oil 
Clopidogrel ratiopharm GmbH contains hydrogenated castor oil which may cause stomach upset and 
diarrhoea.  
 

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4.5 Interaction with other medicinal products and other forms of interaction 
 
Medicinal products associated with bleeding risk: There is an increased risk of bleeding due to the 
potential additive effect. The concomitant administration of medicinal products associated with 
bleeding risk should be undertaken with caution (see section 4.4). 
 
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 who 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). 
 
SSRIs: since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant 
administration of SSRIs with clopidogrel should be undertaken with caution. 
 
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 precaution concomitant use of strong or moderate CYP2C19 inhibitors 
should be discouraged (see sections 4.4 and 5.2). 
 
Medicinal products that are strong or moderate CYP2C19 inhibitors include, for example, omeprazole 
and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, 
carbamazepine, and efavirenz. 
 
A significantly lower exposure to clopidogrel active metabolite and reduced platelet inhibition have 
been demonstrated in HIV-infected patients treated with ritonavir- or cobicistat-boosted anti-retroviral 

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therapies (ART). Although the clinical relevance of these findings is uncertain, there have been 
spontaneous reports of HIV-infected patients treated with boosted ART, who have experienced re-
occlusive events after de-obstruction or have suffered thrombotic events under a clopidogrel loading 
treatment schedule. Exposure of clopidogrel and average platelet inhibition can be decreased with 
concomitant use of ritonavir. Therefore, concomitant use of clopidogrel with boosted ART should be 
discouraged. 
 
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 esomeprazole 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 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. 
 
CYP2C8 substrate medicinal products: Clopidogrel has been shown to increase repaglinide exposure 
in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to 
inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased 
plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by 
CYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution (see section 4.4). 
 
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. 
 

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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. 
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).  
 
Breast-feeding 
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. 
 
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 
 
Summary of the safety profile 
 
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. 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 and 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. 
 
Tabulated list of adverse reactions 
 
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); not known (cannot be estimated from the available data). Within each system organ 
class, adverse reactions are presented in order of decreasing seriousness. 

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System Organ 
Class  

Common  Uncommon  Rare  Very rare, not 
known*  

Blood and the 
lymphatic 
system disorders  

 Thrombocytopenia, 
leucopenia, 
eosinophilia  

Neutropenia, 
including severe 
neutropenia  

Thrombotic 
thrombocytopenic 
purpura (TTP) (see 
section 4.4), aplastic 
anaemia, 
pancytopenia, 
agranulocytosis, 
severe 
thrombocytopenia, 
acquired haemophilia 
A, granulocytopenia, 
anaemia  

Cardiac 
disorders 

   Kounis syndrome 
(vasospastic allergic 
angina / allergic 
myocardial 
infarction) in the 
context of a 
hypersensitivity 
reaction due to 
clopidogrel* 

Immune system 
disorders  

   Serum sickness, 
anaphylactoid 
reactions, 
cross-reactive drug 
hypersensitivity 
among 
thienopyridines (such 
as ticlopidine, 
prasugrel) (see 
section 4.4)*, insulin 
autoimmune 
syndrome, which 
can lead to severe 
hypoglycemia, 
particularly in 
patients with HLA 
DRA4 subtype 
(more frequent in 
the Japanese 
population)* 

Psychiatric 
disorders  

   Hallucinations, 
confusion  

Nervous system 
disorders  

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

 Taste disturbances, 
ageusia  

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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, 
eosinophilic 
pneumonia  

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, 
erythema 
multiforme, acute 
generalised 
exanthematous 
pustulosis (AGEP)), 
angioedema, 
drug-induced 
hypersensitivity 
syndrome, drug rash 
with eosinophilia and 
systemic symptoms 
(DRESS), rash 
erythematous, or 
exfoliative, urticaria, 
eczema, lichen 
planus  

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Reproductive 
systems and 
breast disorders 

  Gynaecomastia  

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  

  

* Information related to clopidogrel with frequency “not known” 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
 
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: B01AC04.  
 
Mechanism of action 
 
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. 
 

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Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or 
subject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition. 
 
Pharmacodynamic effects 
 
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 
60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 
days after treatment was discontinued.  
 
Clinical efficacy and safety 
 
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 
1,000 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. 
 
Acute coronary syndrome 
 
The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome 
(unstable angina or non-Q-wave myocardial infarction), and presenting within 24 hours of onset of the 
most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to 
have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or 
T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading 
dose followed by 75 mg/day, N = 6,259) or placebo (N = 6,303), both given in combination with ASA 
(75-325 mg once daily) and other standard therapies. Patients were treated for up to one year. In 
CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins 

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were administered in more than 90% of the patients and the relative rate of bleeding between 
clopidogrel and placebo was not significantly affected by the concomitant heparin therapy.  
 
The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial 
infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the 
placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the 
clopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29% 
when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent 
and 10% when they underwent coronary artery bypass graft (CABG). New cardiovascular events 
(primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 
46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3, 3-6, 
6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit 
observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage 
persisted (see section 4.4).  
 
The use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy 
(RRR = 43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR = 18.2%; CI: 6.5%, 28.3%).  
 
The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory 
ischaemia) was 1,035 (16.5%) in the clopidogrel-treated group and 1,187 (18.8%) in the 
placebo-treated group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the 
clopidogrel-treated group. This benefit was mostly driven by the statistically significant reduction in 
the incidence of MI [287 (4.6%) in the clopidogrel treated group and 363 (5.8%) in the placebo treated 
group]. There was no observed effect on the rate of rehospitalisation for unstable angina.  
 
The results obtained in populations with different characteristics (e.g. unstable angina or non-Q-wave 
MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with 
the results of the primary analysis. In particular, in a post-hoc analysis in 2,172 patients (17% of the 
total CURE population) who underwent stent placement (Stent-CURE), the data showed that 
clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for 
the co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the second 
co-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of 
clopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this 
subset are in line with the overall trial results. 
 
The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular 
therapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering medicinal products, beta 
blockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of 
ASA (75-325 mg once daily).  
 
In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been 
evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.  
 
The CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation 
MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, 
followed by 75 mg/day, n=1752) or placebo (n=1,739), both in combination with ASA (150 to 325 mg 
as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin. 
The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of 
an occluded infarct-related artery on the predischarge angiogram, or death or recurrent MI before 
coronary angiography. For patients who did not undergo angiography, the primary endpoint was death 
or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient population included 
19.7% women and 29.2% patients ≥ 65 years. A total of 99.7% of patients received fibrinolytics 
(fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta blockers, 54.7% ACE 
inhibitors and 63% statins. 
 
Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached 
the primary endpoint, representing an absolute reduction of 6.7% and a 36% odds reduction in favour 

12 



of clopidogrel (95% CI: 24, 47%; p< 0.001), mainly related to a reduction in occluded infarct-related 
arteries. This benefit was consistent across all prespecified subgroups including patients’ age and 
gender, infarct location, and type of fibrinolytic or heparin used. 
 
The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the 
onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST 
depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or 
placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. 
The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke 
or death. The population included 27.8% women, 58.4% patients ≥ 60 years (26% ≥ 70 years) and 
54.5% patients who received fibrinolytics. 
 
Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the 
relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002), representing an 
absolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and 
with or without fibrinolytics, and was observed as early as 24 hours. 
 
De-escalation of P2Y12 Inhibitor Agents in ACS  
Switching from a more potent P2Y12 receptor inhibitor to clopidogrel in association with aspirin after 
acute phase in ACS has been evaluated in two randomized investigator-sponsored studies (ISS) – 
TOPIC and TROPICAL-ACS – with clinical outcome data. 
 
The clinical benefit provided by the more potent P2Y12 inhibitors, ticagrelor and prasugrel, in their 
pivotal studies is related to a significant reduction in recurrent ischaemic events (including acute and 
subacute stent thrombosis (ST), myocardial infarction (MI), and urgent revascularization). Although 
the ischaemic benefit was consistent throughout the first year, greater reduction in ischaemic 
recurrence after ACS was observed during the initial days following the treatment initiation. In 
contrast, post-hoc analyses demonstrated statistically significant increases in the bleeding risk with the 
more potent P2Y12 inhibitors, occurring predominantly during the maintenance phase, after the first 
month post-ACS. TOPIC and TROPICAL-ACS were designed to study how to mitigate the bleeding 
events while maintaining efficacy. 
 
TOPIC (Timing Of Platelet Inhibition after acute Coronary syndrome) 
This randomized, open-label trial included ACS patients requiring PCI. Patients on aspirin and a more 
potent P2Y12 blocker and without adverse event at one month were assigned to switch to fixed-dose 
aspirin plus clopidogrel (de-escalated dual antiplatelet therapy (DAPT)) or continuation of their drug 
regimen (unchanged DAPT). 
 
Overall, 645 of 646 patients with STEMI or NSTEMI or unstable angina were analyzed (de-escalated 
DAPT (n=322); unchanged DAPT (n=323)). Follow-up at one year was performed for 316 patients 
(98.1%) in the de-escalated DAPT group and 318 patients (98.5%) in the unchanged DAPT group. 
The median follow-up for both groups was 359 days. The characteristics of the studied cohort were 
similar in the 2 groups. 
 
The primary outcome, a composite of cardiovascular death, stroke, urgent revascularization, and 
BARC (Bleeding Academic Research Consortium) bleeding ≥2 at 1 year post ACS, occurred in 
43 patients (13.4%) in the de-escalated DAPT group and in 85 patients (26.3%) in the unchanged 
DAPT group (p<0.01). This statistically significant difference was mainly driven by fewer bleeding 
events, with no difference reported in ischaemic endpoints (p=0.36), while BARC ≥2 bleeding 
occurred less frequently in the de-escalated DAPT group (4.0%) versus 14.9% in the unchanged 
DAPT group (p<0.01). Bleeding events defined as all BARC occurred in 30 patients (9.3%) in the 
de-escalated DAPT group and in 76 patients (23.5%) in the unchanged DAPT group (p<0.01). 
 
TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment 
for Acute Coronary Syndromes) 
This randomized, open-label trial included 2,610 biomarker-positive ACS patients after successful 
PCI. Patients were randomized to receive either prasugrel 5 or 10 mg/d (Days 0-14) (n=1309), or 

13 



prasugrel 5 or 10 mg/d (Days 0-7) then de-escalated to clopidogrel 75 mg/d (Days 8-14) (n=1309), in 
combination with ASA (<100 mg/day). At Day 14, platelet function testing (PFT) was performed. The 
prasugrel-only patients were continued on prasugrel for 11.5 months.  
 
The de-escalated patients underwent high platelet reactivity (HPR) testing. If HPR≥46 units, the 
patients were escalated back to prasugrel 5 or 10 mg/d for 11.5 months; if HPR<46 units, the patients 
continued on clopidogrel 75 mg/d for 11.5 months. Therefore, the guided de-escalation arm had 
patients on either prasugrel (40%) or clopidogrel (60%). All patients were continued on aspirin and 
were followed for one year.  
 
The primary endpoint (the combined incidence of CV death, MI, stroke and BARC bleeding grade ≥2 
at 12 months) was met showing non-inferiority. Ninety five patients (7%) in the guided de-escalation 
group and 118 patients (9%) in the control group (p non-inferiority=0.0004) had an event. The guided 
de-escalation did not result in an increased combined risk of ischemic events (2.5% in the de-
escalation group vs 3.2% in the control group; p non-inferiority=0.0115), nor in the key secondary 
endpoint of BARC bleeding ≥2 ((5%) in the de-escalation group versus 6% in the control group 
(p=0.23)). The cumulative incidence of all bleeding events (BARC class 1 to 5) was 9% (114 events) 
in the guided de-escalation group versus 11% (137 events) in the control group (p=0.14). 
 
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 
clopidogrel 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. 
 
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 

14 



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. 
 
Biotransformation 
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. The active metabolite is formed mostly by 
CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and 
CYP3A4. 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 half-life 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 
(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 

15 



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, ACTIVE-A 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 
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. 
 

16 



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: 
Macrogol 6000 
Cellulose, microcrystalline (E460) 
Crospovidone type A 
Castor oil, hydrogenated 
 
Film-coating: 
Macrogol 6000 
Ethylcellulose (E462) 
Titanium dioxide (E 171) 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
Do not store above 30 °C. 
 
Store in the original blister in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Alu/Alu blisters containing 7, 14, 28, 30, 50, 84, 90 and 100 film-coated tablets packed in cardboard 
cartons. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
No special requirements 
 
 
7. MARKETING AUTHORISATION HOLDER 

17 



 
Archie Samuel s.r.o. 
Slunná 16 
61700 Brno 
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/541/001 - Cartons of 14 film-coated tablets in Alu/Alu blisters 
EU/1/09/541/002 - Cartons of 28 film-coated tablets in Alu/Alu blisters 
EU/1/09/541/003 - Cartons of 30 film-coated tablets in Alu/Alu blisters 
EU/1/09/541/004 - Cartons of 50 film-coated tablets in Alu/Alu blisters 
EU/1/09/541/005 - Cartons of 84 film-coated tablets in Alu/Alu blisters 
EU/1/09/541/006 - Cartons of 90 film-coated tablets in Alu/Alu blisters 
EU/1/09/541/007 - Cartons of 100 film-coated tablets in Alu/Alu blisters 
EU/1/09/541/008 - Cartons of 7 film-coated tablets in Alu/Alu blisters 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 28 July 2009 
Date of latest renewal: 22 May 2014 
 
 
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/ 

  

18 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

19 



A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Merckle GmbH 
Ludwig-Merckle-Strasse 3 
89143 Blaubeuren 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
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. 
 
Periodic Safety Update Reports 
At the time of granting the marketing authorisation, the submission of periodic safety update reports is 
not required for this medicinal product. However, the marketing authorisation holder shall submit 
periodic safety update reports for this medicinal product if the product is included in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 
published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Risk Management Plan (RMP) 
Not applicable. 
The application is based on a reference medicinal product for which no safety concerns requiring 
additional risk minimisation activities have been identified. 
 
  

20 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  

21 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  

22 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel ratiopharm GmbH 75 mg film-coated tablets  
clopidogrel 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 75 mg of clopidogrel (as besilate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains hydrogenated castor oil. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
7 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
50 film-coated tablets 
84 film-coated tablets 
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 SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 

23 



 
Do not store above 30 °C. 
 
Store in the original blister in order to protect from moisture. 
 
 
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 
 
Archie Samuel s.r.o. 
Slunná 16 
61700 Brno 
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/541/001  - 14 film-coated tablets 
EU/1/09/541/002  - 28 film-coated tablets 
EU/1/09/541/003  - 30 film-coated tablets 
EU/1/09/541/004  - 50 film-coated tablets 
EU/1/09/541/005  - 84 film-coated tablets 
EU/1/09/541/006  - 90 film-coated tablets 
EU/1/09/541/007  - 100 film-coated tablets 
EU/1/09/541/008  - 7 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 
 
Clopidogrel ratiopharm GmbH 75 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 

24 



18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 

25 



 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel ratiopharm GmbH 75 mg film-coated tablets 
clopidogrel 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Archie Samuel s.r.o. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. OTHER 
 
 

26 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

27 



 
Package leaflet: Information for the user 

 
Clopidogrel ratiopharm GmbH 75 mg film-coated tablets 

clopidogrel  
 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or your pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
1. What Clopidogrel ratiopharm GmbH is and what it is used for 
2. What you need to know before you take Clopidogrel ratiopharm GmbH 
3. How to take Clopidogrel ratiopharm GmbH 
4. Possible side effects 
5.  How to store Clopidogrel ratiopharm GmbH 
6. Contents of the pack and other information 
 
 
1. What Clopidogrel ratiopharm GmbH is and what it is used for 
 
Clopidogrel ratiopharm GmbH contains the active ingredient Clopidogrel which belongs to a group of 
medicines called antiplatelet medicinal products. Platelets (so-called thrombocytes) are very small 
structures, 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 ratiopharm GmbH is taken by adults 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 ratiopharm GmbH 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 (disturbed blood flow in arms or legs caused by vascular 
occlusions) or 

- You have experienced a severe type of chest pain known as ‘unstable angina’ or ‘myocardial 
infarction’ (heart attack). For the treatment of this condition your doctor may have placed a 
stent in the blocked or narrowed artery to restore effective blood flow. You should also be 
given acetylsalicylic acid (a substance present in many medicines used to relieve pain and 
lower fever as well as to prevent blood clotting) by your doctor. 

 
 
2. What you need to know before you take Clopidogrel ratiopharm GmbH 
 
Do not take Clopidogrel ratiopharm GmbH 
• If you are allergic to clopidogrel or any of the other ingredients of this medicine (listed in 

section 6). 
• 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. 
 

28 



 
If you think any of these apply to you, or if you are in any doubt at all, consult your doctor before 
taking Clopidogrel ratiopharm GmbH. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Clopidogrel ratiopharm GmbH: 
• if you have a risk of bleeding such as 

-  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 
• if you have had an allergy or reaction to any medicine used to treat your disease 
 
While you are taking Clopidogrel ratiopharm GmbH: 
• 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. 
 
Children and adolescents 
Do not give this medicine to children because it does not work. 
 
Other medicines and Clopidogrel ratiopharm GmbH 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  
Some other medicines may influence the use of Clopidogrel ratiopharm GmbH or vice versa.  
 
You should specifically tell your doctor if you take 
- medicines that may increase your risk of bleeding such as: 

o oral anticoagulants, medicines used to reduce blood clotting, 
o a non-steroidal anti-inflammatory medicine, usually used to treat painful and/or 

inflammatory conditions of muscle or joints 
o heparin or any other injectable medicine used to reduce blood clotting 
o ticlopidine, other antiplatelet agent, 
o a selective serotonin reuptake inhibitor (including but not restricted to fluoxetine or 

fluvoxamine), medicines usually used to treat depression, 
- omeprazole or esomeprazole, medicines to treat upset stomach 
- fluconazole or voriconazole medicines to treat fungal infections 
- efavirenz, a medicine to treat HIV (human immunodeficiency virus) infections, 
- anti-retroviral medicines (medicines to treat HIV infections), 
- carbamazepine, a medicine to treat some forms of epilepsy 
- moclobemide, medicine to treat depression, 
- repaglinide, medicine to treat diabetes, 
- paclitaxel, medicine to treat cancer. 

29 



 
 
If you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed 
Clopidogrel ratiopharm GmbH in combination with acetylsalicylic acid, a substance present in many 
medicines used to relieve pain and lower fever. An occasional use of acetylsalicylic acid (no more 
than 1,000 mg in any 24 hour period) should generally not cause a problem, but prolonged use in other 
circumstances should be discussed with your doctor. 
 
Clopidogrel ratiopharm GmbH with food and drink 
Clopidogrel ratiopharm GmbH 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 ratiopharm GmbH. If you become pregnant while taking 
Clopidogrel ratiopharm GmbH, consult your doctor immediately as it is recommended not to take 
clopidogrel while you are pregnant. 
 
You should not breast-feed while taking this medicine. 
If you are breast-feeding or planning to breast-feed, talk to your doctor before taking this medicine. 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
Clopidogrel ratiopharm GmbH is unlikely to affect your ability to drive or to use machines. 
 
Clopidogrel ratiopharm GmbH contains hydrogenated castor oil 
This may cause stomach upset or diarrhoea. 
 
 
3.  How to take Clopidogrel ratiopharm GmbH 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
If you have experienced severe chest pain (unstable angina or heart attack), your doctor may give you 
300 mg of Clopidogrel ratiopharm GmbH (4 tablets of 75 mg) once at the start of treatment. Then, the 
recommended dose is one 75 mg tablet of Clopidogrel ratiopharm GmbH per day to be taken orally 
with or without food, and at the same time each day. 
 
You should take Clopidogrel ratiopharm GmbH for as long as your doctor continues to prescribe it. 
 
If you take more Clopidogrel ratiopharm GmbH 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 ratiopharm GmbH 
If you forget to take a dose of Clopidogrel ratiopharm GmbH, but remember within 12 hours of your 
usual time, take your tablet straight away 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.  
 
If you stop taking Clopidogrel ratiopharm GmbH 
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 medicine, ask your doctor or pharmacist. 

30 



 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Contact your doctor immediately if you experience: 

- 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 ‘Warnings and precautions’).  

- 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 reported with clopidogrel 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 ratiopharm GmbH.  
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 2 ‘Warnings and precautions’). 
 
Other side effects are:  
 
-Common side effects (may affect up to 1 in 10 people):  
Diarrhoea, abdominal pain, indigestion or heartburn.  
 
-Uncommon side effects (may affect up to 1 in 100 people):  
Headache, stomach ulcer, vomiting, nausea, constipation, excessive gas in stomach or intestines, 
rashes, itching, dizziness, sensation of tingling and numbness. 
 
-Rare side effect (may affect up to 1 in 1,000 people):  
Vertigo, enlarged breasts in males.  
 
-Very rare side effects (may affect up to 1 in 10,000 people):  
Jaundice; severe abdominal pain with or without back pain; fever, breathing difficulties sometimes 
associated with cough; generalised allergic reactions (for example, overall sensation of heat with 
sudden general discomfort until fainting); swelling in the mouth; blisters of the skin; skin allergy; sore 
mouth (stomatitis); decrease in blood pressure; confusion; hallucinations; joint pain; muscular pain; 
changes in taste or loss of taste of food. 
 
Side effects with frequency not known (frequency cannot be estimated from the available data): 
Hypersensitivity reactions with chest or abdominal pain, persistent low blood sugar symptoms. 
 
In addition, your doctor may identify changes in your blood or urine test results. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 

31 



 
5. How to store Clopidogrel ratiopharm GmbH 
 
Do not store above 30 °C. 
 
Store in the original blister in order to protect from moisture. 
 
Keep this medicine out of the sight and reach of children.  
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not use Clopidogrel ratiopharm GmbH if you notice any visible sign of damage of blister or 
film-coated tablets. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment.  
 
 
6. Contents of the pack and other information 
 
What Clopidogrel ratiopharm GmbH contains 
The active substance is clopidogrel. Each tablet contains 75 mg of clopidogrel (as besilate). 
 
The other ingredients are (see section 2 ‘Clopidogrel ratiopharm GmbH contains hydrogenated castor 
oil’): 
 
Tablet core: 
Macrogol 6000 
Cellulose, microcrystalline (E460) 
Crospovidone type A 
Castor oil, hydrogenated 
 
Film-coating: 
Macrogol 6000 
Ethylcellulose (E462) 
Titanium dioxide (E 171) 
 
What Clopidogrel ratiopharm GmbH looks like and contents of the pack  
 
Clopidogrel ratiopharm GmbH 75 mg film-coated tablets are white to off-white, marbled, round and 
biconvex. They are supplied in cardboard cartons containing 7, 14, 28, 30, 50, 84, 90 and 100 tablets 
in aluminium blisters. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder  
 
Archie Samuel s.r.o. 
Slunná 16 
61700 Brno 
Czech Republic 
 
Manufacturer 
 
Merckle GmbH 
Ludwig-Merckle-Strasse 3 
89143 Blaubeuren 
Germany 
 

32 



 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Teva Pharma Belgium N.V./S.A./AG 
Tel/Tél: +32 3 820 73 73 
 

Lietuva 
UAB "Sicor Biotech" 
Tel: +370 5 266 02 03 
 

България 
Актавис ЕАД 
Тел: +359 24899585 
 

Luxembourg/Luxemburg 
ratiopharm GmbH 
Allemagne/Deutschland 
Tél/Tel: +49 731 402 02 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251 007 111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel.: +36 1 288 64 00 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44 98 55 11 
 

Malta 
Teva Pharmaceuticals Ireland 
L-Irlanda 
Tel: +353 1963 0330 
 

Deutschland 
ratiopharm GmbH 
Tel: +49 731 402 02 
 

Nederland 
Teva Nederland B.V. 
Tel: +31 800 0228 400 
 

Eesti 
Teva Eesti esindus 
UAB Sicor Biotech Eesti filiaal 
Tel: +372 661 0801 
 

Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 
 

Ελλάδα 
Teva Ελλάς Α.Ε. 
Τηλ: +30 211 880 5000 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1 97 007 0 
 

España 
ratiopharm España, S.A. 
Tél: +34 91 567 29 70 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel.: +48 22 345 93 00 
 

France 
Teva Santé 
Tél: +33 1 55 91 78 00 
 

Portugal 
Teva Pharma - Produtos Farmacêuticos, Lda 
Tel: +351 21 476 75 50 
 

Hrvatska 
Pliva Hrvatska d.o.o 
Tel: +385 1 37 20 000 
 

România 
Teva Pharmaceuticals S.R.L 
Tel: +4021 230 65 24 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 1963 0330 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 
 

Ísland 
ratiopharm Oy 
Finnland 
Sími: +358 20 180 5900 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o. 
Tel: +421 2 57 26 79 11 
 

Italia 
Teva Italia S.r.l. 

Suomi/Finland 
ratiopharm Oy 

33 



 
Tel: +39 02 89 17 98 1 
 

Puh/Tel: +358 20 180 5900 
 

Κύπρος 
Teva Ελλάς Α.Ε., Ελλάδα 
Τηλ: +30 211 880 5000 
 

Sverige 
Teva Sweden AB 
Tel: +46 42 12 11 00 
 

Latvija 
UAB Sicor Biotech filiāle Latvijā 
Tel: +371 67 323 666 
 

United Kingdom 
Teva UK Limited 
Tel: +44 1977 628500 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu/ 

34 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET