Clopidogrel BMS

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel BMS 75 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 75 mg of clopidogrel (as hydrogen sulphate). 
Excipients: each tablet contains 3 mg lactose and 3.3 mg hydrogenated castor oil. 
 
For a full list of excipients, see section 6.1. 
 
 
3.  PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Pink, round, biconvex, engraved with «75» on one side and «1171» on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Clopidogrel is indicated in adults for the prevention of atherothrombotic events in: 
 
• 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. 
 
• 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 
 
• Adults and elderly 
 

Clopidogrel should be given as a single daily dose of 75 mg with or without food.  
 
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). 

- 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 



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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). 

 
• Pharmacogenetics 

CYP2C19 poor metaboliser status is associated with diminished response to clopidogrel. The 
optimal dose regimen for poor metabolisers has yet to be determined (see section 5.2). 
 

• Paediatric patients 
The safety and efficacy of clopidogrel in children and adolescents have not yet been established. 

 
• 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). 

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

 
4.4 Special warnings and precautions for use 

 
Due to the risk of bleeding and haematological undesirable effects, 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) 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. 
 
In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute 
ischaemic stroke. 
 



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Pharmacogenetics: Based on literature data, patients with genetically reduced CYP2C19 function have 
lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses, 
and generally exhibit higher cardiovascular event rates following myocardial infarction than do 
patients with normal CYP2C19 function (see section 5.2). 
 
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs that inhibit 
the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite 
of clopidogrel and a reduction in clinical efficacy. Concomitant use of drugs that inhibit CYP2C19 
should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).  
Although the evidence of CYP2C19 inhibition varies within the class of Proton Pump Inhibitors, 
clinical studies suggest an interaction between clopidogrel and possibly all members of this class. 
Therefore, concomitant use of Proton Pump Inhibitors should be avoided unless absolutely necessary. 
There is no evidence that other drugs that reduce stomach acid such as H2 blockers or antacids 
interfere with antiplatelet activity of clopidogrel. 
 
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). 
 
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). 
 
Clopidogrel BMS contains lactose. Patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 
 
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). 
 
Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who may be at risk 
of increased bleeding from trauma, surgery or other pathological conditions that 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) 
 



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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 drugs that inhibit 
the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite 
of clopidogrel and a reduction in clinical efficacy. Concomitant use of drugs that inhibit CYP2C19  
should be discouraged (see sections 4.4 and 5.2). 
 
Drugs that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, 
moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, 
oxcarbazepine and chloramphenicol. 
 
Proton Pump Inhibitors: 
Although the evidence of CYP2C19 inhibition varies within the class of Proton Pump Inhibitors, 
clinical studies suggest an interaction between clopidogrel and possibly all members of this class. 
Therefore, concomitant use of Proton Pump Inhibitors should be avoided unless absolutely necessary. 
There is no evidence that other drugs that reduce stomach acid such as H2 blockers or antacids 
interfere with antiplatelet activity of clopidogrel. 
 
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 co-administration of 
phenobarbital, cimetidine, 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 studies with human liver microsomes indicated that the carboxylic acid metabolite of 
clopidogrel could inhibit the activity of Cytochrome P450 2C9. This could potentially lead to increased 
plasma levels of medicinal products such as phenytoin and tolbutamide and the NSAIDs, which are 
metabolised by Cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin and 
tolbutamide 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 Pregnancy and lactation 
 
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). 
 



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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 BMS.  
 
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. 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 1.4% for clopidogrel and 1.6% for ASA. 
 
In CURE, the major bleeding event rate for clopidogrel+ASA was dose-dependent on ASA (<100mg: 
2.6%; 100-200mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for placebo+ASA 
(<100mg: 2.0%; 100-200mg: 2.3%; >200mg: 4.0%). The risk of bleeding (life-threatening, major, 
minor, other) decreased during the course of the trial: 0-1 months (clopidogrel: 9.6%; placebo: 6.6%), 
1-3 months (clopidogrel: 4.5%; placebo: 2.3%), 3-6 months (clopidogrel: 3.8%; placebo: 1.6%), 
6-9 months (clopidogrel: 3.2%; placebo: 1.5%), 9-12 months (clopidogrel: 1.9%; placebo: 1.0%). 
There was no excess in major bleeds with clopidogrel + ASA within 7 days after coronary bypass graft 
surgery in patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel+ASA 
vs. 5.3% placebo+ASA). In patients who remained on therapy within five days of bypass graft surgery, 
the event rate was 9.6% for clopidogrel+ASA, and 6.3% for placebo+ASA. 
 
In CLARITY, there was an overall increase in bleeding in the clopidogrel + ASA group (17.4%) vs. 
the placebo + ASA group (12.9%).The incidence of major bleeding was similar between groups (1.3% 
versus 1.1% for the clopidogrel + ASA and the placebo + ASA groups, respectively). 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 (0.6% versus 0.5% in the clopidogrel + ASA and the placebo + ASA groups, 
respectively). 
 
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 drug reactions are presented in order of 
decreasing seriousness. 
 



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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), 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 



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System Organ 
Class 

Common Uncommon Rare Very rare 

Skin and 
subcutaneous tissue 
disorders 

Bruising Rash, pruritus, skin 
bleeding (purpura) 

 Bullous dermatitis 
(toxic epidermal 
necrolysis, Stevens 
Johnson Syndrome, 
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 other drugs, 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 



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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. 
 
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 
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 



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(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=1,752) 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 favor 
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 



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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. 
 
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. 
 
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 
Several polymorphic CYP450 enzymes activate clopidogrel. 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 correspond to reduced metabolism. The 
CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced function alleles in whites and 99% in 
Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but 
these are less frequent in the general population. Published frequencies for the common CYP2C19 
phenotypes and genotypes are listed in the table below.  
 



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CYP2C19 Phenotype and Genotype Frequency 

    Frequency (%) 

 White (n=1356) Black (n=966) Chinese (n=573) 

Extensive metabolism: CYP2C19*1/*1  74  66  38  

Intermediate metabolism: CYP2C19*1/*2 or *1/*3  26  29  50  

Poor metabolism: CYP2C19*2/*2, *2/*3 or *3/*3  2  4  14  

 
To date, the impact of CYP2C19 genotype on the pharmacokinetics of the active metabolite of 
clopidogrel has been evaluated in 227 subjects from 7 reported studies. Reduced CYP2C19 
metabolism in intermediate and poor metabolisers decreased the Cmax and AUC of the active metabolite 
by 30-50% following 300- or 600-mg loading doses and 75-mg maintenance doses. Lower active 
metabolite exposure results in less platelet inhibition or higher residual platelet reactivity. To date, 
diminished antiplatelet responses to clopidogrel have been described for intermediate and poor 
metabolisers in 21 reported studies involving 4,520 subjects. The relative difference in antiplatelet 
response between genotype groups varies across studies depending on the method used to evaluate 
response, but is typically greater than 30%. 
 
The association between CYP2C19 genotype and clopidogrel treatment outcome was evaluated in 2 
post hoc clinical trial analyses (substudies of CLARITY [n=465] and TRITON-TIMI 38 [n=1,477]) 
and 5 cohort studies (total n=6,489). In CLARITY and one of the cohort studies (n=765; Trenk), 
cardiovascular event rates did not differ significantly by genotype. In TRITON-TIMI 38 and 3 of the 
cohort studies (n= 3,516; Collet, Sibbing, Giusti), patients with an impaired metaboliser status 
(intermediate and poor combined) had a higher rate of cardiovascular events (death, myocardial 
infarction, and stroke) or stent thrombosis compared to extensive metabolisers. In the fifth cohort study 
(n=2,208; Simon), the increased event rate was observed only in poor metabolisers. 
 
Pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity. 
 
There may be genetic variants of other CYP450 enzymes with effects on the ability to form the active 
metabolite of clopidogrel. 
 
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. 
 



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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 
 
Core: 

Mannitol (E421) 
Macrogol 6000 
Microcrystalline cellulose 
Hydrogenated castor oil 
Low substituted hydroxypropylcellulose 

 
Coating: 

Hypromellose (E464) 
Lactose 
Triacetin (E1518) 
Titanium dioxide (E171) 
Red iron oxide (E172) 
 

Polishing agent: 
Carnauba wax 

 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf-life 
 
3 years 
 
6.4 Special precautions for storage 
 



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In PVC/PVDC/aluminium blisters, store below 30°C. 
In all aluminium blisters, this medicinal product does not require any special storage conditions. 
 
6.5 Nature and content of container 
 
PVC/PVDC/Aluminium blisters or all aluminium blisters in cardboard cartons containing 7, 14, 28, 30, 
84, 90 and 100 film-coated tablets. 
 
PVC/PVDC/Aluminium or all aluminium perforated unit-dose blister packs in cardboard cartons 
containing 50x1 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bristol Myers Squibb Pharma EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH 
United Kingdom 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/08/464/001 - Cartons of 14 film-coated tablets in PVC/PVDC/Alu blisters 
EU/1/08/464/002 - Cartons of 14 film-coated tablets in all aluminium blisters 
EU/1/08/464/003 - Cartons of 28 film-coated tablets in PVC/PVDC/Alu blisters 
EU/1/08/464/004 - Cartons of 28 film-coated tablets in all aluminium blisters 
EU/1/08/464/005 - Cartons of 30 film-coated tablets in PVC/PVDC/Alu blisters 
EU/1/08/464/006 - Cartons of 30 film-coated tablets in all aluminium blisters 
EU/1/08/464/007 - Cartons of 50x1 film-coated tablets in PVC/PVDC/Alu blisters 
EU/1/08/464/008 - Cartons of 50x1 film-coated tablets in all aluminium blisters 
EU/1/08/464/009 - Cartons of 84 film-coated tablets in PVC/PVDC/Alu blisters 
EU/1/08/464/010 - Cartons of 84 film-coated tablets in all aluminium blisters 
EU/1/08/464/011 - Cartons of 90 film-coated tablets in PVC/PVDC/Alu blisters 
EU/1/08/464/012 - Cartons of 90 film-coated tablets in all aluminium blisters 
EU/1/08/464/013 - Cartons of 100 film-coated tablets in PVC/PVDC/Alu blisters 
EU/1/08/464/014 - Cartons of 100 film-coated tablets in all aluminium blisters 
EU/1/08/464/018 - Cartons of 7 film-coated tablets in PVC/PVDC/Alu blisters 
EU/1/08/464/019 - Cartons of 7 film-coated tablets in all aluminium blisters 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 16 July 2008  
 
 
10. DATE OF REVISION OF THE TEXT  
 
Detailed information on this product is available on the website of the European Medicines Agency 
(EMEA): http://www.emea.europa.eu/  

http://www.emea.europa.eu/


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1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel BMS 300 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 300 mg of clopidogrel (as hydrogen sulphate). 
Excipients: each tablet contains 12 mg lactose and 13.2 mg hydrogenated castor oil.  
 
For a full list of excipients, see section 6.1. 
 
 
3.  PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Pink, oblong, engraved with «300» on one side and «1332» on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Clopidogrel is indicated in adults for the prevention of atherothrombotic events in: 
 
• 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. 
 
• 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 
 
• Adults and elderly 

 
This 300 mg tablet of clopidogrel is intended for use as a loading dose 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). 

− 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 



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combination of clopidogrel with ASA beyond four weeks has not been studied in this 
setting (see section 5.1). 
 

For the maintenance dose, clopidogrel should be given as a single daily dose of 75 mg with or 
without food. For this dose, tablets containing 75 mg are available.  

 
• Pharmacogenetics 

CYP2C19 poor metaboliser status is associated with diminished response to clopidogrel. The 
optimal dose regimen for poor metabolisers has yet to be determined (see section 5.2). 

 
• Paediatric patients 
 The safety and efficacy of clopidogrel in children and adolescents have not yet been established. 
 
• 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). 

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

 
4.4 Special warnings and precautions for use 

 
Due to the risk of bleeding and haematological undesirable effects, 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) 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. 
 
In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute 
ischaemic stroke. 



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Pharmacogenetics: Based on literature data, patients with genetically reduced CYP2C19 function have 
lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses, 
and generally exhibit higher cardiovascular event rates following myocardial infarction than do 
patients with normal CYP2C19 function (see section 5.2). 
 
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs that inhibit 
the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite 
of clopidogrel and a reduction in clinical efficacy. Concomitant use of drugs that inhibit CYP2C19 
should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).  
Although the evidence of CYP2C19 inhibition varies within the class of Proton Pump Inhibitors, 
clinical studies suggest an interaction between clopidogrel and possibly all members of this class. 
Therefore, concomitant use of Proton Pump Inhibitors should be avoided unless absolutely necessary. 
There is no evidence that other drugs that reduce stomach acid such as H2 blockers or antacids 
interfere with antiplatelet activity of clopidogrel. 
 
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). 
 
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). 
 
Clopidogrel BMS contains lactose. Patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 
 
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). 
 
Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who may be at risk 
of increased bleeding from trauma, surgery or other pathological conditions that 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) 
 



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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 drugs that inhibit 
the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite 
of clopidogrel and a reduction in clinical efficacy. Concomitant use of drugs that inhibit CYP2C19 
should be discouraged (see sections 4.4 and 5.2). 
 
Drugs that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, 
moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, 
oxcarbazepine and chloramphenicol. 
 
Proton Pump Inhibitors: 
Although the evidence of CYP2C19 inhibition varies within the class of Proton Pump Inhibitors, 
clinical studies suggest an interaction between clopidogrel and possibly all members of this class. 
Therefore, concomitant use of Proton Pump Inhibitors should be avoided unless absolutely necessary. 
There is no evidence that other drugs that reduce stomach acid such as H2 blockers or antacids 
interfere with antiplatelet activity of clopidogrel. 
 
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 co-administration of 
phenobarbital, cimetidine 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 studies with human liver microsomes indicated that the carboxylic acid metabolite of 
clopidogrel could inhibit the activity of Cytochrome P450 2C9. This could potentially lead to increased 
plasma levels of medicinal products such as phenytoin and tolbutamide and the NSAIDs, which are 
metabolised by Cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin and 
tolbutamide 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 Pregnancy and lactation 
 
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). 
 



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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 BMS. 
 
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. 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 1.4% for clopidogrel and 1.6% for ASA. 
 
In CURE, the major bleeding event rate for clopidogrel+ASA was dose-dependent on ASA (<100mg: 
2.6%; 100-200mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for placebo+ASA 
(<100mg: 2.0%; 100-200mg: 2.3%; >200mg: 4.0%). The risk of bleeding (life-threatening, major, 
minor, other) decreased during the course of the trial: 0-1 months (clopidogrel: 9.6%; placebo: 6.6%), 
1-3 months (clopidogrel: 4.5%; placebo: 2.3%), 3-6 months (clopidogrel: 3.8%; placebo: 1.6%), 
6-9 months (clopidogrel: 3.2%; placebo: 1.5%), 9-12 months (clopidogrel: 1.9%; placebo: 1.0%). 
There was no excess in major bleeds with clopidogrel + ASA within 7 days after coronary bypass graft 
surgery in patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel+ASA 
vs. 5.3% placebo+ASA). In patients who remained on therapy within five days of bypass graft surgery, 
the event rate was 9.6% for clopidogrel+ASA, and 6.3% for placebo+ASA. 
 
In CLARITY, there was an overall increase in bleeding in the clopidogrel + ASA group (17.4%) vs. 
the placebo + ASA group (12.9%).The incidence of major bleeding was similar between groups (1.3% 
versus 1.1% for the clopidogrel + ASA and the placebo + ASA groups, respectively). 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 (0.6% versus 0.5% in the clopidogrel + ASA and the placebo + ASA groups, 
respectively). 
 
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 drug reactions are presented in order of 
decreasing seriousness. 
 



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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), 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 



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System Organ 
Class 

Common Uncommon Rare Very rare 

Skin and 
subcutaneous tissue 
disorders 

Bruising Rash, pruritus, skin 
bleeding (purpura) 

 Bullous dermatitis 
(toxic epidermal 
necrolysis, Stevens 
Johnson Syndrome, 
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 other drugs, 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 



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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. 
 
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 
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 



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(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=1,752) 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 favor 
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 



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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. 
 
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. 
 
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 
Several polymorphic CYP450 enzymes activate clopidogrel. 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 correspond to reduced metabolism. The 
CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced function alleles in whites and 99% in 
Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but 
these are less frequent in the general population. Published frequencies for the common CYP2C19 
phenotypes and genotypes are listed in the table below.  
 



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CYP2C19 Phenotype and Genotype Frequency 

    Frequency (%) 

 White (n=1356) Black (n=966) Chinese (n=573) 

Extensive metabolism: CYP2C19*1/*1  74  66  38  

Intermediate metabolism: CYP2C19*1/*2 or *1/*3  26  29  50  

Poor metabolism: CYP2C19*2/*2, *2/*3 or *3/*3  2  4  14  

 
To date, the impact of CYP2C19 genotype on the pharmacokinetics of the active metabolite of 
clopidogrel has been evaluated in 227 subjects from 7 reported studies. Reduced CYP2C19 
metabolism in intermediate and poor metabolisers decreased the Cmax and AUC of the active metabolite 
by 30-50% following 300- or 600-mg loading doses and 75-mg maintenance doses. Lower active 
metabolite exposure results in less platelet inhibition or higher residual platelet reactivity. To date, 
diminished antiplatelet responses to clopidogrel have been described for intermediate and poor 
metabolisers in 21 reported studies involving 4,520 subjects. The relative difference in antiplatelet 
response between genotype groups varies across studies depending on the method used to evaluate 
response, but is typically greater than 30%. 
 
The association between CYP2C19 genotype and clopidogrel treatment outcome was evaluated in 2 
post hoc clinical trial analyses (substudies of CLARITY [n=465] and TRITON-TIMI 38 [n=1,477]) 
and 5 cohort studies (total n=6,489). In CLARITY and one of the cohort studies (n=765; Trenk), 
cardiovascular event rates did not differ significantly by genotype. In TRITON-TIMI 38 and 3 of the 
cohort studies (n= 3,516; Collet, Sibbing, Giusti), patients with an impaired metaboliser status 
(intermediate and poor combined) had a higher rate of cardiovascular events (death, myocardial 
infarction, and stroke) or stent thrombosis compared to extensive metabolisers. In the fifth cohort study 
(n=2,208; Simon), the increased event rate was observed only in poor metabolisers. 
 
Pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity. 
 
There may be genetic variants of other CYP450 enzymes with effects on the ability to form the active 
metabolite of clopidogrel. 
 
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. 
 



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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 
 
Core: 

Mannitol (E421) 
Macrogol 6000 
Microcrystalline cellulose 
Hydrogenated castor oil 
Low substituted hydroxypropylcellulose 

 
Coating: 

Hypromellose (E464) 
Lactose 
Triacetin (E1518) 
Titanium dioxide (E171) 
Red iron oxide (E172) 
 

Polishing agent: 
Carnauba wax 

 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf-life 
 
3 years 
 
6.4 Special precautions for storage 
 



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This medicinal product does not require any special storage conditions. 
 
6.5 Nature and content of container 
  
Aluminium perforated unit-dose blisters in cardboard cartons containing 4x1, 30x1 and 100x1 
film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused product or waste material should be disposed of in accordance with local requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bristol Myers Squibb Pharma EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/08/464/015 - Cartons of 4x1 film-coated tablets in all aluminium perforated unit-dose blisters 
EU/1/08/464/016 - Cartons of 30x1 film-coated tablets in all aluminium perforated unit-dose blisters 
EU/1/08/464/017 - Cartons of 100x1 film-coated tablets in all aluminium perforated unit-dose blisters 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 16 July 2008  
 
 
10. DATE OF REVISION OF THE TEXT  
 
Detailed information on this product is available on the website of the European Medicines Agency 
(EMEA): http://www.emea.europa.eu/ 

http://www.emea.eu.int/


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ANNEX II 
 
A. MANUFACTURING AUTHORISATION HOLDERS 

RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OF THE MARKETING AUTHORISATION 
 



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A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH 
RELEASE 

 
Name and address of the manufacturers responsible for batch release 
 
- Clopidogrel BMS 75 mg film-coated tablets 
 
Sanofi Winthrop Industrie 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc cedex 
France 
 
Sanofi Winthrop Industrie 
6, Boulevard de l’Europe 
F-21800 Quétigny 
France 
 
Sanofi Synthelabo Limited 
Edgefield Avenue 
Fawdon 
Newcastle upon Tyne NE3 3TT – UK 
United Kingdom 
 
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. 
 
- Clopidogrel BMS 300 mg film-coated tablets 
 
Sanofi Winthrop Industrie 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc cedex 
France 
 
 
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, as described in version 2.0 dated 
25 September 2007 presented in Module 1.8.1. of the Marketing Authorisation Application, is in place 
and functioning before and whilst the product is on the market. 
 
 



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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 BMS 75 mg film-coated tablets 
clopidogrel 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 75 mg of clopidogrel (as hydrogen sulphate). 
 
 
3. LIST OF EXCIPIENTS 
 
It also contains: hydrogenated castor oil and lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
30 film-coated tablets 
50x1 film-coated tablets 
84 film-coated tablets 
90 film-coated tablets 
100 film-coated tablets 
14 film-coated tablets 
7 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 



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9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C (for PVC/PVDC/aluminium blisters) 
Or No special storage conditions (for all aluminium blisters) 
 
 
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 
 
Bristol Myers Squibb Pharma EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/08/464/001  14 tablets 
EU/1/08/464/002  14 tablets 
EU/1/08/464/003  28 tablets 
EU/1/08/464/004  28 tablets 
EU/1/08/464/005  30 tablets 
EU/1/08/464/006  30 tablets 
EU/1/08/464/007  50x1 tablets 
EU/1/08/464/008  50x1 tablets 
EU/1/08/464/009  84 tablets 
EU/1/08/464/010  84 tablets 
EU/1/08/464/011  90 tablets 
EU/1/08/464/012  90 tablets 
EU/1/08/464/013 100 tablets 
EU/1/08/464/014 100 tablets 
EU/1/08/464/018 7 tablets 
EU/1/08/464/019 7 tablets 
 
 
13. BATCH NUMBER 
 
Batch: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 



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Clopidogrel BMS 75 mg 



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 PARTICULARS TO APPEAR ON BLISTERS 
(boxes of 7, 14, 28 or 84 tablets) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel BMS 75 mg film-coated tablets 
clopidogrel 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol Myers Squibb Pharma EEIG 
 
 
3. EXPIRY DATE 
  
EXP {MM/YYYY} 
 
 
4. BATCH NUMBER 
 
Batch: 
 
 
5. OTHER 
 
Calendar days 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
Week 1 
Week 2 (for boxes of 14, 28 and 84 tablets) 
Week 3 (for boxes of 28 and 84 tablets) 
Week 4 (for boxes of 28 and 84 tablets) 
 



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 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS  
 
BLISTER/Boxes of 30, 50x1, 90 or 100 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel BMS 75 mg film-coated tablets 
clopidogrel 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol Myers Squibb Pharma EEIG 
 
 
3. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 
4. BATCH NUMBER 
 
Batch: 
 
 
5. OTHER 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel BMS 300 mg film-coated tablets 
clopidogrel 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 300 mg of clopidogrel (as hydrogen sulphate). 
 
 
3. LIST OF EXCIPIENTS 
 
It also contains: hydrogenated castor oil and lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
4x1 film-coated tablets 
30x1 film-coated tablets 
100x1 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 



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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 
 
Bristol Myers Squibb Pharma EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/464/015     4x1 film-coated tablets 
EU/1/08/464/016   30x1 film-coated tablets 
EU/1/08/464/017 100x1 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 BMS 300 mg 
 
 



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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER / Box of 4x1, 30x1 or 100x1 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel BMS 300 mg film-coated tablets 
clopidogrel 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol Myers Squibb Pharma EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch: 
 
 
5. OTHER 
 



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B. PACKAGE LEAFLET 



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PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Clopidogrel BMS 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 your 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 BMS is and what it is used for 
2. Before you take Clopidogrel BMS 
3. How to take Clopidogrel BMS 
4. Possible side effects 
5 How to store Clopidogrel BMS 
6. Further information 
 
 
1.  WHAT CLOPIDOGREL BMS IS AND WHAT IT IS USED FOR 
 
Clopidogrel BMS belongs to a group of medicines called antiplatelet medicinal products. Platelets are 
very small structures in the blood, smaller than red or white blood cells, 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 BMS 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 BMS 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, 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.  BEFORE YOU TAKE CLOPIDOGREL BMS 
 
Do not take Clopidogrel BMS:  
• If you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of Clopidogrel 

BMS; 
• 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 BMS.  
 



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Take special care with Clopidogrel BMS: 
If any of the situations mentioned below apply to you, you should tell your doctor before taking 
Clopidogrel BMS: 
• 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 are taking another type of medicine (see ‘Taking other medicines’).  
• if you have kidney or liver disease  
 
While you are taking Clopidogrel BMS: 
• 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 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. 
• You should tell your doctor or pharmacist if you notice any side effect not listed in section 4 

‘POSSIBLE SIDE EFFECTS’ or if you notice that a side effect gets serious. 
 
Clopidogrel BMS is not intended for use in children or adolescents. 
 
Taking other medicines:  
Some other medicines may influence the use of Clopidogrel BMS or vice versa.  
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
The use of oral anticoagulants (medicines used to reduce blood clotting) with Clopidogrel BMS is not 
recommended. 
 
You should specifically tell your doctor if you take a non-steroidal anti-inflammatory drug, usually 
used to treat painful and/or inflammatory conditions of muscle or joints, or if you take heparin or any 
other medicine used to reduce blood clotting, or if you take a proton pump inhibitor (e.g, omeprazole) 
for upset stomach. 
 
If you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed 
Clopidogrel BMS 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. 
 
Taking Clopidogrel BMS with food and drink 
Clopidogrel BMS may be taken with or without food. 
 



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Pregnancy and breast-feeding 
It is preferable not to use this product during pregnancy and breast-feeding. 
 
If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist 
before taking Clopidogrel BMS. If you become pregnant while taking Clopidogrel BMS, consult your 
doctor immediately as it is recommended not to take clopidogrel while you are pregnant.  
 
While taking Clopidogrel BMS, consult your doctor about the breast-feeding of a baby. 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines: 
Clopidogrel BMS is unlikely to affect your ability to drive or to use machines. 
 
Important information about some of the ingredients of Clopidogrel BMS: 
Clopidogrel BMS contains lactose. If you have been told by your doctor that you have an intolerance 
to some sugars (e.g. lactose), contact your doctor before taking this medicine. 
 
Clopidogrel BMS also contains hydrogenated castor oil which may cause stomach upset or diarrhoea. 
 
 
3.  HOW TO TAKE CLOPIDOGREL BMS  
 
Always take Clopidogrel BMS exactly as your doctor has told you. You should 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 BMS (1 tablet of 300 mg or 4 tablets of 75 mg) once at the start of treatment. 
Then, the usual dose is one 75-mg tablet of Clopidogrel BMS per day to be taken orally with or 
without food, and at the same time each day. 
 
You should take Clopidogrel BMS for as long as your doctor continues to prescribe it.  
 
If you take more Clopidogrel BMS 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 BMS: 
If you forget to take a dose of Clopidogrel BMS, 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 the forgotten individual doses.  
 
For the 7, 14, 28 and 84 tablets pack sizes, you can check the day on which you last took a tablet of 
Clopidogrel BMS by referring to the calendar printed on the blister. 
 
If you stop taking Clopidogrel BMS:  
Do not stop the treatment. Contact your doctor or pharmacist before stopping. 
 
If you have any further questions on the use of this product, ask your doctor or pharmacist. 
 
 



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4.  POSSIBLE SIDE EFFECTS 
 
Like all medicines, Clopidogrel BMS 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 ‘Take special care with Clopidogrel BMS’). 

- 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 (affects 1 to 10 patients in 100) reported with Clopidogrel BMS 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 BMS 
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 ‘Take special care with 
Clopidogrel BMS’). 
 
Other side effects reported with Clopidogrel BMS are: 
Common side effects (affects 1 to 10 patients in 100):  Diarrhoea, abdominal pain, indigestion or 
heartburn. 
 
Uncommon side effects (affects 1 to 10 patients in 1,000):  Headache, stomach ulcer, vomiting, 
nausea, constipation, excessive gas in stomach or intestines, rashes, itching, dizziness, sensation of 
tingling and numbness. 
 
Rare side effect (affects 1 to 10 patients in 10,000):  Vertigo. 
 
Very rare side effects (affects less than 1 patient in 10,000):  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. 
 
 



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5.  HOW TO STORE CLOPIDOGREL BMS 
 
Keep out of the reach and sight of children.  
Do not use Clopidogrel BMS after the expiry date which is stated on the carton and on the blister. 
 
Refer to the storage conditions on the carton. 
If Clopidogrel BMS is supplied in PVC/PVDC/aluminium blisters, store below 30°C. 
If Clopidogrel BMS is supplied in all aluminium blisters, it does not require any special storage 
conditions. 
Do not use Clopidogrel BMS if you notice any visible sign of deterioration. 
 
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 BMS contains 
The active substance is clopidogrel. Each tablet contains 75 mg of clopidogrel (as hydrogen sulphate). 
  
The other ingredients are mannitol (E421), hydrogenated castor oil, microcrystalline cellulose, 
macrogol 6000 and low-substituted hydroxypropylcellulose in the tablet core, and lactose (milk sugar), 
hypromellose (E464), triacetin (E1518), red iron oxide (E172), titanium dioxide (E171), and carnauba 
wax in the tablet coating. 
 
What Clopidogrel BMS looks like and contents of the pack 
 
Clopidogrel BMS 75-mg film-coated tablets are round, biconvex, pink, engraved on one side with the 
number ‘75’ and on the other side with the number ‘1171’. Clopidogrel BMS is supplied in cardboard 
cartons containing 7, 14, 28, 30, 84, 90 and 100 tablets in PVC/PVDC/Aluminium blisters or in all 
aluminium blisters, or 50x1 tablets in PVC/PVDC/Aluminium blisters or in all aluminium perforated 
unit-dose blisters. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer: 
 
Marketing Authorisation Holder:  
Bristol Myers Squibb Pharma EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH 
United Kingdom 
 
Manufacturer: 
Sanofi Winthrop Industrie 
1, rue de la Vierge, Ambarès & Lagrave, F-33565 Carbon Blanc cedex, France 
and/or 
Sanofi-Synthelabo Limited, 
Edgefield Avenue, Fawdon  
Newcastle Upon Tyne, Tyne & Wear NE3 3TT - UK, United Kingdom  
and/or 
Sanofi Winthrop Industrie 
6, boulevard de l'Europe, F-21800 Quétigny, France 



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For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:  
 
Belgique/België/Belgien 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

Luxembourg/Luxemburg 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

България 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Teл.: + 359 800 12 400 
 

Magyarország 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel.: + 36 1 301 9700 
 

Česká republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: +420 221 016 111 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Danmark 
BRISTOL-MYERS SQUIBB DENMARK 
Tlf: + 45 45 93 05 06 
 

Nederland 
BRISTOL-MYERS SQUIBB BV 
Tel: + 31 34 857 42 22 
 

Deutschland 
BRISTOL-MYERS SQUIBB GMBH & CO. KGAA 
Tel: + 49 89 121 42-0 
 

Norge 
BRISTOL-MYERS SQUIBB NORWAY LTD 
Tlf: + 47 67 55 53 50 
 

Eesti 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT 
Tel: +372 6827 400 
 

Österreich 
BRISTOL-MYERS SQUIBB GESMBH 
Tel: + 43 1 60 14 30 
 
 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 5796666 
 

España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 
 

Portugal 
BRISTOL-MYERS SQUIBB FARMACÊUTICA 
PORTUGUESA, S.A. 
Tel: + 351 21 440 70 00 
 

France 
BRISTOL-MYERS SQUIBB SARL 
Tél: + 33 (0)810 410 500 
 
 

România 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 40 (0)21 260 10 46 
 

Ireland 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS 
LTD 
Tel: + 353 (1 800) 749 749 
 

Slovenija 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 386 1 236 47 00 
 

Ísland 
VISTOR HF 
Sími: + 354 535 7000 
 

Slovenská republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 421 2 59298411  
 

Italia 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
OY BRISTOL-MYERS SQUIBB (FINLAND) AB 
Puh/Tel: + 358 9 251 21 230 
 



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Κύπρος 
ΑΚΗΣ ΠΑΝΑΓΙΩΤΟΥ & ΥΙΟΣ Ε.Π.Ε. 
Τηλ: + 357 22 677038 
 

Sverige 
BRISTOL-MYERS SQUIBB AB 
Tel: + 46 8 704 71 00 
 

Latvija 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 371 750 21 85 
 

United Kingdom 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS 
LTD 
Tel: + 44 (0800) 731 1736 
 
 

Lietuva 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: +370 5 2790 762 
 

 

 
This leaflet was last approved in MM/YYYY  
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) 
website: http://www.emea.europa.eu/  

http://www.emea.europa.eu/


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PACKAGE LEAFLET: INFORMATION FOR THE USER 

 
Clopidogrel BMS 300-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 your 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 BMS is and what it is used for 
2. Before you take Clopidogrel BMS 
3. How to take Clopidogrel BMS 
4. Possible side effects 
5 How to store Clopidogrel BMS 
6. Further information 
 
 
1.  WHAT CLOPIDOGREL BMS IS AND WHAT IT IS USED FOR 
 
Clopidogrel BMS belongs to a group of medicines called antiplatelet medicinal products. Platelets are 
very small structures in the blood, smaller than red or white blood cells, 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 BMS 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 BMS 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, 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.  BEFORE YOU TAKE CLOPIDOGREL BMS 
 
Do not take Clopidogrel BMS:  
 
• If you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of Clopidogrel 

BMS; 
• 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. 

 



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If you think any of these apply to you, or if you are in any doubt at all, consult your doctor before 
taking Clopidogrel BMS.  
 
Take special care with Clopidogrel BMS: 
If any of the situations mentioned below apply to you, you should tell your doctor before taking 
Clopidogrel BMS: 
• 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 (ischemic stroke) which occurred within the last 
seven days  

• if you are taking another type of medicine (see ‘Taking other medicines’).  
• if you have kidney or liver disease  
 
While you are taking Clopidogrel BMS: 
• 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 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. 
• You should tell your doctor or pharmacist if you notice any side effect not listed in section 4 

‘POSSIBLE SIDE EFFECTS’ or if you notice that a side effect gets serious. 
 
Clopidogrel BMS is not intended for use in children or adolescents. 
 
Taking other medicines:  
Some other medicines may influence the use of Clopidogrel BMS or vice versa.  
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
The use of oral anticoagulants (medicines used to reduce blood clotting) with Clopidogrel BMS is not 
recommended. 
 
You should specifically tell your doctor if you take a non-steroidal anti-inflammatory drug, usually 
used to treat painful and/or inflammatory conditions of muscle or joints, or if you take heparin or any 
other medicine used to reduce blood clotting, or if you take a proton pump inhibitor (e.g, omeprazole) 
for upset stomach. 
 
If you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed 
Clopidogrel BMS 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. 
 
Taking Clopidogrel BMS with food and drink 
Clopidogrel BMS may be taken with or without food. 



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Pregnancy and breast-feeding 
It is preferable not to use this product during pregnancy and breast-feeding. 
 
If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist 
before taking Clopidogrel BMS. If you become pregnant while taking Clopidogrel BMS, consult your 
doctor immediately as it is recommended not to take clopidogrel while you are pregnant.  
 
While taking Clopidogrel BMS, consult your doctor about the breast-feeding of a baby. 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines: 
Clopidogrel BMS is unlikely to affect your ability to drive or to use machines. 
 
Important information about some of the ingredients of Clopidogrel BMS: 
Clopidogrel BMS contains lactose. If you have been told by your doctor that you have an intolerance 
to some sugars (e.g. lactose), contact your doctor before taking this medicine. 
 
Clopidogrel BMS also contains hydrogenated castor oil which may cause stomach upset or diarrhoea. 
 
 
3.  HOW TO TAKE CLOPIDOGREL BMS  
 
Always take Clopidogrel BMS exactly as your doctor has told you. You should 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 BMS (1 tablet of 300 mg or 4 tablets of 75 mg) once at the start of treatment. 
Then, the usual dose is one 75 mg tablet of Clopidogrel BMS per day to be taken orally with or 
without food, and at the same time each day. 
 
You should take Clopidogrel BMS for as long as your doctor continues to prescribe it.  
 
If you take more Clopidogrel BMS than you should: 
Contact your doctor or the nearest hospital emergency department because of the increased risk of 
bleeding. 
 
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 BMS 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 ‘Take special care with Clopidogrel BMS’). 

- 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 (affects 1 to 10 patients in 100) reported with Clopidogrel BMS is 
bleeding. Bleeding may occur as bleeding in the stomach or bowels, bruising, haematoma (unusual 



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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 BMS 
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 ‘Take special care with 
Clopidogrel BMS’). 
 
Other side effects reported with Clopidogrel BMS are: 
Common side effects (affects 1 to 10 patients in 100):  Diarrhoea, abdominal pain, indigestion or 
heartburn. 
 
Uncommon side effects (affects 1 to 10 patients in 1,000):  Headache, stomach ulcer, vomiting, 
nausea, constipation, excessive gas in stomach or intestines, rashes, itching, dizziness, sensation of 
tingling and numbness. 
 
Rare side effect (affects 1 to 10 patients in 10,000):  Vertigo. 
 
Very rare side effects (affects less than 1 patient in 10,000):  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 BMS 
 
Keep out of the reach and sight of children.  
Do not use Clopidogrel BMS after the expiry date which is stated on the carton and on the blister. 
This medicinal product does not require any special storage conditions. 
 
Do not use Clopidogrel BMS if you notice any visible sign of deterioration. 
 
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 BMS contains 
The active substance is clopidogrel. Each tablet contains 300 mg of clopidogrel (as hydrogen 
sulphate). 
  
The other ingredients are mannitol (E421), hydrogenated castor oil, microcrystalline cellulose, 
macrogol 6000 and low-substituted hydroxypropylcellulose in the tablet core, and lactose (milk sugar), 
hypromellose (E464), triacetin (E1518), red iron oxide (E172), titanium dioxide (E171), and carnauba 
wax in the tablet coating. 
 



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What Clopidogrel BMS looks like and contents of the pack 
 
Clopidogrel BMS 300-mg film-coated tablets are oblong, pink, engraved on one side with the number 
‘300’ and on the other side with the number ‘1332’. Clopidogrel BMS is supplied in cardboard cartons 
containing 4x1, 30x1 and 100x1 tablets in all aluminium perforated unit-dose blisters. Not all pack 
sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer: 
 
Marketing Authorisation Holder:  
Bristol Myers Squibb Pharma EEIG 
Uxbridge Business Park  
Sanderson Road 
Uxbridge UB8 1DH 
United Kingdom 
 
Manufacturer: 
Sanofi Winthrop Industrie 
1, rue de la Vierge, Ambarès & Lagrave, F-33565 Carbon Blanc cedex, France 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:  
 
Belgique/België/Belgien 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

Luxembourg/Luxemburg 
BRISTOL-MYERS SQUIBB BELGIUM S.A./N.V. 
Tél/Tel: + 32 2 352 76 11 
 

България 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Teл.: + 359 800 12 400 
 

Magyarország 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel.: + 36 1 301 9700 
 

Česká republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: +420 221 016 111 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Danmark 
BRISTOL-MYERS SQUIBB DENMARK 
Tlf: + 45 45 93 05 06 
 

Nederland 
BRISTOL-MYERS SQUIBB BV 
Tel: + 31 34 857 42 22 
 

Deutschland 
BRISTOL-MYERS SQUIBB GMBH & CO. KGAA 
Tel: + 49 89 121 42-0 
 

Norge 
BRISTOL-MYERS SQUIBB NORWAY LTD 
Tlf: + 47 67 55 53 50 
 

Eesti 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT 
Tel: +372 6827 400 
 

Österreich 
BRISTOL-MYERS SQUIBB GESMBH 
Tel: + 43 1 60 14 30 
 
 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 5796666 
 



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España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 
 

Portugal 
BRISTOL-MYERS SQUIBB FARMACÊUTICA 
PORTUGUESA, S.A. 
Tel: + 351 21 440 70 00 
 

France 
BRISTOL-MYERS SQUIBB SARL 
Tél: + 33 (0)810 410 500 
 
 

România 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 40 (0)21 260 10 46 
 

Ireland 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS 
LTD 
Tel: + 353 (1 800) 749 749 
 

Slovenija 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 386 1 236 47 00 
 

Ísland 
VISTOR HF 
Sími: + 354 535 7000 
 

Slovenská republika 
BRISTOL-MYERS SQUIBB SPOL. S R.O. 
Tel: + 421 2 59298411  
 

Italia 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
OY BRISTOL-MYERS SQUIBB (FINLAND) AB 
Puh/Tel: + 358 9 251 21 230 
 

Κύπρος 
ΑΚΗΣ ΠΑΝΑΓΙΩΤΟΥ & ΥΙΟΣ Ε.Π.Ε. 
Τηλ: + 357 22 677038 
 

Sverige 
BRISTOL-MYERS SQUIBB AB 
Tel: + 46 8 704 71 00 
 

Latvija 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: + 371 750 21 85 
 

United Kingdom 
BRISTOL-MYERS SQUIBB PHARMACEUTICALS 
LTD 
Tel: + 44 (0800) 731 1736 
 
 

Lietuva 
BRISTOL-MYERS SQUIBB 
GYÓGYSZERKERESKEDELMI KFT. 
Tel: +370 5 2790 762 
 

 

 
This leaflet was last approved in MM/YYYY  
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) 
website: http://www.emea.europa.eu/ 
 

http://www.emea.eu.int/

	M1 TOC
	SUMMARY OF PRODUCT CHARACTERISTICS
	 A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET