Clopidogrel Winthrop

1.

NAME OF THE MEDICINAL PRODUCT

Clopidogrel Winthrop 75 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipients: each film-coated tablet contains 3 mg of lactose and 3.3 mg of 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

Prevention of atherothrombotic events

Clopidogrel is indicated in:



Adult patients suffering from myocardial infarction (from a few days until less than 35 days),

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



Adult patients suffering from acute coronary syndrome:

- Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave

myocardial infarction), including patients undergoing a stent placement following

percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).

- ST segment elevation acute myocardial infarction, in combination with ASA in medically

treated patients eligible for thrombolytic therapy.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation

In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not

suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk,

clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and

thromboembolic events, including stroke.

For further information please refer to section 5.1.

4.2 Posology and method of administration

Posology



Adults and elderly

Clopidogrel should be given as a single daily dose of 75 mg.

In patients suffering from acute coronary syndrome:

 Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave

myocardial infarction): clopidogrel treatment should be initiated with a single 300-mg

loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA)

75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding

2

- ST segment elevation acute myocardial infarction: clopidogrel should be given as a

single daily dose of 75 mg initiated with a 300-mg loading dose in combination with

ASA and with or without thrombolytics. For patients over 75 years of age clopidogrel

should be initiated without a loading dose. Combined therapy should be started as early

as possible after symptoms start and continued for at least four weeks. The benefit of the

combination of clopidogrel with ASA beyond four weeks has not been studied in this

setting (see section 5.1).

In patients with atrial fibrillation, clopidogrel should be given as a single daily dose of 75 mg.

ASA (75-100 mg daily) should be initiated and continued in combination with clopidogrel (see

section 5.1).

If a dose is missed:

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

immediately and then take the next dose at the regular scheduled time.

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

and should not double the dose.



Paediatric population

The safety and efficacy of clopidogrel in children and adolescents under 18 years old 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).

Method of administration

For oral use

It may be given with or without food.

4.3 Contraindications



Hypersensitivity to the active substance or to any of the excipients.



Severe hepatic impairment.



Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

4.4 Special warnings and precautions for use

Bleeding and haematological disorders

Due to the risk of bleeding and haematological adverse reactions, blood cell count determination

and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive

of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet agents,

clopidogrel should be used with caution in patients who may be at risk of increased bleeding from

trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, heparin,

glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including Cox-2

inhibitors. 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).

3

If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable,

clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and

dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal

product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who

have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel

(alone or in combination with ASA), and that they should report any unusual bleeding (site or duration)

to their physician.

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of

clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and

microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction

or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Recent ischaemic stroke

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

ischaemic stroke.

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended

doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function.

Tests are available to identify a patient's CYP2C19 genotype.

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products

that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active

metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution

concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for

a list of CYP2C19 inhibitors, see also section 5.2).

Renal impairment

Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore

clopidogrel should be used with caution in these patients (see section 4.2).

Hepatic impairment

Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses.

Clopidogrel should therefore be used with caution in this population (see section 4.2).

Excipients

Clopidogrel Winthrop 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). Although the

administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or

International Normalised Ratio (INR) in patients receiving long-term warfarin therapy,

coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent

effects on hemostasis.

Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who receive

concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4).

4

Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced

platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet

aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not

significantly increase the prolongation of bleeding time induced by clopidogrel intake. A

pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to

increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section

4.4). However, clopidogrel and ASA have been administered together for up to one year (see section

5.1).

Heparin : in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification

of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no

effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction

between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore,

concomitant use should be undertaken with caution (see section 4.4).

Thrombolytics : the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific

thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The

incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and

heparin are co-administered with ASA (see section 4.8)

NSAIDs : in a clinical study conducted in healthy volunteers, the concomitant administration of

clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of

interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of

gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and

clopidogrel should be co-administered with caution (see section 4.4).

Other concomitant therapy : Since clopidogrel is metabolised to its active metabolite partly by

CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to

result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this

interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors

should be discouraged (see sections 4.4 and 5.2).

Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine,

fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine,

carbamazepine, oxcarbazepine and chloramphenicol.

Proton Pump Inhibitors (PPI):

Omeprazole 80 mg once daily administered either at the same time as clopidogrel) were administered

for 5 days. The exposure to or with 12 hours between the administrations of the two drugs decreased

the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). The

decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction of

inhibition of platelet aggregation. Esomeprazole is expected to give a similar interaction with

clopidogrel.

Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD)

interaction in terms of major cardiovascular events have been reported from both observational and

clinical studies. As a precaution, concomitant use of omeprazole or esomeprazole should be

discouraged (see section 4.4).

Less pronounced reductions of metabolite exposure has been observed with pantoprazole or

lansoprazole.

The plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced

(maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was

associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%,

respectively. These results indicate that clopidogrel can be administered with pantoprazole.

5

There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers

(except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with antiplatelet activity of

clopidogrel.

Other medicinal products: A number of other clinical studies have been conducted with clopidogrel

and other concomitant medicinal products to investigate the potential for pharmacodynamic and

pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed

when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine.

Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co-

administration of phenobarbital or oestrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of

clopidogrel. Antacids did not modify the extent of clopidogrel absorption.

Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by

CYP2C9 can be safely co-administered with clopidogrel.

Apart from the specific medicinal product interaction information described above, interaction studies

with clopidogrel and some medicinal products commonly administered in patients with

atherothrombotic disease have not been performed. However, patients entered into clinical trials with

clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers,

ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents

(including insulin), antiepileptic agents and GPIIb/IIIa antagonists without evidence of clinically

significant adverse interactions.

4.6 Fertility, pregnancy and lactation

Pregnancy

As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to

use clopidogrel during pregnancy as a precautionary measure.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,

embryonal/foetal development, parturition or postnatal development (see section 5.3).

Breastfeeding

It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown

excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be

continued during treatment with Clopidogrel Winthrop.

Fertility

Clopidogrel was not shown to alter fertility in animal studies.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Clopidogrel has been evaluated for safety in more than 44,000 patients who have participated in

clinical studies, including over 12,000 patients treated for 1 year or more. Overall, clopidogrel

75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. The

clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and

ACTIVE-A studies are discussed below. In addition to clinical studies experience, adverse reactions

have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing

experience where it was mostly reported during the first month of treatment.

6

In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding

was 9.3%. The incidence of severe cases was similar for clopidogrel and ASA.

In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary

bypass graft surgery in patients who stopped therapy more than five days prior to surgery . In patients

who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for

clopidogrel plus ASA, and 6.3% for placebo plus ASA.

In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the

placebo plus ASA group .The incidence of major bleeding was similar between groups . This was

consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or

heparin therapy.

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

in both groups.

In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the

placebo + ASA group (6.7% versus 4.3%). Major bleeding was mostly of extracranial origin in both

groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo +ASA group), mainly from the

gastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial bleeding in the clopidogrel +

ASA treatment group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There

was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + ASA

group and 0.7% in the placebo +ASA group) and haemorrhagic stroke (0.8% and 0.6%, respectively)

between groups.

Adverse reactions that occurred either during clinical studies or that were spontaneously reported are

presented in the table below. Their frequency is defined using the following conventions: common

(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare

(<1/10,000). Within each system organ class, adverse reactions are presented in order of decreasing

seriousness.

System Organ

Class

Common

Uncommon

Rare

Very rare

Blood and the

lymphatic system

disorders

Thrombocytopenia,

leucopenia,

eosinophilia

Neutropenia,

including

severe

neutropenia

Thrombotic

thrombocytopenic

purpura (TTP) (see

section 4.4), 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

7

System Organ

Class

Common

Uncommon

Rare

Very rare

Eye disorders

Eye bleeding

(conjunctival,

ocular, retinal)

Ear and labyrinth

disorders

Vertigo

Vascular disorders Haematoma

Serious haemorrhage,

haemorrhage of

operative wound,

vasculitis, hypotension

Respiratory,

thoracic and

mediastinal

disorders

Epistaxis

Respiratory tract

bleeding (haemoptysis,

pulmonary

haemorrhage),

bronchospasm,

interstitial pneumonitis

Gastrointestinal

disorders

Gastrointestinal

haemorrhage,

diarrhoea,

abdominal

pain, dyspepsia

Gastric ulcer and

duodenal ulcer,

gastritis, vomiting,

nausea,

constipation,

flatulence

Retroperitoneal

haemorrhage

Gastrointestinal and

retroperitoneal

haemorrhage with fatal

outcome, pancreatitis,

colitis (including

ulcerative or

lymphocytic colitis),

stomatitis

Hepato-biliary

disorders

Acute liver failure,

hepatitis, abnormal

liver function test

Skin and

subcutaneous tissue

disorders

Bruising

Rash, pruritus, skin

bleeding (purpura)

Bullous dermatitis

(toxic epidermal

necrolysis, Stevens

Johnson Syndrome,

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

8

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 P2Y 12 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 medicinal products, not all patients will have adequate platelet inhibition.

Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation

from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At

steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and

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 5 double-blind studies involving over

88,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY,

COMMIT and ACTIVE-A 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

9

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

(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).

10

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

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.

Atrial fibrillation

The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patients

with atrial fibrillation (AF) who had at least one risk factor for vascular events. Based on enrollment

criteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist

(VKA) therapy (such as warfarin). The ACTIVE-A study included patients who could not receive

VKA therapy because they were unable or unwilling to receive the treatment.

The ACTIVE-W study demonstrated that anticoagulant treatment with vitamin K antagonists was

more effective than with clopidogrel and ASA.

The ACTIVE-A study (N=7,554) was a multicenter, randomized, double-blind, placebo-controlled

study which compared clopidogrel 75 mg/day + ASA (N=3,772) to placebo + ASA (N=3,782). The

recommended dose for ASA was 75 to 100 mg/day. Patients were treated for up to 5 years.

Patients randomized in the ACTIVE program were those presenting with documented AF, i.e., either

permanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least one of the

following risk factors: age 75 years or age 55 to 74 years and either diabetes mellitus requiring drug

therapy, or documented previous MI or documented coronary artery disease; treated for systemic

hypertension; prior stroke, transient ischaemic attack (TIA), or non-CNS systemic embolus; left

ventricular dysfunction with left ventricular ejection fraction <45%; or documented peripheral

vascular disease. The mean CHADS 2 score was 2.0 (range 0-6).

11

The major exclusion criteria for patients were documented peptic ulcer disease within the previous

6 months; prior intracerebral hemorrhage; significant thrombocytopenia (platelet count < 50 x 10 9 /l);

requirement for clopidogrel or oral anticoagulants (OAC); or intolerance to any of the two compounds.

Seventy-three percent (73%) of patients enrolled into the ACTIVE-A study were unable to take VKA

due to physician assessment, inability to comply with INR (international normalised ratio) monitoring,

predisposition to falling or head trauma, or specific risk of bleeding; for 26% of the patients, the

physician’s decision was based on the patient’s unwillingness to take VKA.

The patient population included 41.8 % women. The mean age was 71 years, 41.6% of patients were

≥75 years. A total of 23.0% of patients received anti-arrhythmics, 52.1% beta-blockers, 54.6% ACE

inhibitors, and 25.4% statins.

The number of patients who reached the primary endpoint (time to first occurrence of stroke, MI,

non-CNS systemic embolism or vascular death) was 832 (22.1%) in the group treated with clopidogrel

+ ASA and 924 (24.4%) in the placebo + ASA group (relative risk reduction of 11.1%; 95% CI of

2.4% to 19.1%; p=0.013), primarily due to a large reduction in the incidence of strokes. Strokes

occurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receiving

placebo + ASA (relative risk reduction, 28.4%; 95% CI, 16.8% to 38.3%; p=0.00001).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with

Clopidogrel Winthrop in one or more subsets of the paediatric population for the prevention of

thromboembolic events (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak

plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after a single 75 mg oral dose)

occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion

of clopidogrel metabolites.

Distribution

Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma

proteins (98% and 94% respectively). The binding is non-saturable in vitro over a wide concentration

range.

Metabolism

Clopidogrel is extensively metabolised by the liver. In vitro and in vivo , clopidogrel is metabolised

according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into

its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple

cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite.

Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the

active metabolite, a thiol derivative of clopidogrel. In vitro , this metabolic pathway is mediated by

CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite which has been isolated

in vitro , binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.

The C max of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose

as it is after four days of 75-mg maintenance dose. C max occurs approximately 30 to 60 minutes after

dosing.

Elimination

Following an oral dose of 14 C-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

12

dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the

main circulating (inactive) metabolite was 8 hours after single and repeated administration.

Pharmacogenetics

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel

intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as

measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype.

The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and

CYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the

majority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other

alleles associated with absent or reduced metabolism are less frequent and include CYP2C19*4, *5,

*6, *7, and *8. A patient with poor metaboliser status will possess two loss-of-function alleles as

defined above. Published frequencies for the poor CYP2C19 metaboliser genotypes are

approximately 2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to

determine a patient’s CYP2C19 genotype.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid,

extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg

followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state).

No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation

(IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor

metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive

metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor

metabolisers with mean IPA (5 μM ADP) of 24% (24 hours) and 37% (Day 5) as compared to IPA of

39% (24 hours) and 58% (Day 5) in the extensive metabolisers and 37% (24 hours) and 60% (Day 5)

in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active

metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32%

(24 hours) and 61% (Day 5), which were greater than in the poor metabolisers receiving the

300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the

300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been

established in clinical outcome trials.

Consistent with the above results, in a meta-analysis including 6 studies of 335 clopidogrel-treated

subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for

intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 μM

ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to

extensive metabolisers.

The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not

been evaluated in prospective, randomised, controlled trials. There have been a number of

retrospective analyses, however, to evaluate this effect in patients treated with clopidogrel for whom

there are genotyping results: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227),

TRITON-TIMI 38 (n=1477), and ACTIVE-A (n=601), as well as a number of published cohort

studies.

In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of

patients with either intermediate or poor metaboliser status had a higher rate of cardiovascular events

(death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers.

In CHARISMA and one cohort study (Simon), an increased event rate was observed only in poor

metabolisers when compared to extensive metabolisers.

In CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), no increased event rate was

observed based on metaboliser status.

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

13

Special populations

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

Renal impairment

After repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease (creatinine

clearance from 5 to 15 ml/min), inhibition of ADP-induced platelet aggregation was lower (25%) than

that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen

in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in

all patients.

Hepatic impairment

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic

impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy

subjects. The mean bleeding time prolongation was also similar in the two groups.

Race

The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs

according to race/ethnicity (see Pharmacogenetics). From literature, limited data in Asian populations

are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.

5.3 Preclinical safety data

During non clinical studies in rat and baboon, the most frequently observed effects were liver changes.

These occurred at doses representing at least 25 times the exposure seen in humans receiving the

clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No

effect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the

therapeutic dose.

At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of

clopidogrel was also reported in rat and baboon.

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

14

Low substituted hydroxypropylcellulose

Coating:

Hypromellose (E464)

Lactose monohydrate

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

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

sanofi-aventis

174 Avenue de France

F-75013 Paris

France

8.

MARKETING AUTHORISATION NUMBERS

EU/1/08/465/001 - Cartons of 14 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/08/465/002 - Cartons of 14 film-coated tablets in all aluminium blisters

EU/1/08/465/003 - Cartons of 28 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/08/465/004 - Cartons of 28 film-coated tablets in all aluminium blisters

EU/1/08/465/005 - Cartons of 30 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/08/465/006 - Cartons of 30 film-coated tablets in all aluminium blisters

EU/1/08/465/007 - Cartons of 50x1 film-coated tablets in PVC/PVDC/Alu blisters

15

EU/1/08/465/008 - Cartons of 50x1 film-coated tablets in all aluminium blisters

EU/1/08/465/009 - Cartons of 84 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/08/465/010 - Cartons of 84 film-coated tablets in all aluminium blisters

EU/1/08/465/011 - Cartons of 90 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/08/465/012 - Cartons of 90 film-coated tablets in all aluminium blisters

EU/1/08/465/013 - Cartons of 100 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/08/465/014 - Cartons of 100 film-coated tablets in all aluminium blisters

EU/1/08/465/018 - Cartons of 7 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/08/465/019 - 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 medicinal product is available on the website of the European Medicines

Agency: http://www.ema.europa.eu/

16

1.

NAME OF THE MEDICINAL PRODUCT

Clopidogrel Winthrop 300 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 300 mg of clopidogrel (as hydrogen sulphate).

Excipients: each film-coated tablet contains 12 mg of lactose and 13.2 mg of 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

Prevention of atherothrombotic events

Clopidogrel is indicated in:



Adult patients suffering from myocardial infarction (from a few days until less than 35 days),

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



Adult patients suffering from acute coronary syndrome:

- Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave

myocardial infarction), including patients undergoing a stent placement following

percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).

- ST segment elevation acute myocardial infarction, in combination with ASA in medically

treated patients eligible for thrombolytic therapy.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation

In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not

suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk,

clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and

thromboembolic events, including stroke.

For further information please refer to section 5.1.

4.2 Posology and method of administration

Posology



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

17

 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,