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Section 4.2: Addition of section on Pharmacogenetics

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

Section 4.4 Addition of following paragraphs:

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.

Section 4.5: Addition of following paragraphs:

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.

Section 5.1: Revision to the paragraph on mode of action:

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

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.

Section 5.2 Addition of following paragraphs:

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.

CYP2C19 Phenotype and Genotype Frequency

                                                                                                            Frequency (%)

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 C_max 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.

Clopidogrel is indicated 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.

5.1     Pharmacodynamic properties

Acute coronary syndrome (following information has been added under this heading)

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 2172 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.

Section 4.1: Therapeutic indications: Addition of :

Clopidogrel is indicated for the prevention of atherothrombotic events in:       

·                Patients suffering from acute coronary syndrome:

-         ST segment elevation acute myocardial infarction, in combination with

ASA in medically treated patients eligible for thrombolytic therapy.

Section 4.2: Posology and method of administration: Addition of:

In patients suffering from acute coronary syndrome:

-          ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a loading dose in combination with ASA and with or without thrombolytics. For patients greater than 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).

Section 4.4: Special warnings and precautions for use: Addition of:

Non-Steroidal Anti-Inflammatory Drugs (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).

Section 4.8: Undesirable effects and Section 5.1: Pharmacodynamic properties: details are provided from the CLARITY and COMMIT studies.

Section 10: Date of Revision of the Text: 1^st September 2006