PLAVIX 75mg tablets medication leaflet

Plavix 75 mg film-coated tablets

Plavix 300 mg film-coated tablets

Plavix 75 mg film-coated tablets

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

Each film-coated tablet contains 3 mg of lactose and 3.3 mg of hydrogenated castor oil.

Plavix 300 mg film-coated tablets

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

Each film-coated tablet contains 12 mg of lactose and 13.2 mg of hydrogenated castor oil.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Plavix 75 mg film-coated tablets

Pink, round, biconvex, engraved with «75» on one side and «1171» on the other side.

Plavix 300 mg film-coated tablets

Pink, oblong, engraved with «300» on one side and «1332» on the other side.

Secondary prevention of atherothrombotic events

Clopidogrel is indicated in:

* Adult patients suffering from myocardial infarction (from a few days until less than 35 days),ischemic 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-wavemyocardial infarction), including patients undergoing a stent placement followingpercutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).

- ST segment elevation acute myocardial infarction, in combination with ASA in patientsundergoing percutaneous coronary intervention (including patients undergoing a stentplacement) or medically treated patients eligible for thrombolytic/fibrinolytic therapy.

In patients with moderate to high-risk Transient Ischemic Attack (TIA) or minor Ischemic Stroke (IS)

Clopidogrel in combination with ASA is indicated in:

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- Adult patients with moderate to high-risk TIA (ABCD21 score ≥4) or minor IS (NIHSS2 ≤3)within 24 hours of either the TIA or IS event.

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 notsuitable 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 andthromboembolic events, including stroke.

For further information please refer to section 5.1.

* Adults and elderly

Plavix 75 mg film-coated tablets

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

Plavix 300 mg film-coated tablets

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-wavemyocardial infarction): clopidogrel treatment should be initiated with a single 300 mg or600 mg loading dose. A 600 mg loading dose may be considered in patients <75 years ofage when percutaneous coronary intervention is intended (see section 4.4). Clopidogreltreatment should be 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 bleedingrisk it is recommended that the dose of ASA should not be higher than 100 mg. Theoptimal duration of treatment has not been formally established. Clinical trial datasupport use up to 12 months, and the maximum benefit was seen at 3 months (seesection 5.1).

− ST segment elevation acute myocardial infarction:

- For medically treated patients eligible for thrombolytic/fibrinolytic therapy,clopidogrel should be given as a single daily dose of 75 mg initiated with a 300 mgloading dose in combination with ASA and with or without thrombolytics. Formedically treated patients over 75 years of age clopidogrel should be initiatedwithout a loading dose. Combined therapy should be started as early as possible aftersymptoms start and continued for at least four weeks. The benefit of the combinationof clopidogrel with ASA beyond four weeks has not been studied in this setting (seesection 5.1).

- When percutaneous coronary intervention (PCI) is intended:

- Clopidogrel should be initiated at a loading dose of 600 mg in patientsundergoing primary PCI and in patients undergoing PCI more than 24 hoursof receiving fibrinolytic therapy. In patients ≥ 75 years old the 600 mg LDshould be administered with caution (see section 4.4).

- Clopidogrel 300 mg loading dose should be given in patients undergoing

PCI within 24 hours of receiving fibrinolytic therapy.

Clopidogrel treatment should be continued at 75 mg once a day with ASA 75 mg -100 mg daily. Combined therapy should be started as early as possible aftersymptoms start and continued up to 12 months (see section 5.1).

1 Age, Blood pressure, Clinical features, Duration, and Diabetes mellitus diagnosis2 National Institutes of Health Stroke Scale

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Adult patients with moderate to high-risk TIA or minor IS:

Adult patients with moderate to high-risk TIA (ABCD2 score ≥4) or minor IS (NIHSS ≤3)should be given a loading dose of clopidogrel 300 mg followed by clopidogrel 75 mg once dailyand ASA (75 mg -100 mg once daily). Treatment with clopidogrel and ASA should be startedwithin 24 hours of the event and be continued for 21 days followed by single antiplatelettherapy.

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 (seesection 5.1).

If a dose is missed:

- Within less than 12 hours after regular scheduled time: patients should take the doseimmediately 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 timeand should not double the dose.

* Elderly patients

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

- A 600 mg loading dose may be considered in patients <75 years of age when percutaneouscoronary intervention is intended (see section 4.4).

ST segment elevation acute myocardial infarction:

- For medically treated patients eligible for thrombolytic/fibrinolytic therapy: in patientsover 75 years of age clopidogrel should be initiated without a loading dose.

For patients undergoing primary PCI and in patients undergoing PCI more than 24 hours ofreceiving fibrinolytic therapy:

- In patients ≥ 75 years old the 600 mg LD should be administered with caution (see section4.4).

* Paediatric population

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

* Renal impairment

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

* Hepatic impairment

Therapeutic experience is limited in patients with moderate hepatic disease who may havebleeding diatheses (see section 4.4).

For oral use

It may be given with or without food.

* Hypersensitivity to the active substance or to any of the excipients listed in section 2 or section6.1.

* Severe hepatic impairment.

* Active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

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Bleeding and haematological disorders

Due to the risk of bleeding and haematological adverse reactions, blood cell count determinationand/or other appropriate testing should be promptly considered whenever clinical symptomssuggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplateletagents, clopidogrel should be used with caution in patients who may be at risk of increased bleedingfrom trauma, surgery or other pathological conditions and in patients receiving treatment with ASA,heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including

Cox-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs), or CYP2C19 strong inducers orother medicinal products associated with bleeding risk such as pentoxifylline (see section 4.5). Due tothe increased risk of haemorrhage, triple antiplatelet therapy (clopidogrel + ASA + dipyridamole) forstroke secondary prevention is not recommended in patients with acute non-cardioembolic ischemicstroke or TIA (see section 4.5 and section 4.8). Patients should be followed carefully for any signs ofbleeding including occult bleeding, especially during the first weeks of treatment and/or after invasivecardiac procedures or surgery. The concomitant administration of clopidogrel with oral anticoagulantsis 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 anddentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinalproduct is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients whohave 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.

The use of clopidogrel 600 mg loading dose is not recommended in patients with non-ST segmentelevation acute coronary syndrome and ≥75 years of age due to increased bleeding risk in thispopulation.

Due to the limited clinical data in patients ≥75 years old with STEMI PCI, and increased risk ofbleeding, the use of clopidogrel 600 mg loading dose should be considered only after an individualassessment of the bleeding risk of the patient by the physician.

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

Acquired haemophilia

Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolatedactivated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquiredhaemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia shouldbe managed and treated by specialists, and clopidogrel should be discontinued.

Recent ischemic stroke

* Initiation of therapyo In acute minor IS or moderate to high-risk TIA patients, dual antiplatelet therapy(clopidogrel and ASA) should be started no later than 24 hours after the event onset.

o There is no data regarding the benefit-risk of short term dual antiplatelet therapy in acuteminor IS or moderate to high-risk TIA patients, with a history of (non-traumatic)intracranial hemorrhage.

Internalo In non-minor IS patients, clopidogrel monotherapy should be started only after the first7 days of the event.

* Non-minor IS patients (NIHSS >4)

In view of the lack of data, use of dual antiplatelet therapy is not recommended (see section 4.1).

* Recent minor IS or moderate to high-risk TIA in patients for whom intervention is indicated orplanned

There is no data to support the use of dual antiplatelet therapy in patients for whom treatment withcarotid endarterectomy or intravascular thrombectomy is indicated, or in patients planned forthrombolysis or anticoagulant therapy. Dual antiplatelet therapy is not recommended in thesesituations.

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommendeddoses 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 productsthat inhibit the activity of this enzyme would be expected to result in reduced drug levels of the activemetabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precautionconcomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 fora list of CYP2C19 inhibitors, see also section 5.2).

Use of medicinal products that induce the activity of CYP2C19 would be expected to result inincreased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. Asa precaution concomitant use of strong CYP2C19 inducers should be discouraged (see section 4.5).

CYP2C8 substrates

Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate medicinalproducts (see section 4.5).

Cross-reactions among thienopyridines

Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel,ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see section 4.8).

Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, orhaematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who haddeveloped a previous allergic reaction and/or haematological reaction to one thienopyridine may havean increased risk of developing the same or another reaction to another thienopyridine. Monitoring forsigns of hypersensitivity in patients with a known allergy to thienopyridines is advised.

Therapeutic experience with clopidogrel is limited in patients with renal impairment. Thereforeclopidogrel 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).

Plavix contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains hydrogenated castor oil which may cause stomach upset anddiarrhoea.

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Medicinal products associated with bleeding risk: There is an increased risk of bleeding due to thepotential additive effect. The concomitant administration of medicinal products associated withbleeding risk should be undertaken with caution (see section 4.4).

Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is notrecommended since it may increase the intensity of bleedings (see section 4.4). Although theadministration 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 independenteffects on hemostasis.

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

Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-inducedplatelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced plateletaggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did notsignificantly increase the prolongation of bleeding time induced by clopidogrel intake. Apharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading toincreased risk of bleeding. Therefore, concomitant use should be undertaken with caution (seesection 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 modificationof the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had noeffect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interactionbetween 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 specificthrombolytic agents and heparins was assessed in patients with acute myocardial infarction. Theincidence of clinically significant bleeding was similar to that observed when thrombolytic agents andheparin are co-administered with ASA (see section 4.8)

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

SSRIs: since SSRIs affect platelet activation and increase the risk of bleeding, the concomitantadministration of SSRIs with clopidogrel should be undertaken with caution.

Inducers of CYP2C19

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal productsthat induce the activity of this enzyme would be expected to result in increased drug levels of theactive metabolite of clopidogrel.

Rifampicin strongly induces CYP2C19, resulting in both an increased level of clopidogrel activemetabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As aprecaution, concomitant use of strong CYP2C19 inducers should be discouraged (see section 4.4).

Inhibitors of CYP2C19

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal productsthat inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active

Internalmetabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precautionconcomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see sections 4.4and 5.2).

Medicinal products that are strong or moderate CYP2C19 inhibitors include, for example, omeprazoleand esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine,carbamazepine, and efavirenz.

Proton Pump Inhibitors (PPI):

Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hoursbetween 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 expectedto 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 andclinical studies. As a precaution, concomitant use of omeprazole or esomeprazole should bediscouraged (see section 4.4).

Less pronounced reductions of metabolite exposure has been observed with pantoprazole orlansoprazole.

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 wasassociated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%,respectively. These results indicate that clopidogrel can be administered with pantoprazole.

There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers orantacids interfere with antiplatelet activity of clopidogrel.

Boosted anti-retroviral therapy (ART): HIV patients treated with boosted anti-retroviral therapies(ART) are at high-risk of vascular events.

A significantly reduced platelet inhibition has been shown in HIV patients treated with ritonavir-orcobicistat-boosted ART. Although the clinical relevance of these findings is uncertain, there have beenspontaneous reports of HIV-infected patients treated with ritonavir boosted ART, who haveexperienced re-occlusive events after de-obstruction or have suffered thrombotic events under aclopidogrel loading treatment schedule. Average platelet inhibition can be decreased with concomitantuse of clopidogrel and ritonavir. Therefore, concomitant use of clopidogrel with ART boostedtherapies should be discouraged.

Other medicinal products: A number of other clinical studies have been conducted with clopidogreland other concomitant medicinal products to investigate the potential for pharmacodynamic andpharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observedwhen 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 ofclopidogrel. Antacids did not modify the extent of clopidogrel absorption.

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

CYP2C9 can be safely co-administered with clopidogrel.

CYP2C8 substrate medicinal products: Clopidogrel has been shown to increase repaglinide exposure inhealthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibitionof CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma

Internalconcentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution (see section 4.4).

Apart from the specific medicinal product interaction information described above, interaction studieswith clopidogrel and some medicinal products commonly administered in patients withatherothrombotic disease have not been performed. However, patients entered into clinical trials withclopidogrel 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 clinicallysignificant adverse interactions.

As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay andreduce the absorption of clopidogrel presumably because of slowed gastric emptying. The clinicalrelevance is unknown. Consider the use of a parenteral antiplatelet agent in acute coronary syndromepatients requiring co-administration of morphine or other opioid agonists.

Rosuvastatin: Clopidogrel has been shown to increase rosuvastatin exposure in patients by 2-fold(AUC) and 1.3-fold (Cmax) after administration of a 300 mg clopidogrel dose, and by 1.4-fold (AUC)without effect on Cmax after repeated administration of a 75 mg clopidogrel dose.

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

It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shownexcretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not becontinued during treatment with Plavix.

Clopidogrel was not shown to alter fertility in animal studies.

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

Clopidogrel has been evaluated for safety in more than 44,000 patients who have participated inclinical studies, including over 12,000 patients treated for 1 year or more. Overall, clopidogrel75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. Theclinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and

ACTIVE-A studies are discussed below. In addition to clinical studies experience, adverse reactionshave been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in post-marketingexperience 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 bleedingwas 9.3%. The incidence of severe cases was similar for clopidogrel and ASA.

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In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronarybypass graft surgery in patients who stopped therapy more than five days prior to surgery. In patientswho remained on therapy within five days of bypass graft surgery, the event rate was 9.6% forclopidogrel 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. theplacebo plus ASA group. The incidence of major bleeding was similar between groups. This wasconsistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic orheparin therapy.

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

In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in theplacebo + ASA group (6.7% versus 4.3%). Major bleeding was mostly of extracranial origin in bothgroups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo +ASA group), mainly from thegastrointestinal 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). Therewas no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + ASAgroup and 0.7% in the placebo +ASA group) and hemorrhagic stroke (0.8% and 0.6%, respectively)between groups.

In TARDIS, patients with recent ischemic stroke receiving intensive antiplatelet therapy with threemedicinal products (ASA + clopidogrel + dipyridamole) had more bleeding and bleeding of greaterseverity when compared with either clopidogrel alone or combined ASA and dipyridamole (adjustedcommon OR 2.54, 95% CI 2.05-3.16, p<0.0001).

Adverse reactions that occurred either during clinical studies or that were spontaneously reported arepresented in the table below. Their frequency is defined using the following conventions: common(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare(<1/10,000), not known (cannot be estimated from the available data). Within each system organ class,adverse reactions are presented in order of decreasing seriousness.

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System Organ Common Uncommon Rare Very rare, not

Class known*

Blood and the Thrombocytopenia, Neutropenia, Thromboticlymphatic system leucopenia, including thrombocytopenicdisorders eosinophilia severe purpura (TTP) (seeneutropenia section 4.4), aplasticanaemia,pancytopenia,agranulocytosis,severethrombocytopenia,acquired haemophilia

A, granulocytopenia,anaemia

Cardiac disorders Kounis syndrome(vasospastic allergicangina/allergicmyocardialinfarction) in thecontext of ahypersensitivityreaction due toclopidogrel*

Immune system Serum sickness,disorders anaphylactoidreactions,cross-reactive drughypersensitivityamongthienopyridines (suchas ticlopidine,prasugrel) (seesection 4.4)*, insulinautoimmunesyndrome, which canlead to severehypoglycemia,particularly inpatients with HLA

DRA4 subtype (morefrequent in the

Japanesepopulation)*

Psychiatric Hallucinations,disorders confusion

Nervous system Intracranial Taste disturbances,disorders bleeding (some ageusiacases were reportedwith fataloutcome),headache,paraesthesia,dizziness

Eye disorders Eye bleeding(conjunctival,ocular, retinal)

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System Organ Common Uncommon Rare Very rare, not

Class known*

Ear and labyrinth Vertigodisorders

Vascular Haematoma Serious hemorrhage,disorders hemorrhage ofoperative wound,vasculitis,hypotension

Respiratory, Epistaxis Respiratory tractthoracic and bleedingmediastinal (haemoptysis,disorders pulmonaryhemorrhage),bronchospasm,interstitialpneumonitis,eosinophilicpneumonia

Gastrointestinal Gastrointestinal Gastric ulcer and Retroperitoneal Gastrointestinal anddisorders hemorrhage, duodenal ulcer, hemorrhage retroperitonealdiarrhoea, gastritis, vomiting, hemorrhage withabdominal pain, nausea, fatal outcome,dyspepsia constipation, pancreatitis, colitisflatulence (including ulcerativeor lymphocyticcolitis), stomatitis

Hepato-biliary Acute liver failure,disorders hepatitis, abnormalliver function test

Skin and Bruising Rash, pruritus, skin Bullous dermatitissubcutaneous bleeding (purpura) (toxic epidermaltissue disorders necrolysis, Stevens

Johnson Syndrome,erythemamultiforme, acutegeneralisedexanthematouspustulosis (AGEP)),angioedema,drug-inducedhypersensitivitysyndrome, drug rashwith eosinophilia andsystemic symptoms(DRESS), rasherythematous orexfoliative, urticaria,eczema, lichenplanus

Reproductive Gynaecomastiasystems andbreast disorders

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System Organ Common Uncommon Rare Very rare, not

Class known*

Musculoskeletal, Musculo-skeletalconnective tissue bleedingand bone (haemarthrosis),disorders arthritis, arthralgia,myalgia

Renal and urinary Haematuria Glomerulonephritis,disorders blood creatinineincreased

General disorders Bleeding at Feverand puncture siteadministrationsite conditions

Investigations Bleeding timeprolonged,neutrophil countdecreased, plateletcount decreased

* Information related to clopidogrel with frequency “not known”.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequentbleeding complications. Appropriate therapy should be considered if bleedings are observed.

No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction ofprolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.

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. Clopidogrelmust be metabolised by CYP450 enzymes to produce the active metabolite that inhibits plateletaggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosinediphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of theglycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversiblebinding, 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. Plateletaggregation induced by agonists other than ADP is also inhibited by blocking the amplification ofplatelet activation by released ADP.

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

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Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregationfrom the first day; this increased progressively and reached steady state between Day 3 and Day 7. Atsteady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within5 days after treatment was discontinued.

The safety and efficacy of clopidogrel have been evaluated in 7 double-blind studies involving over100,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY,

COMMIT, CHANCE, POINT and ACTIVE-A studies comparing clopidogrel to placebo, bothmedicinal 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 recentmyocardial infarction (<35 days), recent ischemic stroke (between 7 days and 6 months) or establishedperipheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or ASA325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of thepatients received ASA for the first few days following the acute myocardial infarction.

Clopidogrel significantly reduced the incidence of new ischemic events (combined end point ofmyocardial infarction, ischemic stroke and vascular death) when compared to ASA. In the intention totreat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA (relativerisk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p=0.045), which corresponds, for every1,000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented fromexperiencing a new ischemic event. Analysis of total mortality as a secondary endpoint did not showany significant difference between clopidogrel (5.8%) and ASA (6.0%).

In a subgroup analysis by qualifying condition (myocardial infarction, ischemic stroke, and PAD) thebenefit appeared to be strongest (achieving statistical significance at p=0.003) in patients enrolled dueto PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 to36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardialinfarction, 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 thebenefit 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 clearwhether the differences in relative risk reduction across qualifying conditions are real, or a result ofchance.

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 themost recent episode of chest pain or symptoms consistent with ischemia. Patients were required tohave either ECG changes compatible with new ischemia or elevated cardiac enzymes or troponin I or Tto at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loadingdose 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. Heparinswere administered in more than 90% of the patients and the relative rate of bleeding betweenclopidogrel and placebo was not significantly affected by the concomitant heparin therapy.

Internal

The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardialinfarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in theplacebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for theclopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29%when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stentand 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 benefitobserved in the clopidogrel + ASA group was not further increased, whereas the risk of hemorrhagepersisted (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 refractoryischemia) was 1,035 (16.5%) in the clopidogrel-treated group and 1,187 (18.8%) in the placebo-treatedgroup, 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 noobserved 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 withthe results of the primary analysis. In particular, in a post-hoc analysis in 2,172 patients (17% of thetotal CURE population) who underwent stent placement (Stent-CURE), the data showed thatclopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel forthe co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the secondco-primary endpoint (CV death, MI, stroke or refractory ischemia). Moreover, the safety profile ofclopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from thissubset are in line with the overall trial results.

The benefits observed with clopidogrel were independent of other acute and long-term cardiovasculartherapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering medicinal products, betablockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of

ASA (75-325 mg once daily).

ST-segment Elevation Myocardial Infarction

In patients with acute ST-segment elevation MI (STEMI), safety and efficacy of clopidogrel have beenevaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY, a prospectivesubgroup analysis of CLARITY (CLARITY PCI) 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 to325 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 thecomposite 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 endpointwas death or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient populationincluded 19.7% women and 29.2% patients ≥ 65 years. A total of 99.7% of patients receivedfibrinolytics (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 reachedthe primary endpoint, representing an absolute reduction of 6.7% and a 36 % odds reduction in favor

Internalof clopidogrel (95% CI: 24, 47%; p < 0.001), mainly related to a reduction in occluded infarct-relatedarteries. This benefit was consistent across all prespecified subgroups including patients’ age andgender, infarct location, and type of fibrinolytic or heparin used.

CLARITY PCI sub-group analysis involved 1,863 STEMI patients undergoing PCI. Patientsreceiving 300 mg loading dose (LD) of clopidogrel (n=933) had a significant reduction in incidence ofcardiovascular death, MI or stroke following PCI compared to those receiving placebo (n=930) (3.6%with clopidogrel pre-treatment versus 6.2% with placebo, OR: 0.54; 95% CI: 0.35-0.85; p=0.008). Thepatients receiving 300 mg LD of clopidogrel had a significant reduction in incidence of cardiovasculardeath, MI or stroke through 30 days following PCI compared to those receiving placebo (7.5% withclopidogrel pre-treatment versus 12.0% with placebo, OR: 0.59; 95% CI: 0.43-0.81; p=0.001).

However, this composite endpoint when assessed in the overall population of the CLARITY study wasnot statistically significant as a secondary endpoint. No significant difference was observed in the ratesof major or minor bleeding between both the treatments (2.0% with clopidogrel pre-treatment versus1.9% with placebo, p>0.99). The findings of this analysis support the early use of clopidogrel loadingdose in STEMI and the strategy of routine clopidogrel pretreatment in patients undergoing PCI.

The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of theonset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, STdepression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) orplacebo (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, strokeor death. The population included 27.8% women, 58.4% patients ≥ 60 years (26% ≥ 70 years) and54.5% patients who received fibrinolytics.

Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and therelative risk of the combination of re-infarction, stroke or death by 9% (p=0.002), representing anabsolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender andwith or without fibrinolytics, and was observed as early as 24 hours.

Clopidogrel 600 mg Loading Dose in Acute Coronary Syndrome Patients Undergoing PCI

CURRENT-OASIS-7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events

Seventh Organization to Assess Strategies in Ischemic Syndromes)

This randomized factorial trial included 25,086 individuals with acute coronary syndrome (ACS)intended for early PCI. Patients were randomly assigned to either double-dose (600 mg on Day 1, then150 mg on Days 2-7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily)clopidogrel, and high-dose (300-325 mg daily) versus low-dose (75-100 mg daily) ASA. The 24,835enrolled ACS patients underwent coronary angiography and 17,263 received PCI. Among the 17,263patients receiving PCI treatment, when compared with the standard dose, double-dose clopidogrelreduced the rate of the primary endpoint (3.9% vs 4.5% adjusted HR= 0.86, 95% CI 0.74-0.99,p=0.039) and significantly reduced stent thrombosis (1.6% vs 2.3%, HR: 0.68; 95% CI: 0.55 0.85;p=0.001). Major bleeding was more common with double-dose than with standard-dose clopidogrel(1.6% vs 1.1%, HR=1.41, 95% CI 1.09-1.83, p=0.009). In this trial, clopidogrel 600 mg loading dosehas shown consistent efficacy in patients age ≥75 years of age and patients <75 years of age.

ARMYDA-6 MI (The Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty -

Myocardial Infarction)

This randomized, prospective, international, multicenter trial evaluated pre-treatment with a 600 mgversus 300 mg clopidogrel LD in the setting of urgent PCI for STEMI. Patients received a clopidogrel600 mg LD (n=103) or clopidogrel 300 mg LD (n=98) prior to PCI, then were prescribed 75 mg/dayfrom the day after PCI up to 1 year. Patients receiving a 600 mg LD of clopidogrel had a significantlyreduced infarct size compared to those receiving a 300 mg LD. There was less frequent thrombolysisin MI flow Grade <3 after PCI in 600 mg LD (5.8% versus 16.3%, p=0.031), improved LVEF atdischarge (52.1 ±9.5% versus 48.8 ±11.3%, p=0.026), and 30-day major adverse cardiovascular eventswere fewer (5.8% versus 15%, p=0.049). No increase in bleeding or entry-site complications wereobserved (secondary endpoints at Day 30).

Internal

HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial

Infarction)

This post-hoc analysis trial was conducted to evaluate whether a 600 mg clopidogrel LD providesfaster and greater inhibition of platelet activation. The analysis examined the impact of a LD of 600mg compared with 300 mg on 30-day clinical outcomes in 3,311 patients from the main trial (n=1,153;300 mg LD group; n=2,158; 600 mg LD group) before cardiac catheterization followed by 75 mg/daydose for ≥6 months post-discharge. The results showed significantly lower 30-day unadjusted rates ofmortality (1.9% versus 3.1%, p=0.03), reinfarction (1.3% versus 2.3%, p=0.02), and definite orprobable stent thrombosis (1.7% versus 2.8%, p=0.04) with the 600 mg LD without higher bleedingrates. By multivariable analysis, a 600 mg LD was an independent predictor of lower rates of 30-daymajor adverse cardiac events (HR: 0.72 [95% CI: 0.53-0.98], p=0.04). Major bleeding rate (non-

CABG related) was 6.1% in 600 mg LD group and 9.4% in 300 mg LD group (p=0.0005). Minorbleeding rate was 11.3% in 600 mg LD group and 13.8% in 300 mg LD group (p=0.03).

Long Term (12 Months) Treatment with Clopidogrel in STEMI Patients after PCI

CREDO (Clopidogrel for the Reduction of Adverse Events During Observation)

This randomized, double-blind, placebo-controlled trial was conducted in the United States and

Canada to evaluate the benefit of long-term (12 month) treatment with clopidogrel after PCI. Therewere 2,116 patients randomized to receive a 300 mg clopidogrel LD (n=1,053) or placebo (n=1,063) 3to 24 hours before PCI. All patients also received 325 mg of aspirin. Thereafter, all patients receivedclopidogrel 75 mg/day through Day 28 in both groups. From Day 29 through 12 months, patients inclopidogrel group received 75 mg/day clopidogrel and in control group received placebo. Both groupsreceived ASA throughout the study (81 to 325 mg/day). At 1-year, significant reduction in thecombined risk of death, MI or stroke was observed with clopidogrel (26.9% relative reduction, 95%

CI: 3.9%-44.4%; p=0.02; absolute reduction 3%) compared to placebo. No significant increase in therate of major bleeding (8.8% with clopidogrel versus 6.7% with placebo, p=0.07) or minor bleeding(5.3% with clopidogrel versus 5.6% with placebo, p=0.84) at 1-year was observed. The major findingof this study is that continuation of clopidogrel and ASA for at least 1-year leads to a statistically andclinically significant reduction in major thrombotic events.

EXCELLENT (Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting)

This prospective, open-label, randomized trial was conducted in Korea to evaluate whether 6-monthdual antiplatelet therapy (DAPT) would be noninferior to 12-month DAPT after implantation of drug-eluting stents. The study included 1,443 patients undergoing implantation who were randomized toreceive 6-month DAPT (ASA 100-200 mg/day plus clopidogrel 75 mg/day for 6 months andthereafter ASA alone up to 12 months) or 12-month DAPT (ASA 100-200 mg/day plus clopidogrel75 mg/day for 12 months). No significant difference was observed in the incidence of target vesselfailure (composite of cardiac death, MI or target vessel revascularization) which was primary end pointbetween 6-month and 12-month DAPT groups (HR: 1.14; 95% CI: 0.70 1.86; p=0.60). Also, the studyshowed no significant difference in the safety end point (composite of death, MI, stroke, stentthrombosis or TIMI major bleeding) between 6-month and 12-month DAPT groups (HR: 1.15; 95%

CI: 0.64-2.06; p=0.64). The major finding of this study was that 6-month DAPT was non-inferior to12-month DAPT in the risk of target vessel failure.

De-escalation of P2Y12 Inhibitor Agents in Acute Coronary Syndrome

Switching from a more potent P2Y12 receptor inhibitor to clopidogrel in association with aspirin afteracute phase in Acute Coronary Syndrome (ACS) has been evaluated in two randomized investigator-sponsored studies (ISS) - TOPIC and TROPICAL-ACS - with clinical outcome data.

The clinical benefit provided by the more potent P2Y12 inhibitors, ticagrelor and prasugrel, in theirpivotal studies is related to a significant reduction in recurrent ischemic events (including acute andsubacute stent thrombosis (ST), myocardial infarction (MI), and urgent revascularization). Althoughthe ischemic benefit was consistent throughout the first year, greater reduction in ischemic recurrenceafter ACS was observed during the initial days following the treatment initiation. In contrast, post-hocanalyses demonstrated statistically significant increases in the bleeding risk with the more potent

P2Y12 inhibitors, occurring predominantly during the maintenance phase, after the first month

Internalpost-ACS. TOPIC and TROPICAL-ACS were designed to study how to mitigate the bleeding eventswhile maintaining efficacy.

TOPIC (Timing Of Platelet Inhibition after acute Coronary syndrome)

This randomized, open-label trial included ACS patients requiring percutaneous coronary intervention(PCI). Patients on aspirin and a more potent P2Y12 blocker and without adverse event at one monthwere assigned to switch to fixed-dose aspirin plus clopidogrel (de-escalated dual antiplatelet therapy(DAPT)) or continuation of their drug regimen (unchanged DAPT).

Overall, 645 of 646 patients with ST-elevation-MI (STEMI) or non-ST-elevation-MI (NSTEMI) orunstable angina were analyzed (de-escalated DAPT (n=322); unchanged DAPT (n=323)). Follow-up atone year was performed for 316 patients (98.1%) in the de-escalated DAPT group and 318 patients(98.5%) in the unchanged DAPT group. The median follow-up for both groups was 359 days. Thecharacteristics of the studied cohort were similar in the 2 groups.

The primary outcome, a composite of cardiovascular death, stroke, urgent revascularization, and

BARC (Bleeding Academic Research Consortium) bleeding ≥2 at 1 year post ACS, occurred in43 patients (13.4%) in the de-escalated DAPT group and in 85 patients (26.3%) in the unchanged

DAPT group (p<0.01). This statistically significant difference was mainly driven by fewer bleedingevents, with no difference reported in ischemic endpoints (p=0.36), while BARC ≥2 bleeding occurredless frequently in the de-escalated DAPT group (4.0%) versus 14.9% in the unchanged DAPT group(p<0.01). Bleeding events defined as all BARC occurred in 30 patients (9.3%) in the de-escalated

DAPT group and in 76 patients (23.5%) in the unchanged DAPT group (p<0.01).

TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatmentfor Acute Coronary Syndromes)

This randomized, open-label trial included 2,610 biomarker-positive ACS patients after successful

PCI. Patients were randomized to receive either prasugrel 5 or 10 mg/d (Days 0-14) (n=1306), orprasugrel 5 or 10 mg/d (Days 0-7) then de-escalated to clopidogrel 75 mg/d (Days 8-14) (n=1304), incombination with ASA (<100 mg/day). At Day 14, platelet function testing (PFT) was performed. Theprasugrel-only patients were continued on prasugrel for 11.5 months.

The de-escalated patients underwent high platelet reactivity (HPR) testing. If HPR≥46 units, thepatients were escalated back to prasugrel 5 or 10 mg/d for 11.5 months; if HPR<46 units, the patientscontinued on clopidogrel 75 mg/d for 11.5 months. Therefore, the guided de-escalation arm hadpatients on either prasugrel (40%) or clopidogrel (60%). All patients were continued on aspirin andwere followed for one year.

The primary endpoint (the combined incidence of CV death, MI, stroke and BARC bleeding grade ≥2at 12 months) was met showing non-inferiority. Ninety-five patients (7%) in the guided de-escalationgroup and 118 patients (9%) in the control group (p non-inferiority=0.0004) had an event. The guidedde-escalation did not result in an increased combined risk of ischemic events (2.5% in the de-escalation group vs 3.2% in the control group; p non-inferiority=0.0115), nor in the key secondaryendpoint of BARC bleeding ≥2 ((5%) in the de-escalation group versus 6% in the control group(p=0.23)). The cumulative incidence of all bleeding events (BARC class 1 to 5) was 9% (114 events)in the guided de-escalation group versus 11% (137 events) in the control group (p=0.14).

Dual Antiplatelet Therapy (DAPT) in Acute Minor IS or Moderate to High-risk TIA

DAPT with combination clopidogrel and ASA as a treatment to prevent stroke after an acute minor ISor moderate to high-risk TIA has been evaluated in two randomized investigator-sponsored studies(ISS) - CHANCE and POINT - with clinical safety and efficacy outcome data.

CHANCE (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events)

This randomized, double-blinded, multicenter, placebo-controlled clinical trial included 5,170 Chinesepatients with acute TIA (ABCD2 score ≥4) or acute minor stroke (NIHSS ≤3). Patients in both groupsreceived open-label ASA on day 1 (with the dose ranging from 75 to 300 mg, at the discretion of the

Internaltreating physician). Patients randomly assigned to the clopidogrel-ASA group received a loading doseof 300 mg of clopidogrel on day 1, followed by a dose of 75 mg of clopidogrel per day on days 2through 90, and ASA at a dose of 75 mg per day on days 2 through 21. Patients randomly assigned tothe ASA group received a placebo version of clopidogrel on days 1 through 90 and ASA at a dose of75 mg per day on days 2 through 90.

The primary efficacy outcome was any new stroke event (ischemic and hemorrhagic) in the first 90days after acute minor IS or high-risk TIA. This occurred in 212 patients (8.2%) in the clopidogrel-

ASA group compared with 303 patients (11.7%) in the ASA group (hazard ratio [HR], 0.68; 95%confidence interval [CI], 0.57 to 0.81; P<0.001). IS occurred in 204 patients (7.9%) in the clopidogrel-

ASA group compared with 295 (11.4%) in the ASA group (HR, 0.67; 95% CI, 0.56 to 0.81; P<0.001).

Hemorrhagic stroke occurred in 8 patients in each of the two study groups (0.3% of each group).

Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-ASA group andin eight (0.3%) in the ASA group (P = 0.73). The rate of any bleeding event was 2.3% in theclopidogrel-ASA group as compared with 1.6% in the ASA group (HR, 1.41; 95% CI, 0.95 to 2.10;

P = 0.09).

POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke)

This randomized, double-blinded, multicenter, placebo-controlled clinical trial included 4,881international patients with acute TIA (ABCD2 score ≥4) or minor stroke (NIHSS ≤3). All patients inboth groups received open-label ASA on day 1 to 90 (50-325 mg depending upon the discretion of thetreating physician). Patients randomly assigned to the clopidogrel group received a loading dose of 600mg of clopidogrel on day 1, followed by 75 mg of clopidogrel per day on days 2 through 90. Patientsrandomly assigned to the placebo group received clopidogrel placebo on days 1 through 90.

The primary efficacy outcome was a composite of major ischemic events (IS, MI or death from anischemic vascular event) at day 90. This occurred in 121 patients (5.0%) receiving clopidogrel plus

ASA compared with 160 patients (6.5%) receiving ASA alone (HR, 0.75; 95% CI, 0.59 to 0.95;

P = 0.02). The secondary outcome of IS occurred in 112 patients (4.6%) receiving clopidogrel plus

ASA compared with 155 patients (6.3%) receiving ASA alone (HR, 0.72; 95% CI, 0.56 to 0.92;

P = 0.01). The primary safety outcome of major hemorrhage occurred in 23 of 2,432 patients (0.9%)receiving clopidogrel plus ASA and in 10 of 2,449 patients (0.4%) receiving ASA alone (HR, 2.32;95% CI, 1.10 to 4.87; P = 0.02). Minor hemorrhage occurred in 40 patients (1.6%) receivingclopidogrel plus ASA and in 13 (0.5%) receiving ASA alone (HR, 3.12; 95% CI, 1.67 to 5.83;

P < 0.001).

CHANCE and POINT Time Course Analysis

There was no efficacy benefit of continuing DAPT beyond 21 days. A time-course distribution ofmajor ischemic events and major hemorrhages by treatment assignment was done to analyze theimpact of the short-term time-course of DAPT.

Table 1- Time course distribution of major ischemic events and major hemorrhages bytreatment assignment in CHANCE and POINT

No. of events

Outcomes in

CHANCE and Total 1st week 2nd week 3rd weekassignment

POINT

Major ischemic ASA (n=5,035) 458 330 36 21events

CLP+ASA(n=5,016) 328 217 30 14

Difference 130 113 6 7

Major Hemorrhage ASA (n=5,035) 18 4 2 1

CLP+ASA(n=5,016) 30 10 4 2

Difference -12 -6 -2 -1

Internal

Atrial fibrillation

The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patientswith atrial fibrillation (AF) who had at least one risk factor for vascular events. Based on enrollmentcriteria, 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 wasmore effective than with clopidogrel and ASA.

The ACTIVE-A study (N=7,554) was a multicenter, randomized, double-blind, placebo-controlledstudy which compared clopidogrel 75 mg/day + ASA (N=3,772) to placebo + ASA (N=3,782). Therecommended 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., eitherpermanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least one of thefollowing risk factors: age 75 years or age 55 to 74 years and either diabetes mellitus requiring drugtherapy, or documented previous MI or documented coronary artery disease; treated for systemichypertension; prior stroke, transient ischemic attack (TIA), or non-CNS systemic embolus; leftventricular dysfunction with left ventricular ejection fraction <45%; or documented peripheralvascular disease. The mean CHADS2 score was 2.0 (range 0-6).

The major exclusion criteria for patients were documented peptic ulcer disease within the previous6 months; prior intracerebral hemorrhage; significant thrombocytopenia (platelet count < 50 x 109/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 VKAdue 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, thephysician’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% ACEinhibitors, 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 of2.4% to 19.1%; p=0.013), primarily due to a large reduction in the incidence of strokes. Strokesoccurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receivingplacebo + ASA (relative risk reduction, 28.4%; 95% CI, 16.8% to 38.3%; p=0.00001).

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

Plavix 75 mg/day.

In a randomised, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonatesand infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterialshunt were randomised to receive clopidogrel 0.2 mg/kg (n=467) or placebo (n=439) along withconcomitant background therapy up to the time of second stage surgery. The mean time between shuntpalliation and first administration of study medicinal product was 20 days. Approximately 88% ofpatients received concomitant ASA (range of 1 to 23 mg/kg/day). There was no significant differencebetween groups in the primary composite endpoint of death, shunt thrombosis or cardiac-related

Internalintervention prior to 120 days of age following an event considered of thrombotic nature (89 [19.1%]for the clopidogrel group and 90 [20.5%] for the placebo group) (see section 4.2). Bleeding was themost frequently reported adverse reaction in both clopidogrel and placebo groups; however, there wasno significant difference in the bleeding rate between groups. In the long-term safety follow-up of thisstudy, 26 patients with the shunt still in place at one year of age received clopidogrel up to 18 monthsof age. No new safety concerns were noted during this long-term follow-up.

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

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

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

Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolisedaccording to two main metabolic pathways: one mediated by esterases and leading to hydrolysis intoits inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiplecytochromes 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 theactive metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by

CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and

CYP3A4. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly toplatelet receptors, thus inhibiting platelet aggregation.

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

Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in theurine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oraldose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of themain 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-clopidogrelintermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, asmeasured 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 themajority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Otheralleles 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 asdefined above. Published frequencies for the poor CYP2C19 metaboliser genotypes are approximately

Internal2% 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 mgfollowed 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 poormetabolisers, active metabolite exposure was decreased by 63-71% compared to extensivemetabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poormetabolisers with mean IPA (5 μM ADP) of 24% (24 hours) and 37% (Day 5) as compared to IPA of39% (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, activemetabolite 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 the300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not beenestablished in clinical outcome trials.

Consistent with the above results, in a meta-analysis including 6 studies of 335 clopidogrel-treatedsubjects at steady state, it was shown that active metabolite exposure was decreased by 28% forintermediate 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 toextensive metabolisers.

The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has notbeen evaluated in prospective, randomised, controlled trials. There have been a number ofretrospective analyses, however, to evaluate this effect in patients treated with clopidogrel for whomthere 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 cohortstudies.

In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group ofpatients 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 poormetabolisers when compared to extensive metabolisers.

In CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), no increased event rate wasobserved based on metaboliser status.

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

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

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

Internal

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

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

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 theclinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. Noeffect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at thetherapeutic dose.

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

There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to miceand 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times theexposure 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 nogenotoxic activity.

Clopidogrel was found to have no effect on the fertility of male and female rats and was notteratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay inthe development of the offspring. Specific pharmacokinetic studies performed with radiolabelledclopidogrel 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 beexcluded.

Core:

Mannitol (E421)

Macrogol 6000

Microcrystalline cellulose

Hydrogenated castor oil

Low substituted hydroxypropylcellulose

Hypromellose (E464)

Lactose monohydrate

Triacetin (E1518)

Titanium dioxide (E171)

Red iron oxide (E172)

Polishing agent:

Carnauba wax

Internal

Not applicable

3 years

In PVC/PVDC/aluminium blisters, store below 30°C.

In all aluminium blisters, this medicinal product does not require any special storage conditions.

Plavix 75 mg film-coated tablets

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 unit-dose blister packs in cardboard cartons containing 50x1film-coated tablets.

Plavix 300 mg film-coated tablets

Aluminium unit-dose blisters in cardboard cartons containing 4x1, 10x1, 30x1 and 100x1 film-coatedtablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sanofi Winthrop Industrie82 avenue Raspail94250 Gentilly

France

Plavix 75 mg film-coated tablets

EU/1/98/069/001 - Cartons of 28 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/98/069/002 - Cartons of 50x1 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/98/069/003 - Cartons of 84 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/98/069/004 - Cartons of 100 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/98/069/005 - Cartons of 30 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/98/069/006 - Cartons of 90 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/98/069/007 - Cartons of 14 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/98/069/011 - Cartons of 7 film-coated tablets in PVC/PVDC/Alu blisters

EU/1/98/069/013 - Cartons of 28 film-coated tablets in all aluminium blisters

EU/1/98/069/014 - Cartons of 50x1 film-coated tablets in all aluminium blisters

EU/1/98/069/015 - Cartons of 84 film-coated tablets in all aluminium blisters

Internal

EU/1/98/069/016 - Cartons of 100 film-coated tablets in all aluminium blisters

EU/1/98/069/017 - Cartons of 30 film-coated tablets in all aluminium blisters

EU/1/98/069/018 - Cartons of 90 film-coated tablets in all aluminium blisters

EU/1/98/069/019 - Cartons of 14 film-coated tablets in all aluminium blisters

EU/1/98/069/020 - Cartons of 7 film-coated tablets in all aluminium blisters

Plavix 300 mg film-coated tablets

EU/1/98/069/008 - Cartons of 4x1 film-coated tablets in all aluminium unit-dose blisters

EU/1/98/069/009 - Cartons of 30x1 film-coated tablets in all aluminium unit-dose blisters

EU/1/98/069/010 - Cartons of 100x1 film-coated tablets in all aluminium unit-dose blisters

EU/1/98/069/012 - Cartons of 10x1 film-coated tablets in all aluminium unit-dose blisters

Date of first authorisation: 15 July 1998

Date of latest renewal: 19 June 2008

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Detailed information on this medicinal product is available on the website of the European Medicines

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