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Clopidogrel Teva Generics B.V. (clopidogrel hydrochloride) – Summary of product characteristics - B01AC04

Updated on site: 06-Oct-2017

Medication nameClopidogrel Teva Generics B.V.
ATC CodeB01AC04
Substanceclopidogrel hydrochloride
ManufacturerTeva Pharma B.V.
1. NAME OF THE MEDICINAL PRODUCT
Clopidogrel Teva Generics B.V. 75 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride).
Excipient:
Each film-coated tablet contains 13 mg hydrogenated castor oil. For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

 

authorised

Film-coated tablet.

 

Pink, round and slightly convex film-coated tablets.

4.

CLINICAL PARTICULARS

 

4.1

Therapeutic indications

 

 

 

Clopidogrel is indicated in adults for the prevention of atherothrombotic events in:

Patients suffering from myocardial infarction (fr m a few days until less than 35 days),

 

ischaemic stroke (from 7 days until less than 6 months)longeror established peripheral arterial

disease.

 

 

Patients suffering from acute coronary syndrome:

 

 

-

 

no

 

 

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

 

 

myocardial infarction), incl ing patients undergoing a stent placement following

 

-

percutaneous coronaryproductintervention, in combination with acetylsalicylic acid (ASA).

 

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

 

 

treated patients e igible for thrombolytic therapy.

 

 

ClopidogrelMedicinalshould be given as a single daily dose of 75 mg with or without food.

For further information please refer to section 5.1.

 

4.2

Posology and method of administration

 

 

Adults and elderly

 

 

 

In patients suffering from acute coronary syndrome:

 

Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): clopidogrel treatment should be initiated with a single 300 mg loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The

optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months (see section 5.1).

ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a 300 mg loading dose in combination with ASA and with or without thrombolytics. For patients over 75 years of age clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least four weeks. The benefit of the combination

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

Pharmacogenetics

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

Paediatric patients

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

Renal impairment

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

Hepatic impairment

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

4.3 Contraindications

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

Severe liver impairment.

Active pathological bleeding such as peptic ulcer or intracrani l h emorrhage.

4.4 Special warnings and precautions for use

authorised

Bleeding and haematological disorderslonger

Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing should be promptly c nsidered whenever clinical symptoms

suggestive of bleeding arise during the course ofnotreatment (see section 4.8). As with other antiplatelet agents, clopidogrel should be usedproductwith cau ion in patients who may be at risk of increased bleeding

from trauma, surgery or other pathological onditions 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 f ll wed carefully for any signs of bleeding including occult bleeding, especially during the fi st weeks of treatment and/or after invasive cardiac procedures or

surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it mayMedicinalincrease 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 dis ontinued 7 days prior to surgery. Patients should inform physicians and dentists that th y are taking clopidogrel before any surgery is scheduled and before any new medicinal product is tak n. 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: 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 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 medicinal products that inhibit CYP2C19 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 secti n 4.2).

Excipients

 

 

 

This medicinal product contains hydrogenated castor oil which may c use stomach upset and

diarrhoea.

 

 

authorised

 

 

 

4.5 Interaction with other medicinal products and other forms of interaction

Oral anticoagulants: the concomitant administrati

n f clopidogrel with oral anticoagulants is not

recommended since it may increase the intensity

 

longer

 

f bleedings (see section 4.4).

no

 

 

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

Acetylsalicylic acid (ASA): ASA did n t modify the clopidogrel-mediated inhibition of ADP-induced

pharmacodynamic intera t on between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleed ng. 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).

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

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 medicinal products that inhibit CYP2C19 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 at the same time as clopidogrel) were administered for 5 days. The xposure to the active metabolite of clopidogrel was decreased by 45% (Day 1) and 40% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) with

In a crossover clinical study, clopidogrel (300-mg loading dose followedauthorisedby 75 mg/day) alone and with

5 μM ADP was diminished by 39% (24 hours) and 21% (Day 5) when clopid grel and omeprazole were administered together. In another study it was shown that adminis ering clopidogrel and omeprazole 12 hours apart did not prevent their interaction that is likely to be driven by the inhibitory

effect of omeprazole on CYP2C19. Esomeprazole is expected to give similar interaction with clopidogrel.longer

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 f meprazole or esomeprozole should be discouraged (see section 4.4). No conclusive data on the pharmacodynamic interaction of clopidogrel

and other PPIs are available.

product

no

 

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 medicinalMedicinalproducts:

A number of other clin cal studies have been conducted with clopidogrel and other concomitant medicinal products to nvestigate the potential for pharmacodynamic and pharmacokinetic interactions. No cl n ally significant pharmacodynamic interactions were observed when clopidogrel was co-administ r with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration of phenobarbital, or oestrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.

Data from studies with human liver microsomes indicated that the carboxylic acid metabolite of clopidogrel could inhibit the activity of Cytochrome P450 2C9. This could potentially lead to increased plasma levels of medicinal products such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by Cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.

Apart from the specific medicinal product interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers,

ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.

4.6 Pregnancy and lactation

As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

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 Teva Generics B.V..

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

authorised

 

Clopidogrel has been evaluated for safety in more than 42,000 patients who have participated in

longer

 

clinical studies, including over 9,000 patients treated for 1 year or more. The clinically relevant

adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed below. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. In addition to clinical studies experience, adverse reactions have been spontaneously reported.

no Bleeding is the most common productreaction repor ed both in clinical studies as well as in post-marketing experience where it was mostly reported during he first month of treatment.

In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding was 9.3%. The incidence of seve e cases was 1.4% for clopidogrel and 1.6% for ASA.

In CURE, the major bleeding event rate for clopidogrel + ASA was dose-dependent on ASA (<100 mg: 2.6%;Medicinal100-200 mg: 3.5%; >200 mg: 4.9%) as was the major bleeding event rate for placebo + ASA (<100 mg: 2.0%; 100-200 mg: 2.3%; >200 mg: 4.0%).The risk of bleeding

(life-threatening, major, minor, other) decreased during the course of the trial: 0-1 months (clopidogrel: 9.6%; placebo: 6.6%), 1-3 months (clopidogrel: 4.5%; placebo: 2.3%), 3-6 months (clopidogrel: 3.8%; placebo: 1.6%), 6-9 months (clopidogrel: 3.2%; placebo: 1.5%), 9-12 months (clopidogrel: 1.9%; placebo: 1.0%). There was no excess in major bleeds with clopidogrel + ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel + ASA vs. 5.3% placebo + ASA). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel+ASA, and 6.3% for placebo + ASA.

In CLARITY, there was an overall increase in bleeding in the clopidogrel + ASA group (17.4%) vs. the placebo + ASA group (12.9%). The incidence of major bleeding was similar between groups (1.3% versus 1.1% for the clopidogrel + ASA and the placebo + ASA groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy.

In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups (0.6% versus 0.5% in the clopidogrel + ASA and the placebo + ASA groups, respectively).

Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table below. Their frequency is defined using the following conventions: common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Within each system organ class, adverse drug reactions are presented in order of decreasing seriousness.

System Organ

Common

 

Uncommon

 

Rare

 

Very rare

Class

 

 

 

 

 

 

 

 

Blood and the

 

 

Thrombocytopenia,

Neutropenia,

Thrombotic

lymphatic system

 

 

leucopenia,

 

including severe

thrombocytopenic

disorders

 

 

 

eosinophilia

 

neutropenia

purpura (TTP) (see

 

 

 

 

 

 

 

 

section 4.4),

 

 

 

 

 

 

 

 

aplastic anaemia,

 

 

 

 

 

 

 

 

pancytopenia,

 

 

 

 

 

 

 

 

agranulocytosis,

 

 

 

 

 

 

 

 

s v re

 

 

 

 

 

 

 

 

thrombocytopenia,

 

 

 

 

 

 

 

 

granulocytopenia,

 

 

 

 

 

 

 

 

anaemia

Immune system

 

 

 

 

 

 

Serum sickness,

disorders

 

 

 

 

 

 

 

anaphylactoid

 

 

 

 

 

 

 

 

reactions

 

 

 

 

 

 

 

authorised

Psychiatric

 

 

 

 

 

 

 

Hallucinations,

disorders

 

 

 

 

 

 

 

confusion

Nervous system

 

 

Intracranial

 

 

 

Taste disturbances

disorders

 

 

 

bleeding (some

 

 

 

 

 

 

 

cases were

longer

 

 

 

 

 

 

 

 

 

 

 

 

 

reported with fatal

 

 

 

 

 

 

 

outcome),

 

 

 

 

 

 

 

 

no

 

 

 

 

 

 

 

 

heada he,

 

 

 

 

 

 

 

 

paraesthesia,

 

 

 

 

 

 

 

 

izziness

 

 

 

 

Eye disorders

 

 

Eye bleeding

 

 

 

 

 

 

 

 

(conjunctival,

 

 

 

 

 

 

 

productocular, retinal)

 

 

 

Ear and labyrinth

 

 

 

 

Vertigo

 

disorders

 

 

 

 

 

 

 

 

Vascular

 

Haematoma

 

 

 

 

Serious

disorders

Medicinal

 

 

 

 

 

haemorrhage,

 

 

 

 

 

 

haemorrhage of

 

 

 

 

 

 

operative wound,

 

 

 

 

 

 

vasculitis,

 

 

 

 

 

 

hypotension

 

 

 

 

 

 

 

 

Respiratory,

Epistaxis

 

 

 

 

 

Respiratory tract

thoracic and

 

 

 

 

 

 

bleeding

mediastinal

 

 

 

 

 

 

 

(haemoptysis,

disorders

 

 

 

 

 

 

 

pulmonary

 

 

 

 

 

 

 

 

haemorrhage),

 

 

 

 

 

 

 

 

bronchospasm,

 

 

 

 

 

 

 

 

interstitial

 

 

 

 

 

 

 

 

pneumonitis

System Organ

Common

Uncommon

 

Rare

 

Very rare

Class

 

 

 

 

 

 

Gastrointestinal

Gastrointestinal

Gastric ulcer and

Retroperitoneal

Gastrointestinal and

disorders

haemorrhage,

duodenal ulcer,

haemorrhage

retroperitoneal

 

diarrhoea,

gastritis, vomiting,

 

 

haemorrhage with

 

abdominal pain,

nausea,

 

 

 

fatal outcome,

 

dyspepsia

constipation,

 

 

 

pancreatitis, colitis

 

 

flatulence

 

 

 

(including

 

 

 

 

 

 

ulcerative or

 

 

 

 

 

 

lymphocytic

 

 

 

 

 

 

colitis), stomatitis

Hepato-biliary

 

 

 

 

 

Acute liver failure,

disorders

 

 

 

 

 

hepatitis, abnormal

 

 

 

 

 

 

liver function test

Skin and

Bruising

Rash, pruritus, skin

 

 

Bullous dermatitis

subcutaneous

 

bleeding (purpura)

 

authorised

 

 

 

(toxic epidermal

tissue disorders

 

 

 

 

 

n crolysis, Stevens

 

 

 

 

 

 

Johnson Syndrome,

 

 

 

 

 

 

erythema

 

 

 

 

 

 

multiforme),

 

 

 

 

 

 

angioedema, rash

 

 

 

 

 

 

erythematous,

 

 

 

longer

 

urticaria, eczema,

 

 

 

 

lichen planus

 

 

 

 

 

 

Musculoskeletal,

 

 

 

 

 

Musculo-skeletal

connective tissue

 

 

 

 

 

bleeding

and bone

 

 

 

 

 

(haemarthrosis),

disorders

 

no

 

 

 

arthritis, arthralgia,

 

 

 

 

 

myalgia

 

 

 

 

 

 

administration

product

 

 

 

Glomerulonephritis,

Renal and urinary

 

Haema uria

 

 

 

disorders

 

 

 

 

 

blood creatinine

 

 

 

 

 

 

increased

General disorders

Bleeding at

 

 

 

 

Fever

and

puncture site

 

 

 

 

 

site conditions

 

 

 

 

 

 

Medicinal

Bleeding time

 

 

 

Investigations

 

 

 

 

 

 

prolonged,

 

 

 

 

 

 

neutrophil count

 

 

 

 

 

decreased, platelet

 

 

 

 

 

count decreased

 

 

 

4.9 Overdose

 

 

 

 

 

 

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleedings are observed. No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin, ATC code: B01AC-04.

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

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

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

60%. Platelet aggregation and bleeding time gradually returned to baseline values, g n rally within 5 days after treatment was discontinued.

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 mgauthorisedper day was between 40% and

The safety and efficacy of clopidogrel have been evaluated in 4 double-blind studies involving over 80,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY and COMMIT studies comparing clopidogrel to placebo, both medicin l products given in combination with ASA and other standard therapy.

Recent myocardial infarction (MI), recent stroke or establishlongerd p ripheral arterial disease

The CAPRIE study included 19,185 patients with ather thr mbosis as manifested by recent myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or established peripheral arterial disease (PAD). Patienots were randomized 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 theproductfirst few days following the acute myocardial infarction.

Clopidogrel significantly reduced the inci ence of new ischaemic events (combined end point of myocardial infarction, ischaemic st ke 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

any significant differen e between clopidogrel (5.8%) and ASA (6.0%).

(relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p = 0.045), which corresponds, for every 1,000 patientsMedicinaltreated for 2 ye rs, 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

In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the benefit appeared to be strongest (achieving statistical significance at p = 0.003) in patients enrolled due to PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 to 36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to 18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR = - 4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel in patients over 75 years was less than that observed in patients ≤75 years.

Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear whether the differences in relative risk reduction across qualifying conditions are real, or a result of chance.

Acute coronary syndrome

The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), and presenting within 24 hours of onset of the

most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading dose followed by 75 mg/day, N=6,259) or placebo (N=6,303), both given in combination with ASA (75-325 mg once daily) and other standard therapies. Patients were treated for up to one year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in more than 90% of the patients and the relative rate of bleeding between clopidogrel and placebo was not significantly affected by the concomitant heparin therapy.

The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the clopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent and 10% when they underwent coronary artery bypass graft (CABG)). New cardiovascular events

(primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI: 12.8,

The use of clopidogrel in CURE was associated with a decrease in theauthorisedneed of thrombolytic therapy (RRR=43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR=18.2%; CI: 6.5%, 28.3%).

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 treatm nt, the benefit

observed in the clopidogrel + ASA group was not further increased, whereas the sk of haemorrhage persisted (see section 4.4).

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 f 6%-21%, p=0.0005) for the clopidogrel-

treated group. This benefit was mostly driven by the statistically significant reduction in the incidence

 

longer

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.

no

 

The results obtained in populationsproductwith 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 unde went stent placement (Stent-CURE), the data showed that

clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for the co-primaryMedicinalendpoint (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 w th the overall trial results.

The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular therapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering medicinal products, beta blockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of ASA (75-325 mg once daily).

In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.

The CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, followed by 75 mg/day, n=1,752) or placebo (n=1,739), both in combination with ASA (150 to

325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded infarct-related artery on the predischarge angiogram, or death or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient population

included 19.7% women and 29.2% patients ≥65 years. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non- fibrin specific: 31.1%), 89.5% heparin, 78.7% beta blockers, 54.7% ACE inhibitors and 63% statins.

Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached the primary endpoint, representing an absolute reduction of 6.7% and a 36% odds reduction in favor of clopidogrel (95% CI: 24, 47%; p<0.001), mainly related to a reduction in occluded infarct-related arteries. This benefit was consistent across all prespecified subgroups including patients’ age and gender, infarct location, and type of fibrinolytic or heparin used.

The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke

or death. The population included 27.8% women, 58.4% patients ≥60 years (26% ≥70 years) and

54.5% patients who received fibrinolytics.

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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 consis ent across age, gender and with or without fibrinolytics, and was observed as early as 24 hours.

5.2 Pharmacokinetic properties

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Absorption

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

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

 

 

no

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

excretion of clopidogrel metabolites.

 

Distribution

product

 

 

 

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

Medicinal

 

Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to two ma n metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxyl c acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite which has been isolated

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

Elimination

Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the main circulating (inactive) metabolite was 8 hours after single and repeated administration.

Pharmacogenetics

Several polymorphic CYP450 enzymes activate clopidogrel. CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional

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

CYP2C19 Phenotype and Genotype Frequency

 

 

Frequency (%)

 

 

White (n=1356)

Black (n=966)

Chinese (n=573)

 

 

 

 

 

Extensive metabolism: CYP2C19*1/*1

 

Intermediate metabolism: CYP2C19*1/*2 or *1/*3

 

 

 

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

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To date, the impact of CYP2C19 genotype on the pharmacokinetics of the active metabolite of clopidogrel has been evaluated in 227 subjects from 7 reported studies. Reduced CYP2C19 metabolism in intermediate and poor metabolisers decreased the Cmax and AUC of the active metabolite by 30-50% following 300- or 600-mg loading doses and 75-mg maintenance doses. Lower

active metabolite exposure results in less platelet inhibition or higher residual platelet reactivity. To date, diminished antiplatelet responses to clopidogrel havelongerbe n d sc ibed for intermediate and poor

metabolisers in 21 reported studies involving 4,520 subjects. The r lative difference in antiplatelet response between genotype groups varies across studies depe ding on the method used to evaluate response, but is typically greater than 30%.

The association between CYP2C19 genotype a dnocl pidogrel treatment outcome was evaluated in 2

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

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)product. 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

Pharmacogenetic testing an identify genotypes associated with variability in CYP2C19 activity.

infarction, and stroke) or stent thrombosis compared to extensive metabolisers. In the fifth cohort study (n=2,208; Simon),Medicinalthe incre sed event rate was observed only in poor metabolisers.

There may be g n tic variants of other CYP450 enzymes with effects on the ability to form the active metabolite of clopidogrel.

Special populations

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

Renal impairment

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

Hepatic impairment

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

Race

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

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.

authorised

 

At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vom ting) of clopidogrel was also reported in rat and baboon.

There was no evidence of carcinogenic effect when clopidogrel was adminis ered 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/d y).

 

 

 

 

longer

Clopidogrel has been tested in a range of in vitro and in vivo notoxicity studies, and showed no

genotoxic activity.

 

 

 

Clopidogrel was found to have no effect on the fertility of male and female rats and was not

 

 

 

no

 

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

 

 

product

 

 

clopidogrel have shown that the parent compound or its metabolites are excreted in the milk.

Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be

excluded.

 

 

 

6.

PHARMACEUTICAL PARTICULARS

 

6.1

List of excipients

 

 

 

Tablet core:Medicinal

Cellulose, microcrystalline

Colloidal anhydrous silica

Crospovidone (type A)

Macrogol 6000

Hydrogenated castor oil

Film coating:

Hydroxypropylcellulose (E463)

Titanium dioxide (E171)

Red iron oxide (E172)

Talc

Propylene glycol

6.2Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store in the original package in order to protect from moisture and light.

6.5 Nature and contents of container

OPA/Al/PVC-Al blisters containing 28, 30, 50, 56, 84, 90 and 100 film-coated tablets or perforated unit dose blister containing 28x1, 28x1 (calendar pack), 30x1, 50x1, 56x1, 84x1, 90x1 and 100x1 film-coated tablets in a carton.

Not all pack sizes may be marketed.

 

 

authorised

 

 

 

6.6 Special precautions for disposal

 

 

 

No special requirements.

 

 

 

 

7.

MARKETING AUTHORISATION HOLDER

 

The Netherlands

 

 

longer

 

Teva Generics B.V.

 

 

 

 

Computerweg 10

 

 

 

 

3542 DR Utrecht

 

no

 

 

8.

 

product

 

 

 

 

 

 

MARKETING AUTHORISATION NUMBER(S)

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.

Medicinal

 

 

 

 

DATE OF REVISION OF THE TEXT

 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency (E A) http://www.ema.europa.eu/.

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