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Clopidogrel DURA (clopidogrel hydrochloride) – Summary of product characteristics - B01AC04

Updated on site: 06-Oct-2017

Medication nameClopidogrel DURA
ATC CodeB01AC04
Substanceclopidogrel hydrochloride
ManufacturerMylan dura GmbH

1. NAME OF THE MEDICINAL PRODUCT

Clopidogrel dura 75 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride).
Excipient with known effect:
Each film-coated tablet contains 13 mg hydrogenated castor oil.

For the full list of excipients, see section 6.1.

authorised

3.

PHARMACEUTICAL FORM

Film-coated tablet.

Pink, round and slightly convex film-coated tablets.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Prevention of atherothrombotic events

 

longer

Clopidogrel is indicated in:

 

Adults patients suffering from myocardial i farction (from a few days until less than 35 days),

 

ischaemic stroke (from 7 days until less

han 6 months) or established peripheral arterial

 

disease.

 

no

 

For further information please refer to section 5.1.

 

4.2

Posology and method f administration

 

Posology

product

 

 

 

 

Adults a d elderly

 

 

IfMedicinala dose s m ssed:

 

 

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

-Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time.

-For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose.

Paediatric population

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 have bleeding diatheses (see section 4.4).

Method of administration

For oral use

It may be given with or without food.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

from trauma, surgery or other pathological conditions and in patients eceivingauthorisedtreatment with ASA,

Severe hepatic impairment.

Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

4.4

Special warnings and precautions for use

Bleeding and haematological disorders

Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be t risk of increased bleeding

heparin, glycoprotein IIb/IIIa inhibitors or non-steroidallongeranti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors. Patients should be followed carefully for any si ns of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of clopidogrel with ral anticoagulants is not recommended since it may increase the intensity of bleedings (see secti n 4.5).

product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

If a patient is to undergo elective surgery and a notiplatelet effect is temporarily not desirable, clopidogrel should be discontinuedproduct7 days prior o surgery. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal

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.

ThromboticMedicinalThrombocytopenic Purpura (TTP)

Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, somet mes after a short exposure. It is characterised by thrombocytopenia and microang opath haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Acquir d haemophilia

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

Recent ischaemic stroke

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

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Tests are available to identify a patient's CYP2C19 genotype.

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).

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 s ction 4.8). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopy id ne may have an increased risk of developing the same or another reaction to another thienopyridine. M nitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised.

Renal impairment

Hepatic impairment

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

 

authorised

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

longer

 

Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this p pulation (see section 4.2).

Excipients

product

This medicinal product contains hydrogena ed castor oil which may cause stomach upset and

diarrhoea.

 

no

4.5 Interaction with other medicinal products and other forms of interaction

Oral anticoagulants: the conc

mitant administration of clopidogrel with oral anticoagulants is not

recommended since it may inc ease the intensity of bleedings (see section 4.4). Although the

administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or InternationalMedicinalNormalised Ratio (INR) in patients receiving long-term warfarin therapy,

coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostas s.

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

Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4). However, clopidogrel and ASA have been administered together for up to one year (see section 5.1).

Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic

interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4).

Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with ASA (see section 4.8).

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).

authorised

 

Other concomitant therapy:

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of med c nal products that inhibit the activity of this enzyme would be expected to result in reduced d ug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see sections 4.4 and 5.2).

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

fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, cip ofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

Proton Pump Inhibitors (PPI):

Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours

between the administrations of the two drugs decreased the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). Thenodecrease was associated with a 39% (loading dose)

and 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected to give a similar interactionproductwith clopidogrel.

Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) interaction in terms of major car iovascular events have been reported from both observational and clinical studies. As a precauti n, c ncomitant use of omeprazole or esomeprazole should be discouraged (see section 4.4).

LessMedicinalpronounced reductions of metabolite exposure has been observed with pantoprazole or lansoprazole.

The plasma co ce trations of the active metabolite was 20% reduced (loading dose) and 14% reduced (maintenan e dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated w th 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 (except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with antiplatelet activity of clopidogrel.

Other medicinal products: A number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co- administration of phenobarbital, or oestrogen.

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

Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by CYP2C9 can be safely co-administered with clopidogrel.

Apart from the specific medicinal product interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.

4.6 Fertility, pregnancy and lactation

Pregnancy

authorised

 

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).

Breast-feeding

longer

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 dura.

Fertility

 

no

 

 

Clopidogrel was not shown to alter fertility in a imal studies.

 

product

 

4.7 Effects on ability to drive and se machines

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

4.8 Undesirable effects

SummaryMedicinalof the safety profile

Clopidogrel has been evaluated for safety in more than 42,000 patients, who have participated in clinical stud es, in luding over 9,000 patients treated for 1 year or more. The clinically relevant adverse react ons observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed below. Ov rall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of ag , g nd r and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT studies are discussed below. In addition to clinical studies experience, adverse reactions have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing experience where it was mostly reported during the first month of treatment.

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

In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery . In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel plus ASA, and 6.3% for placebo plus ASA.

In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the placebo plus ASA group. The incidence of major bleeding was similar between groups. This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy.

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

Tabulated list of adverse reactions

Adverse reactions that occurred either during clinical studies or that were spontaneously eported are presented in the table below. Their frequency is defined using the following conventi ns: 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.

System Organ

Common

Uncommon

 

Rare

 

Very rare, not

Class

 

 

 

 

 

 

authorised

 

 

 

 

 

 

 

known*

Blood and the

 

 

Thrombocytopenia,

N utrop nia,

Thrombotic

lymphatic system

 

 

leucopenia,

 

i cluding severe

thrombocytopenic

disorders

 

 

eosinophilia

 

eutropenia

purpura (TTP) (see

 

 

 

 

 

longer

 

section 4.4),

 

 

 

 

no

 

aplastic anaemia,

 

 

 

 

 

pancytopenia,

 

 

 

 

 

 

 

 

 

 

 

 

 

 

agranulocytosis,

 

 

 

 

 

 

 

severe

 

 

 

 

 

 

 

thrombocytopenia,

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

acquired

 

 

 

 

 

 

 

 

haemophilia A,

 

 

 

 

 

 

 

 

granulocytopenia,

 

 

 

 

 

 

 

 

anaemia

Immune system

 

product

 

 

 

 

Serum sickness,

disorders

 

 

 

 

 

anaphylactoid

 

 

 

 

 

 

reactions, cross

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

reactive drug

 

 

 

 

 

 

 

 

hypersensitivity

 

 

 

 

 

 

 

 

among

 

 

 

 

 

 

 

 

thienopyridines

 

 

 

 

 

 

 

 

(such as ticlopidine,

 

 

 

 

 

 

 

 

prasugrel) (see

 

 

 

 

 

 

 

 

section 4.4)*

Psychiatric

 

 

 

 

 

 

 

Hallucinations,

Medicinal

 

 

 

 

 

 

 

confusion

disorders

 

 

 

 

 

 

 

Nervous system

 

 

Intracranial

 

 

 

Taste disturbances

disorders

 

 

bleeding (some

 

 

 

 

 

 

cases were

 

 

 

 

 

 

 

reported with fatal

 

 

 

 

 

 

outcome),

 

 

 

 

 

 

 

headache,

 

 

 

 

 

 

 

paraesthesia,

 

 

 

 

 

 

 

dizziness

 

 

 

 

Eye disorders

 

 

Eye bleeding

 

 

 

 

 

 

 

(conjunctival,

 

 

 

 

 

 

ocular, retinal)

 

 

 

Ear and labyrinth

 

 

 

 

 

Vertigo

 

 

disorders

 

 

 

 

 

 

 

 

Vascular

Haematoma

 

 

 

 

 

Serious

disorders

 

 

 

 

 

 

 

haemorrhage,

 

 

 

 

 

 

 

 

haemorrhage of

 

 

 

 

 

 

 

 

operative wound,

 

 

 

 

 

 

 

 

vasculitis,

 

 

 

 

 

 

 

 

hypotension

Respiratory,

Epistaxis

 

 

 

 

 

Respiratory tract

thoracic and

 

 

 

 

 

 

 

bleeding

mediastinal

 

 

 

 

 

 

 

(haemoptysis,

disorders

 

 

 

 

 

 

 

pulmonary

 

 

 

 

 

 

 

 

haemo hage),

 

 

 

 

 

 

 

 

br nch spasm,

 

 

 

 

 

 

 

 

interstitial

 

 

 

 

 

 

 

 

pneumonitis,

 

 

 

 

 

 

 

 

eosinophilic

 

 

 

 

 

 

 

 

pneumonia

Gastrointestinal

Gastrointestinal

Gastric ulcer and

Retrope itoneal

Gastrointestinal and

disorders

haemorrhage,

duodenal ulcer,

 

authorised

ha mo hage

retroperitoneal

 

diarrhoea,

gastritis, vomiting,

 

 

haemorrhage with

 

abdominal pain,

nausea,

longer

 

fatal outcome,

 

dyspepsia

constipation,

 

pancreatitis, colitis

 

 

 

flatulence

 

(including

 

 

 

 

 

 

ulcerative or

 

 

 

 

 

 

 

 

lymphocytic

 

 

 

 

 

 

 

 

colitis), stomatitis

Hepato-biliary

 

 

 

no

 

 

 

Acute liver failure,

disorders

 

 

 

 

 

 

hepatitis, abnormal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

liver function test

Skin and

Bruising

Rash, pruritus, skin

 

 

Bullous dermatitis

subcutaneous

 

 

bleeding (purpura)

 

 

(toxic epidermal

tissue disorders

 

product

 

 

 

 

necrolysis, Stevens

 

 

 

 

 

 

Johnson Syndrome,

Medicinal

 

 

 

 

 

erythema

 

 

 

 

 

multiforme),

 

 

 

 

 

 

 

 

 

 

 

 

 

 

angioedema, drug

 

 

 

 

 

 

 

induced

 

 

 

 

 

 

 

hypersensitivity

 

 

 

 

 

 

 

syndrome, drug

 

 

 

 

 

 

 

rash with

 

 

 

 

 

 

 

eosinophilia and

 

 

 

 

 

 

 

systemic symptoms

 

 

 

 

 

 

 

(DRESS), rash

 

 

 

 

 

 

 

erythematous,

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

urticaria, eczema,

 

 

 

 

 

 

 

 

lichen planus

Musculoskeletal,

 

 

 

 

 

 

 

Musculo-skeletal

connective tissue

 

 

 

 

 

 

 

bleeding

and bone

 

 

 

 

 

 

 

(haemarthrosis),

disorders

 

 

 

 

 

 

 

arthritis, arthralgia,

 

 

 

 

 

 

 

 

myalgia

Mechanism of action

Renal and urinary

Haematuria

Glomerulonephritis,

disorders

 

blood creatinine

 

 

increased

General disorders

Bleeding at

Fever

and

puncture site

 

administration

 

 

site conditions

 

 

Investigations

Bleeding time

 

 

prolonged,

 

 

neutrophil count

 

 

decreased, platelet

 

 

count decreased

 

Reporting suspected adverse reactions after authorisation of the medicinal product is impo tant. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

authorised

Reporting of suspected adverse reactions

 

4.9Overdose

Overdose following clopidogrel administration may leadlongerto prolong d 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 PROPERTIESnoproperties5.1 Pharmacodynamic

Pharmacotherapeutic group:productAntithrombotic agents, platelet aggregation inhibitors excl. heparin, ATC code: B01AC04.

ClopidogrelMedicinalis 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 glycoprote n 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 r cov ry 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 medicinal products, not all patients will have adequate platelet inhibition.

Pharmacodynamic effects

Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and

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

Clinical efficacy and safety

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

Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease

myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or

The CAPRIE study included 19,185 patients with atherothrombosis as manifestedauthorisedby recent

established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or

ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subg oup, most of the patients received ASA for the first few days following the acute myocardial infarcti n. Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of

myocardial infarction, ischaemic stroke and vascular death) when compared o ASA. In the intention to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA

any significant difference 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 1000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from experiencing a new ischaemic event. Analysis of total mortalitylongeras a s condary endpoint did not show

In a subgroup analysis by qualifying condition (myocardial i farction, ischaemic stroke, and PAD) the

benefit appeared to be strongest (achieving statistical significa ce at p = 0.003) in patients enrolled

due to PAD (especially those who also had a history of my cardial 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 noin the trial on the sole basis of a recent myocardial

infarction, clopidogrel was numerically inferior, but ot statistically different from ASA (RRR = - 4.0%; CI: -22.5 to 11.7 [p=0.639])product. In addi io , 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 red ction across qualifying conditions are real, or a result of chance.

Paediatric population

of 49.3% (5 µM ADP-induced platelet aggregation) which was comparable to that of adults taking Clopidogrel 75 mg/day.

In a dose escalation study of 86 neonates or infants up to 24 months of age at risk for thrombosis (PICOLO),Medicinalclopidogrel w s evaluated at consecutive doses of 0.01, 0.1 and 0.2 mg/kg in neonates and infants and 0.15 mg/kg only in neonates. The dose of 0.2 mg/kg achieved the mean percent inhibition

In a ran omised, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonates and infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt were randomised to receive clopidogrel 0.2 mg/kg (n=467) or placebo (n=439) along with concomitant background therapy up to the time of second stage surgery. The mean time between shunt palliation and first administration of study medicinal product was 20 days. Approximately 88% of patients received concomitant ASA (range of 1 to 23 mg/kg/day). There was no significant difference between groups in the primary composite endpoint of death, shunt thrombosis or cardiac-related intervention 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 the most frequently reported adverse reaction in both clopidogrel and placebo groups; however, there was no significant difference in the bleeding rate between groups. In the long-term safety follow-up of this study, 26 patients with the shunt still in place at one year of age received clopidogrel up to 18 months of 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. In a relative bioavailability study in adults, the constituted solution of clopidogrel showed a similar extent and slightly higher rate of absorption of the main circulating (inactive) metabolite compared to the authorised tablet.

5.2 Pharmacokinetic properties

Absorption

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

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

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

excretion of clopidogrel metabolites.

authorised

 

Distribution

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

Biotransformation

its inactive carboxylic acid derivative (85% of circulating metabolit s), 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 thi l metabolite which has been isolated

Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to two main metabolic pathways: one mediatedlongerby esterases and leading to hydrolysis into

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

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

as it is after four days of 75-mg maintenan e dose. Cmax occurs approximately 30 to 60 minutes after dosing.

Elimination

Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the

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

maxproduct

urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral Medicinaldose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half life of the

Pharmacogenet cs

CYP2C19 s nvolved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermed ate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype.

The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the majority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other alleles associated with absent or reduced metabolism are less frequent and include CYP2C19*4, *5, *6, *7, and *8. A patient with poor metaboliser status will possess two loss-of-function alleles as defined above. Published frequencies for the poor CYP2C19 metaboliser genotypes are approximately 2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to determine a patient’s CYP2C19 genotype.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state).

No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation (IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor metabolisers with mean IPA (5 μM ADP) of 24% (24 hours) and 37% (Day 5) as compared to IPA of 39% (24 hours) and 58% (Day 5) in the extensive metabolisers and 37% (24 hours) and 60% (Day 5) in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32%

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

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

subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregati n inhibition (5 μM ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when c mpared to extensive metabolisers.

300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.authorised Consistent with the above results, in a meta-analysis including 6 studies of 335 clopidogrel-tr at d

The influence of CYP2C19 genotype on clinical outcomes in patients tre ted with clopidogrel has not been evaluated in prospective, randomised, controlled trials. There have been number of retrospective analyses, however, to evaluate this effectlongerin patients t eated with clopidogrel for whom there are genotyping results: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227), TRITON-TIMI 38 (n=1477), and ACTIVE-A (n=601), as well as a number of published cohort studies.

In TRITON-TIMI 38 and 3 of the cohort studies (Co et, Sibbing, Giusti) the combined group of patients with either intermediate or poor metaboliser status had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or ste t thr mbosis compared to extensive metabolisers.

no In CHARISMA and one cohortproductstudy (Simon), an increased event rate was observed only in poor metabolisers when compared to extensive metabolisers.

In CURE, CLARITY and one of the cohort studies (Trenk), no increased event rate was observed based on metaboliser status.

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

The pharma ok net cs of the active metabolite of clopidogrel is not known in these special populations.

Renal impairment

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

Hepatic impairment

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

Race

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

5.3 Preclinical safety data

During non clinical studies in rat and baboon, the most frequently observed effects were liver changes. These occurred at doses representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No effect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the therapeutic dose.

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

There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day).

Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity st dies, and showed no genotoxic activity.

authorised

Clopidogrel was found to have no effect on the fertility longerof male and f male rats and was not

teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be excluded.

6. PHARMACEUTICAL PARTICULARSno

6.1 List of excipients

product

Tablet core:

 

Cellulose, microcrystalline

Colloidal anhydrous silica

 

Medicinal

 

Crospovidone (type A)

 

Macrogol 6000

Hydrogenated castor oil

Film coat ng:

Polyvinyl alcohol

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172)

Talc

Macrogol 3000 (Polyethyleneglycol)

6.2Incompatibilities

Not applicable.

6.3Shelf life

3 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

Blister of OPA/Al/PVC-Al containing 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in the box.

Not all pack sizes may be marketed.

8.

MARKETING AUTHORISATION NUMBER(S)

authorised

6.6 Special precautions for disposal

 

 

 

No special requirements.

 

 

 

 

7.

MARKETING AUTHORISATION HOLDER

 

Mylan dura GmbH, Wittichstraße 6, D-64295 Darmstadt, Germany

 

EU/1/09/560/001-009

 

 

longer

 

 

 

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 September 2009

no

 

 

 

 

 

Date of latest renewal:

 

 

 

 

10.

DATE OF REVISION OF THE TEXT

 

 

 

 

product

 

 

 

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

Agency http://www.ema.euro a.eu/.

 

 

 

Medicinal

 

 

 

 

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