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Clopidogrel Hexal (clopidogrel) – Summary of product characteristics - B01AC04

Updated on site: 06-Oct-2017

Medication nameClopidogrel Hexal
ATC CodeB01AC04
Substanceclopidogrel
ManufacturerAcino Pharma GmbH
Film-coated tablet.
Each film-coated tablet contains 75 mg of clopidogrel (as besilate).
Excipients: each film-coated tablet contains 3.80 mg of hydrogenated castor oil. For a full list of excipients, see section 6.1.

1. NAME OF THE MEDICINAL PRODUCT

Clopidogrel HEXAL 75 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

White to off-white, marbled, round and biconvex film-coated tablets.authorised

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 m

nths) or established peripheral arterial

 

disease.

 

 

no

longer

 

 

 

 

 

 

 

 

 

 

 

 

Patients suffering from acute coronary syndrome:

 

 

 

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

 

 

 

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

 

 

 

percutaneous co ona y intervention, in combination with acetylsalicylic acid (ASA).

 

 

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

 

 

 

medically treated atients eligible for thrombolytic therapy.

 

 

 

 

product

 

 

 

For further information please refer to section 5.1.

 

 

4.2 Posology and method of administration

 

 

 

Posology

 

 

 

 

 

 

 

Adults and elderly

 

 

 

 

 

 

Medicinal

 

 

 

 

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

In patients suffering from acute coronary syndrome:

-Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): clopidogrel treatment should be initiated with a single 300 mg loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding 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

Method of administration For oral use
It may be given with or without food.

4.3 Contraindications

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).

If a dose is missed:

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

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

 

Paediatric population

 

 

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

authorised

 

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

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

Severe hepatic impairment.

Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.longer

 

no

4.4 Special warnings and precautions for use

product

 

Bleeding and haematological disorders

 

Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing sh uld be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet

agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma,Medicinalsurgery or other pathological conditions and in patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) including

Cox-2 inhibitors. Pat ents should be followed carefully for any signs of bleeding including occult bleeding,especially uring the first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.5).

If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician.

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and

microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Recent ischaemic stroke

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

Cytochrome P450 2C19 (CYP2C19)

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

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution

concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).

Hepatic impairmentauthorised

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).

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

Excipients

Clopidogrel HEXAL contains hydrogenated castor oil which may cause stomach upset and diarrhoea.

 

 

longer

4.5

Interaction with other medicinal products and other forms of interaction

 

no

 

Oral anticoagulants: the concomitantproductadministration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.4). Although the administration of clopidogrel 75 mg/ ay id not modify the pharmacokinetics of S-warfarin or

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

International Normalised Ratio (INR) in patients receiving long-term warfarin therapy, coadministrationMedicinalof clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis.

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

Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4).

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

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

Other concomitant therapy: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors

should be discouraged (see sections 4.4 and 5.2).

carbamazepine, oxcarbazepine and chloramphenicol.

Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole,authorisedfluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, c metidine,

Proton Pump Inhibitors (PPI):

Omeprazole 80 mg once daily administered either at the same time s clopidogrel or with 12 hours (loading dose) and 40% (maintenance dose). The decreaselongerwas associated with a 39% (loading dose)

between the administrations of the two drugs decreased the exposu e of the active metabolite by 45%

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

clinical studies. As a precaution, con omi antnouse of omeprazole or esomeprazole should be discouraged (see section 4.4).

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

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

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

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

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.

(maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated withMedicinala reduction of the mean inhibition of platelet aggregation by 15% and 11%, respectively. These results i dicate that clopidogrel can be administered with pantoprazole.

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 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 the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by CYP2C9can be safely co-administered with clopidogrel.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

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

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

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

Clopidogrel was not shown to alter fertility in animal studies.

authorised

Breastfeeding

 

It is unknown whether clopidogrel is excreted in human breast milk. Animal stud es have shown excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be continued during treatment with clopidogrel.

Fertility

4.7Effects on ability to drive and use machines

 

 

longer

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

4.8 Undesirable effects

product

no

 

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

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 spontaneouslyMedicinalreported.

Bleeding is the most ommon 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 pati nts 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.

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

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

System Organ

Common

 

Uncommon

 

Rare

 

Very rare

Class

 

 

 

 

 

 

 

 

Blood and the

 

 

Thrombocytopenia,

Neutropenia,

Thrombotic

lymphatic

 

 

 

leucopenia,

 

including severe

thrombocytopenic

system disorders

 

 

eosinophilia

 

neutropenia

purpura (TTP) (see

 

 

 

 

 

 

 

 

section 4.4), aplastic

 

 

 

 

 

 

 

 

anaemia,

 

 

 

 

 

 

 

 

pancytopenia,

 

 

 

 

 

 

 

 

agranulocytosis,

 

 

 

 

 

 

 

 

severe

 

 

 

 

 

 

 

 

thrombocytopenia,

 

 

 

 

 

 

 

 

granulocytopenia,

 

 

 

 

 

 

 

 

anaemia

Immune system

 

 

 

 

 

 

Serum sickness,

disorders

 

 

 

 

 

 

 

anaphylactoid

 

 

 

 

 

 

 

 

reactions

 

 

 

 

 

 

 

 

Psychiatric

 

 

 

 

 

 

Hallucinations,

disorders

 

 

 

 

 

 

authorised

 

 

 

 

 

 

 

confusion

Nervous system

 

 

Intracranial

 

 

 

Taste disturbances

disorders

 

 

 

bleeding (some

 

 

 

 

 

 

 

cases were rep

rted

 

 

 

 

 

 

 

with fatal

longer

 

 

 

 

 

 

outcome),

 

 

 

 

 

 

 

 

headache,no

 

 

 

 

 

 

 

 

paraesthesia,

 

 

 

 

 

 

 

 

izziness

 

 

 

 

 

 

 

 

 

 

 

 

Eye disorders

 

 

Eye bleeding

 

 

 

 

 

 

 

 

(conjunctival,

 

 

 

 

 

 

 

 

ocular, retinal)

 

 

 

 

 

 

 

product

 

 

 

 

Ear and

 

 

 

 

 

Vertigo

 

labyrinth

 

 

 

 

 

 

 

 

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

Gastrointestinal

Gastrointestinal

Gastric ulcer and

Retroperitoneal

Gastrointestinal and

disorders

haemorrhage,

duodenal ulcer,

haemorrhage

retroperitoneal

 

diarrhoea,

 

gastritis, vomiting,

 

 

haemorrhage with

 

abdominal pain,

nausea, constipation,

 

 

fatal outcome,

 

dyspepsia

 

flatulence

 

 

 

pancreatitis, colitis

 

 

 

 

 

 

 

 

(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)

 

 

(toxic epidermal

tissue disorders

 

 

 

 

 

 

 

necrolysis, Stevens

 

 

 

 

 

 

 

 

Johnson Syndrome,

 

 

 

 

 

 

 

authorised

 

 

 

 

 

 

 

 

erythema

 

 

 

 

 

 

 

 

multiforme),

 

 

 

 

 

 

 

 

angioedema, rash

 

 

 

 

 

 

 

 

e ythematous,

 

 

 

 

 

 

 

 

urticaria, eczema,

 

 

 

 

 

 

 

 

lichen planus

Musculoskeletal

 

 

 

 

 

 

 

Musculo-skeletal

, connective

 

 

 

 

 

 

 

bleeding

tissue and bone

 

 

 

 

 

 

 

(haemarthrosis),

disorders

 

 

 

 

 

 

 

arthritis, arthralgia,

 

 

 

 

 

 

 

 

myalgia

Renal and

 

 

Haematuria

longer

 

Glomerulonephritis,

urinary

 

 

 

no

 

blood creatinine

disorders

 

product

 

 

 

increased

General

Bleeding at

 

 

 

 

 

Fever

disorders and

puncture site

 

 

 

 

 

 

administration

 

 

 

 

 

 

 

 

site conditions

 

 

 

 

 

 

 

 

Investigations

 

 

Bleeding time

 

 

 

 

Medicinal

 

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

Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At

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

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

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.

longer

Recent myocardial infarction (MI), recent stroke or establish d 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 str

ke (between 7 days and 6 months) or

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

ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of

product

 

the patients received ASA for the first few days followingno

the acute myocardial infarction.

Clopidogrel significantly reduced the inci ence of new ischaemic events (combined end point of myocardial infarction, ischaemic str 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 appear d 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

persisted (see section 4.4).

authorised

clopidogrel-treated group (17% relative risk reduction when patients were treated cons rvatively, 29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) w th or without stent and 10% when they underwent coronary artery bypass graft (CABG). New ca d ovascular events (primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3, 3-6, 6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit

observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage The use of clopidogrel in CURE was associated with alongerdecrease in the need of thrombolytic therapy (RRR = 43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibit rs (RRR = 18.2%; CI: 6.5%, 28.3%).

The number of patients experiencing the co-primarynoendpoint (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% relativeproductrisk reduc ion (95% CI of 6%-21%, p=0.0005) for the clopidogrel-treated group. This benefit was mostly driven by the statistically significant reduction in

the incidence of MI [287 (4.6%) in the clopidogrel treated group and 363 (5.8%) in the placebo treated group]. There was no observed effect n the rate of rehospitalisation for unstable angina.

The resultsMedicinalobtained in popu ations with different characteristics (e.g. unstable angina or non-Q-wave MI, low to high risk levels, di betes, need for revascularisation, age, gender, etc.) were consistent with

the results of the primary a alysis. In particular, in a post-hoc analysis in 2,172 patients (17% of the total CURE populat on) who underwent stent placement (Stent-CURE), the data showed that clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for the co-primary n point (CV death, MI, stroke) and also a significant RRR of 23.9% for the second co-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of clopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this subset are in line with the overall trial results.

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

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=1752) 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.

Paediatric population

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 favour 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

The co-primary endpoints were death from any cause and the first occurrence of e- nfarction, stroke or death. The population included 27.8% women, 58.4% patients ≥ 60 years (26% ≥ 70 years) and 54.5% patients who received fibrinolytics.

onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients received clopidogrelauthorised(75 mg/day, n = =22,961) or placebo (n==22,891), in combination with ASA (162 mg/day), for 28 days or unt l ho pital discharge.

Clopidogrel significantly reduced the relative risk of death from any c use 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. Thislongerbenefit was consistent across age, gender and with or without fibrinolytics, and was observed as early as 24 hours.

In a dose escalation study of 86 neonates or i nofa ts up to 24 months of age at risk for thrombosis (PICOLO), clopidogrel was evaluatedproductat onse utive 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 of 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, arallel-group study (CLARINET), 906 paediatric patients (neonates and infants)Medicinalwith 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 a ministration of study medicinal product was 20 days. Approximately 88% of patients receiv 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.

Distribution

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

Metabolism

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

authorised

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

rolysis into

its inactive carboxylic acid derivative (85% of circulating metabolites), and one m diat

by multiple

cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermed ate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results n 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 metaboli e w ich has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.

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

The Cmax of the active metabolite is twice as high followinglongera single 300-mg clopidogrel loading dose

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

product

 

dose of 75 mg, clopidogrel has a half-life of approximatelyno

6 hours. The elimination half-life of the

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

Pharmacogenetics

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

intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured byMedicinalex vivo platelet ggregation assays, differ according to CYP2C19 genotype.

The CYP2C19*1 allele orresponds 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 reduc function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other alleles associat d 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 poorCYP2C19 metaboliser genotypes are approximately 2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to determine a patient’s CYP2C19 genotype.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation (IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor metabolisers with mean IPA (5 μM ADP) of 24% (24 hours) and 37% (Day 5) as compared to IPA of 39% (24 hours) and 58% (Day 5) in the extensive metabolisers and 37% (24 hours) and 60% (Day 5) in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active

metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% (24 hours) and 61% (Day 5), which were greater than in the poor metabolisers receiving the 300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.

Consistent with the above results, in a meta-analysis including 6 studies of 335 clopidogrel-treated subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 μM ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to extensive metabolisers.

The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomised, controlled trials. There have been a number of retrospective analyses, however, to evaluate this effect in patients treated with clopidogrel for whom

In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of patients with either intermediate or poor metaboliser status had a higher ra e of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers.

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 asauthoriseda number of published cohort studies.

In CHARISMA and one cohort study (Simon), an increased event rate was observed only in poor metabolisers when compared to extensive metabolisers.

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

observed based on metaboliser status.

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

Special populations

 

no

 

 

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

populations.

product

 

Renal impairment

 

Medicinal

 

 

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 subj cts receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients.

Hepatic impairment

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

Race

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

5.3 Preclinical safety data

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

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

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

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

Clopidogrel was found to have no effect on the fertility of male and female rats and was not teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be

authorised

excluded.

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6.PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

product

no

Macrogol 6000

 

 

Cellulose, microcrystalline (E460)

 

Crospovidone type A

 

 

Castor oil, hydrogenated

 

 

 

Medicinal

 

 

Film-coating:

 

 

Macrogol 6000

 

 

Ethylcellulose (E462)

 

 

Titanium dioxide (E 171)

 

 

6.2

Incompatibilities

 

 

Not applicable

 

 

6.3

Shelf life

 

 

3 years

6.4Special precautions for storage

Store in the original blister in order to protect from moisture.

6.5 Nature and contents of container

Alu/Alu blisters containing 14, 28, 30, 50, 84, 90 and 100 film-coated tablets packed in cardboard cartons.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7. MARKETING AUTHORISATION HOLDER

Acino Pharma GmbH

 

 

Am Windfeld 35

 

authorised

83714 Miesbach

 

 

 

Germany

 

 

8.

MARKETING AUTHORISATION NUMBER(S)

 

EU/1/09/534/001 – 007

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9.

 

 

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28.07.2009

 

 

 

product

 

 

10.

DATE OF REVISION OF THE TEXT no

 

 

Detailed information on this medicinal prod ct is available on the website of the European Medicines Agency: http://www.ema.europa.eu/

Medicinal

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