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Clopidogrel Acino Pharma GmbH (clopidogrel) – Summary of product characteristics - B01AC04

Updated on site: 06-Oct-2017

Medication nameClopidogrel Acino Pharma GmbH
ATC CodeB01AC04
Substanceclopidogrel
ManufacturerAcino Pharma GmbH
Film-coated tablet.

1. NAME OF THE MEDICINAL PRODUCT

Clopidogrel Acino Pharma GmbH 75 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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.

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.

 

longer

For further information please refer to section 5.1.no

 

 

4.2 Posology and method of administration

 

 

Posology

product

 

 

 

Adults and elderly

 

 

 

 

 

 

 

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

If a dose is missed:

-With n less than 12 hours after regular scheduled time: patients should take the dose

imm iately 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).Medicinal

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.

 

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 at risk of incr ased bleeding from trauma, surgery 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. Patients should be followed carefully for any signs 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 oral anticoag lants is not recommended

since it may increase the intensity of bleedings (see section 4.5).

authorised

 

If a patient is to undergo elective surgery and antiplatelet effect is t mporarily 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

 

longer

have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

no

 

Patients should be told that it might take longer han usual to stop bleeding when they take

clopidogrel, and that they shouldproductreport any nusual bleeding (site or duration) to their physician.

Thrombotic Thrombocytopenic Pu pura (TTP)

Thrombotic Thrombocytopenic Pu ura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathicMedicinalhaemolytic naemia associated with either neurological findings, renal dysfunction or fever. TTP is a pote t ally 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).

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 section 4.2).

Excipients

Clopidogrel Acino Pharma GmbH contains hydrogenated castor oil which may cause stomach upset and diarrhoea.

4.5 Interaction with other medicinal products and other forms of interaction

Oral anticoagulants: the concomitant administration 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/day did not modify the pharmacokinetics of S-warfarin or International Normalised Ratio (INR) in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent

effects on hemostasis.

Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with cautionauthorisedin pat ents who receive concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4).

Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated in ibition 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 andlongeracetylsalicylic acid is possible, leading to

increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4).

of the heparin dose or alter the effect of heparin onnocoagulation. Co-administration of heparin had no effect on the inhibition of plateletproductaggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be un ertaken with caution (see section 4.4).

Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification

Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin

specific thrombolytic agents and he arins was assessed in patients with acute myocardial infarction. The incidenceMedicinalof clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-adm stered 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 studi s 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).

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 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). The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected to give a similar interaction with clopidogrel.

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

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

There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers (except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with antiplatelet activity of

clopidogrel.

authorised

 

Other medicinal products:

 

A number of other clinical studies have been conducted with clopidogrel and other concomitant

medicinal products to investigate the potential for pharmac dynamic and pharmacokinetic

 

longer

interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel

was co-administered with atenolol, nifedipine, or b th atenolol and nifedipine. Furthermore, the

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

pharmacodynamic activity of clopidogrel was ot significantly influenced by the coadministration of

phenobarbital, or oestrogen.

product

no

 

 

 

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

Apart from the spec f medicinal products interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic isease have not been performed. However, patients entered into clinical trials with clopidogrel rec iv d 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.

4.6Fertility, 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).

Breastfeeding

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.

Fertility

Clopidogrel was not shown to alter fertility in animal studies.

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

Clopidogrel has been evaluated for safety for 1 year or more. The clinically relevant adverse reactions

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.

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

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

Adverse reactions that occurred either during clinical studies or that were spontaneously reported are

presented in the table below. Their frequency is defined usi

g 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

 

 

 

 

longer

 

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

seriousness.

 

 

no

 

 

 

 

 

 

 

 

 

 

 

System Organ

Common

Un ommon

 

 

Rare

Very rare

Class

 

 

 

 

 

 

 

Blood and the

 

Thrombocytopenia,

 

Neutropenia,

Thrombotic

lymphatic

 

leucopenia,

 

 

including severe

thrombocytopenic

system disorders

 

eosinophilia

 

 

neutropenia

purpura (TTP) (see

Medicinal

product

 

 

 

 

section 4.4), aplastic

 

 

 

 

 

 

 

 

 

 

anaemia,

 

 

 

 

 

pancytopenia,

 

 

 

 

 

agranulocytosis,

 

 

 

 

 

severe

 

 

 

 

 

thrombocytopenia,

 

 

 

 

 

granulocytopenia,

 

 

 

 

 

anaemia

 

 

 

 

 

 

 

Immune system

 

 

 

 

 

 

Serum sickness,

disorders

 

 

 

 

 

 

anaphylactoid

 

 

 

 

 

 

 

reactions

 

 

 

 

 

 

 

 

Psychiatric

 

 

 

 

 

 

Hallucinations,

disorders

 

 

 

 

 

 

confusion

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

 

 

 

 

Vertigo

 

labyrinth

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

Vascular

Haematoma

 

 

 

 

Serious

disorders

 

 

 

 

 

 

ha morrhage,

 

 

 

 

 

 

 

haemorrhage of

 

 

 

 

 

 

 

operative wound,

 

 

 

 

 

 

 

vasculitis,

 

 

 

 

 

 

 

hypotension

Respiratory,

Epistaxis

 

 

 

 

 

Respiratory tract

thoracic and

 

 

 

 

 

 

bleeding

mediastinal

 

 

 

longer

authorised

 

 

 

 

(haemoptysis,

disorders

 

 

 

 

pulmonary

 

 

 

 

 

haemorrhage),

 

 

 

 

 

bronchospasm,

 

 

 

 

 

interstitial

 

 

 

 

 

pneumonitis

 

 

 

 

 

 

 

Gastrointestinal

Gastrointestinal

Gas ric ulcer and

Retroperitoneal

Gastrointestinal and

disorders

haemorrhage,

no

 

haemorrhage

retroperitoneal

duodenal ulcer,

 

diarrhoea,

gastritis, vomiting,

 

 

haemorrhage with

 

abdominal pain,

nausea, constipation,

 

 

fatal outcome,

 

dyspepsia

 

flatulence

 

 

 

pancreatitis, colitis

 

 

product

 

 

 

(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 disordersMedicinal

 

 

 

 

necrolysis, Stevens

 

 

 

 

 

 

 

Johnson Syndrome,

 

 

 

 

 

 

 

erythema

 

 

 

 

 

 

 

multiforme),

 

 

 

 

 

 

 

angioedema, rash

 

 

 

 

 

 

 

erythematous,

 

 

 

 

 

 

 

urticaria, eczema,

 

 

 

 

 

 

 

lichen planus

Musculoskeletal

 

 

 

 

 

 

Musculo-skeletal

, connective

 

 

 

 

 

 

bleeding

tissue and bone

 

 

 

 

 

 

(haemarthrosis),

disorders

 

 

 

 

 

 

arthritis, arthralgia,

 

 

 

 

 

 

 

myalgia

Renal and

 

Haematuria

 

Glomerulonephritis,

urinary

 

 

 

blood creatinine

disorders

 

 

 

increased

General

Bleeding at

 

 

Fever

disorders and

puncture site

 

 

 

administration

 

 

 

 

site conditions

 

 

 

 

Investigations

 

Bleeding time

 

 

 

 

prolonged,

 

 

 

 

neutrophil count

 

 

 

 

decreased, platelet

 

 

 

 

count decreased

 

 

4.9 Overdose

Overdose following clopidogrel administration may lead to prolongedauthorisedbleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleedings are obs rved. 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 f clopidogrel.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

 

 

 

longer

Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin,

ATC Code: B01AC-04.

 

no

 

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

 

product

 

 

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

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

The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent myocardial infarction (< 35 days), recent ischaemic stroke (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 the patients received ASA for the first few days following the acute myocardial infarction.

Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of myocardial infarction, ischaemic stroke 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 (relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p=0.045), which corresponds, for every 1,000 patients treated for 2 years, 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 any significant difference between clopidogrel (5.8%) and ASA (6.0%).

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.

Paediatric population

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 conditionsauthorisedare r al, or a result of chance.

In a dose escalation study of 86 neonates or infants up to 24 months of age at risk for thrombosis (PICOLO), clopidogrel was evaluated at consecutive doses of 0.01, 0.1 and 0.2 mg/kg in neonates 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, parallel-group study (CLARINET),longer 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 ofnosecond stage surgery.

The mean time between shunt

palliation and first administration of st dy 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 c mp site 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

product

dverse reaction in both clopidogrel and placebo groups; however, there was

no significant difference

the bleeding rate between groups. In the long-term safety follow-up of this

study, 26 patientsMedicinalw th 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.

5.2Pharmacokinetic 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 according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic 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.

The Cmax 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 maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing.

dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. Theauthorisedelimination half-life of the main circulating (inactive) metabolite was 8 hours after single and epeated administration.

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

Pharmacogenetics

 

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

 

longer

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 funcnoional 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 Ca casian (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 oor metaboliser status will possess two loss-of-function alleles as

defined above. Published frequencies for the poor CYP2C19 metaboliser genotypes are approximately

 

 

product

2% for Caucasians, 4% for B cks and 14% for Chinese. Tests are available to determine a patient’s

CYP2C19 genotype.

 

A crossover study

n 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid,

extensive, int rm

iate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg

Medicinal

 

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 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 (Collet, 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 stent thrombosis compared to extensive metabolisers.

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

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, h wever, 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.

In CURE, CLARITY, ACTIVE-A 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 inauthorisedoutcome in poor metabolisers.

Special populations

 

 

 

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

populations.

 

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Renal impairment

product

 

 

 

 

Hepatic impairmentMedicinal

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic

impairment, inhibit on of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The m an 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 excluded.

Crospovidone type A

 

 

 

authorised

6.

PHARMACEUTICAL PARTICULARS

 

 

6.1

List of excipients

 

 

 

 

Tablet core:

 

 

 

 

Macrogol 6000

 

 

 

 

Cellulose, microcrystalline (E460)

 

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Castor oil, hydrogenated

 

 

 

 

 

 

 

Film-coating:

 

 

 

 

Macrogol 6000

 

no

 

 

Ethylcellulose (E462)

 

 

 

 

 

 

 

Titanium dioxide (E 171)

product

 

 

 

6.2

Incompatibilities

 

 

 

 

 

 

 

Not applicable

 

 

 

 

6.3

Shelf life

 

 

 

 

3 years

 

 

 

 

6.4Specialstorageprecaut ons for

Store in the Medicinaloriginal 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.

6.6Special precautions for disposal

No special requirements

7. MARKETING AUTHORISATION HOLDER

Acino Pharma GmbH

Am Windfeld 35

83714 Miesbach

Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/548/001 – 007

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21.09.2009

10. DATE OF REVISION OF THE TEXT

 

 

 

 

authorised

Detailed information on this medicinal product is available on the websi e of t e European Medicines

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

 

 

 

 

 

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product

 

 

Medicinal

 

 

 

 

 

 

 

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