English
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Select site language

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

Updated on site: 06-Oct-2017

Medication nameClopidogrel Sandoz
ATC CodeB01AC04
Substanceclopidogrel
ManufacturerAcino Pharma GmbH

1. NAME OF THE MEDICINAL PRODUCT

Clopidogrel Sandoz 75 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 75 mg of clopidogrel (as besilate). Excipients: each tablet contains 3.80 mg hydrogenated castor oil.
For a full list of excipients, see section 6.1.

For further information please refer to sec ion 5.1.

3.

PHARMACEUTICAL FORM

 

 

authorised

Film-coated tablet.

 

 

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

4.

CLINICAL PARTICULARS

 

 

4.1

Therapeutic indications

 

 

 

 

 

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

 

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

 

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

 

disease.

no

longer

 

 

 

 

 

 

 

 

4.2 Posology and method of administration

Adults and elderly

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

Pharmacogenetics

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

Paed atr patients

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

Renal impairment

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

Hepatic impairment

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

4.3 Contraindications

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

Severe liver impairment.

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

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 increased 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 anticoagulants 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 temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery. Patients should inform phys c ans 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 cauti n 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, and that they should report any unusual bleeding (site or du tion) 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 requiringlongerprompt treatment including plasmapheresis.

Recent ischaemic stroke

no

 

product

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

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: Based on literature ata, patients with genetically reduced CYP2C19 function have lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses, and generally exhibit higher ca diovascular event rates following myocardial infarction than do

patients with normal CYP2C19 function (see section 5.2).

metabolite of lopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of medicinal products that inhibit CYP2C19 should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).

SinceMedicinalclopidogrel is met bolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the act vity of this enzyme would be expected to result in reduced drug levels of the active

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 Sandoz 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).

Glycoprotein 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

effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamicauthorised interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding.

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

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 f eparin had no

Therefore, concomitant use should be undertaken with caution (see section 4.4).

Thrombolytics: the safety of the concomitant administration of clopidog el, 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 gastr

 

longer

intestinal blood loss. However, due to the lack of

interaction studies with other NSAIDs it is prese

tly unclear whether there is an increased risk of

no

 

gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administeredproductwi h au ion (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 f this enzyme would be expected to result in reduced drug levels of the active metabolite of clo idog el. The clinical relevance of this interaction is uncertain. As a

Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, mo lobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazep ne, oxcarbazepine and chloramphenicol.

precaution concomitant use of medicinal products that inhibit CYP2C19 should be discouraged (see sectionsMedicinal4.4 and 5.2).

Proton Pump Inhibitors (PPI):

In a crossover clinical study, clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 45% (Day 1) and 40% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) with

5 μM ADP was diminished by 39% (24 hours) and 21% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole 12 hours apart did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Esomeprazole is expected to give 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 esomeprozole should be discouraged (see section 4.4). No conclusive data on the pharmacodynamic interaction of clopidogrel and other PPIs are available.

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

pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration of phenobarbital, or oestrogen.

interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine.authorisedFurthermore, the

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

Data from studies with human liver microsomes indicated that the carboxylic acid metabolite of clopidogrel could inhibit the activity of Cytochrome P450 2C9. This could potentially lead to

increased plasma levels of medicinal products such as phenytoin and tolbut mide and the NSAIDs, which are metabolised by Cytochrome P450 2C9. Data longerfrom the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.

Apart from the specific medicinal products interaction inf rmation described above, interaction studies with clopidogrel and some medicinal products common y administered in patients with

ACEI, calcium antagonists, cholesterol loweri g age ts, coronary vasodilators, antidiabetic agents

atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinalno products including diuretics, beta blockers,

(including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.product

4.6 Fertility, pregnancy and lactation

As no clinical data on exposu e to cl pidogrel 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/foetalMedicinaldeve opment, parturition or postnatal development (see section 5.3).

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

4.7 Eff cts on ability to drive and use machines

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

4.8Undesirable effects

Clopidogrel has been evaluated for safety for 1 year or more. The clinically relevant adverse reactions 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. 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 1.4% for clopidogrel and 1.6% for ASA.

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

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

System Organ

Common

Uncommon

 

 

Rare

 

Very rare

Class

 

 

 

 

 

 

 

 

Blood and the

 

Thrombocytopenia,

Neutropenia,

Thrombotic

lymphatic

 

leucopenia,

 

 

 

authorised

 

 

 

including severe

thrombocytop nic

system disorders

 

eosinophilia

 

 

neutropenia

purpura (TTP) (s e

 

 

 

 

 

 

 

 

section 4.4), aplastic

 

 

 

 

 

 

 

 

anaem a,

 

 

 

 

 

 

 

 

pancyt penia,

 

 

 

 

 

 

 

 

agranulocytosis,

 

 

 

 

 

 

 

 

severe

 

 

 

 

 

 

 

 

thrombocytopenia,

 

 

 

 

 

 

 

 

granulocytopenia,

 

 

 

 

 

 

 

 

anaemia

Immune system

 

 

 

 

 

 

 

Serum sickness,

disorders

 

 

 

 

 

 

 

anaphylactoid

 

 

 

 

 

 

 

 

reactions

 

 

 

 

 

 

 

 

 

Psychiatric

 

 

 

 

longer

 

Hallucinations,

disorders

 

 

no

 

confusion

Nervous system

 

Intracranial

me

 

 

Taste disturbances

disorders

 

bleedi g (s

 

 

 

 

 

 

cases were reported

 

 

 

product

 

 

 

 

 

 

 

 

wi h fa al

 

 

 

 

 

 

 

o t ome),

 

 

 

 

 

 

 

headache,

 

 

 

 

 

 

 

paraesthesia,

 

 

 

 

 

 

dizziness

 

 

 

 

 

Eye disorders

 

Eye bleeding

 

 

 

 

Medicinal

 

(conjunctival,

 

 

 

 

 

ocular, retinal)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ear and

 

 

 

 

 

Vertigo

 

 

labyrinth

 

 

 

 

 

 

 

 

disor ers

 

 

 

 

 

 

 

 

Vascular

Haematoma

 

 

 

 

 

 

Serious

disord rs

 

 

 

 

 

 

 

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

Musculoskeletal

 

 

 

 

 

liver function test

 

 

 

 

authorisedMusculo-skeletal

Skin and

Bruising

Rash, pruritus, skin

 

 

Bullous dermatitis

subcutaneous

 

bleeding (purpura)

 

 

(toxic epid rmal

tissue disorders

 

 

 

 

 

necroly i , St v ns

 

 

 

 

 

 

Johnson Syndrome,

 

 

 

 

 

 

erythema

 

 

 

 

 

 

multif rme),

 

 

 

 

 

 

angioedema, rash

 

 

 

 

 

 

erythematous,

 

 

 

 

 

 

rticaria, eczema,

 

 

 

 

 

 

lichen planus

, connective

 

 

 

 

 

bleeding

tissue and bone

 

 

 

 

 

(haemarthrosis),

disorders

 

 

 

 

 

arthritis, arthralgia,

 

 

 

 

 

 

myalgia

Renal and

 

Haematuria

longer

 

Glomerulonephritis,

urinary

 

no

 

blood creatinine

disorders

 

 

 

 

 

increased

General

Bleeding at

 

 

 

 

Fever

disorders and

productcount decreased

 

 

 

puncture site

 

 

 

 

 

administration

 

 

 

 

 

 

site conditions

 

 

 

 

 

 

Investigations

 

Bleeding time

 

 

 

 

 

 

prolonged,

 

 

 

 

 

 

neutrophil count

 

 

 

 

 

decreased, platelet

 

 

 

 

 

 

 

 

 

 

Medicinal

 

 

 

 

 

 

4.9 Overdose

 

 

 

 

 

 

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

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin,

ATC Code: B01AC-04.

Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet

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

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

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

established peripheral arterial disease (PAD). Patients were randomised toauthorisedclopidogrel 75 mg/day or ASA 325 mg/day, and were followed for 1 to 3 years. In the myoca dial infarction subgroup, most of

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 d ys nd 6 months) or

myocardial infarction, ischaemic stroke and vascular death)longerwhen 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

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

experiencing a new ischaemic event. Analysis ofnototal mortality as a secondary endpoint did not show any significant difference between clopidogrel (5.8%) and ASA (6.0%).

1,000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from

18.7 [p = 0.258]). In patientsproductwho were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel w s numerically inferior, but not statistically different from ASA (RRR =

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

-4.0%; CI: -22.5 to 11.7 [p = 0.639]). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel patie ts 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

wh th

r the ifferences in relative risk reduction across qualifying conditions are real, or a result of

chance.

5.2

Pharmacokinetic properties

Medicinal

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.

Elimination

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

metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation

Pharmacogenetics

 

authorised

 

 

Several polymorphic CYP450 enzymes activate clopidogrel. CYP2C19 is involved in the formation of

both the active metabolite and the 2-oxo-clopidogrel intermediate m tabolite. Clopidogrel active

 

longer

 

assays, differ according to CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional

metabolism while the CYP2C19*2 and CYP2C19*3 a e es c rrespond to reduced metabolism. The

CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced function alleles in whites and 99%

in Asians. Other alleles associated with reduced metab lism include CYP2C19*4, *5, *6, *7, and *8,

but these are less frequent in the general population. Published frequencies for the common CYP2C19

phenotypes and genotypes are listed in the

able below.

 

 

 

 

 

 

 

 

no

 

 

 

 

 

 

 

CYP2C19 Phenotype and Genotype Frequency

 

 

 

 

 

 

 

 

 

 

 

 

product

 

Frequency (%)

 

 

 

White

 

Black

 

Chinese

 

 

(n=1356)

 

(n=966)

 

(n=573)

 

Extensive metabolism: CYP2C19*1/*1

 

 

 

 

Intermediate met bolism: CYP2C19*1/*2

 

 

 

 

or *1/*3

 

 

 

 

 

 

 

 

Poor metabol sm: CYP2C19*2/*2, *2/*3

 

 

 

 

or *3/*3

 

 

 

 

 

 

 

 

Medicinal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

To dat , the impact of CYP2C19 genotype on the pharmacokinetics of the active metabolite of clopidogrel has been evaluated in 227 subjects from 7 reported studies. Reduced CYP2C19 metabolism in intermediate and poor metabolisers decreased the Cmax and AUC of the active metabolite by 30-50% following 300- or 600 - mg loading doses and 75 - mg maintenance doses. Lower active metabolite exposure results in less platelet inhibition or higher residual platelet reactivity. To date, diminished antiplatelet responses to clopidogrel have been described for intermediate and poor metabolisers in 21 reported studies involving 4,520 subjects. The relative difference in antiplatelet response between genotype groups varies across studies depending on the method used to evaluate response, but is typically greater than 30%.

The association between CYP2C19 genotype and clopidogrel treatment outcome was evaluated in 2 post hoc clinical trial analyses (substudies of CLARITY [n = 465] and TRITON-TIMI 38 [n = 1,477]) and 5 cohort studies (total n = 6,489). In CLARITY and one of the cohort studies (n = 765; Trenk),

cardiovascular event rates did not differ significantly by genotype. In TRITON-TIMI 38 and 3 of the cohort studies (n = 3,516; Collet, Sibbing, Giusti), patients with an impaired metaboliser status (intermediate and poor combined) had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers. In the fifth cohort study (n = 2,208; Simon), the increased event rate was observed only in poor metabolisers.

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

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

Special populations

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

Renal impairment

authorised

 

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

subjects. The mean bleeding time prolongation was a so similar in the two groups.

Race

no

longer

 

 

The prevalence of CYP2C19 alleles that result in i termediate and poor CYP2C19 metabolism differs according to race/ethnicityproduct(see Pharmacogene ics). From literature, limited data in Asian populations are available to assess the clinical impli a ion of genotyping of this CYP on clinical outcome events.

5.3 Preclinical safety data

During non clinical studies in at and baboon, the most frequently observed effects were liver changes. These occurred at doses re esenting at least 25 times the exposure seen in humans receiving the

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

clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No effectMedicinalon hepatic met bo ising enzymes was observed in humans receiving clopidogrel at the therapeutic dose.

Th re 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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Macrogol 6000

Cellulose, microcrystalline (E460)

Crospovidone type A

Castor oil, hydrogenated

Film-coating:

Macrogol 6000

Ethylcellulose (E462)

Titanium dioxide (E 171)

6.2

Incompatibilities

 

authorised

Not applicable

 

6.3

Shelf life

 

3 years

 

6.4

Special precautions for storage

 

 

 

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

 

6.5

Nature and contents of container

longer

 

 

 

 

Alu/Alu blisters containing 14, 28, 30, 50, 84, 90 a d 100 film-coated tablets packed in cardboard

cartons.

 

no

 

 

 

Not all pack sizes may be marketed.

 

6.6

Special precautions f r disp sal

 

No special requirements

product

 

 

 

 

7.

MARKETING AUTHORISATION HOLDER

83714 Mi sbach Germany

AcinoMedicinalPharma GmbH

Am Win feld 35

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/547/001-007

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/09/2009

10. DATE OF REVISION OF THE TEXT

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

 

 

 

longer

authorised

 

 

no

 

 

product

 

 

Medicinal

 

 

 

 

 

 

 

Comments

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
  • Help
  • Get it on Google Play
  • About
  • Info on site by:

  • Presented by RXed.eu

  • 27558

    prescription drugs listed