Formulation:

Each film-coated tablet contains:

Clopidogrel (as bisulfate) ………… 75 mg

Description:

Pink colored, biconvex, film coated tablet plain on both sides.

Indications:

Clopidogrel is indicated for the prevention of atherothrombotic events in patients suffering from myocardial infarction,

ischaemic stroke or established peripheral arterial disease, acute coronary syndrome, also for the prevention of

atherothrombotic and thromboticboembolic events in arterial fibrillation.

Dosage and Administration:

Adults and Elderly:

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

The 300 mg tablet of clopidogrel is intended for use as a loading dose 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.

– ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated

with a 300-mg loading dose in combination with ASA and with or without thrombolytics. For patients over 75 years of age

clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after

symptoms start and continued for at least four weeks. The benefit of the combination of clopidogrel with ASA beyond four

weeks has not been studied in this setting.

In patients with atrial fibrillation, clopidogrel should be given as a single daily dose of 75 mg. ASA (75-100 mg daily) should

be initiated and continued in combination with clopidogrel.

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.

Pediatric population:

Clopidogrel should not be used in children because of efficacy concerns.

Renal impairment:

Therapeutic experience is limited in patients with renal impairment.

Hepatic impairment:

Therapeutic experience is limited in patients with moderate hepatic disease who may have

bleeding diatheses.

ADVERSE REACTIONS:

Clopidogrel has been evaluated for safety in more than 44,000 patients who have participated in clinical studies, including

over 12,000 patients treated for 1 year or more. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in

CAPRIE regardless of age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE,

CLARITY, COMMIT and ACTIVE-A studies are discussed below. In addition to clinical studies experience, adverse

reactions have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing experience where it was

mostly reported during the first month of treatment.

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

incidence of severe cases was similar for clopidogrel and ASA.

In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary bypass graft surgery

in patients who stopped therapy more than five days prior to surgery. In patients who remained on therapy within five days of

bypass graft surgery, the event rate was 9.6% for clopidogrel plus ASA, and 6.3% for placebo plus ASA.

In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the placebo plus ASA group.

The incidence of major bleeding was similar between groups . This was consistent across subgroups of patients defined by

baseline characteristics, and type of fibrinolytic or heparin therapy.

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

In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7%

versus 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in

the placebo +ASA group), mainly from the gastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial

bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% versus 0.8%, respectively).

There was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + ASA group and 0.7%

in the placebo +ASA group) and haemorrhagic stroke (0.8% and 0.6%, respectively) between 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.

Blood and the lymphatic system disorders

Uncommon: Thrombocytopenia, leucopenia and eosinophilia.

Rare: Neutropenia including severe neutropenia.

Very rare: Thrombotic thrombocytopenic purpura (TTP), aplastic anaemia, pancytopenia, agranulocytosis, severe

thrombocytopenia, granulocytopenia and anaemia.

Immune system disorders

Very rare:

Serum sickness, anaphylactic reactions.

Psychiatric disorders

Very rare:

Hallucinations, confusion.

Nervous system disorders

Uncommon:

Intracranial bleeding (some cases were reported with fatal outcome), headache, paraesthesia, dizziness.

Very rare:

Taste disturbances.

Eye disorders

Uncommon:

Eye bleeding (conjunctival, ocular, retinal).

Ear and labyrinth disorders

Rare:

Common:

Haematoma

Very rare:

Serious haemorrhage, haemorrhage of operative wound, vasculitis, hypotension.

Respiratory, thoracic and mediastinal disorders

Common:

Epistaxis

Very rare:

Respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), bronchospasm, interstitial pneumonitis.

Gastrointestinal disorders

Common: Gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia.

Uncommon: Gastric ulcer

and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence.

Rare: Retroperitoneal haemorrhage

Very rare:

Gastrointestinal and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or

lymphocytic colitis), stomatitis.

Hepato-biliary disorders

Very rare:

Acute liver failure, hepatitis, abnormal liver function test.

Skin and subcutaneous tissue disorders

Common:

Bruishing

Uncommon: Rash, pruritus, skin bleeding (purpura).

Very rare:

Bullous dermatitis (toxic epidermal necrolysis, Stevens Johnson Syndrome, erythema multiforme), angioedema,

rash erythematous, urticaria, eczema, lichen planus.

Musculoskeletal connective tissue and bone disorders

Very rare:

Musculo-skeletal bleeding (haemarthrosis), arthritis, arthralgia, myalgia.

Renal and urinary disorders

Uncommon:

Haematuria.

Very rare:

Glomerulonephritis blood creatinine increased.

General disorders and administration site conditions

Common:

Bleeding at puncture site

Very rare:

Fever.

Investigations

Uncommon:

Bleeding time prolonged, neutrophil count decreased, platelet count decreased.

Drug Intractions

Oral anticoagulants

The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the

intensity of bleedings. Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of Swarfarin

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 caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors.

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. However, clopidogrel and ASA have been

administered together for up to one year.

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.

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.

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.

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.

Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide,

voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

Proton Pump Inhibitor (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

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 esomeprozole should be discouraged.

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 daily. 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.

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 was 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 metabolized by CYP2C9 can be safely coadministered

with clopidogrel.

Apart from the specific medicinal product interaction information described above, interaction studies with clopidogrel and

some medicinal products commonly administered in patients with atherothrombotic disease have not been performed.

However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including

diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic

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

interactions.

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

Breast-feeding

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

75 mg Film-Coated Tablets.

Fertility

Clopidogrel was not shown to alter fertility in animal studies.

Effects on ability to drive and use machines:

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

Precautions:

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. 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 non-steroidal 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.

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 anemia 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.

Renal impairment

Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used

with caution in these patients.

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.

Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorbtion

Clopidogrel 75 mg Film-Coated Tablets contains lactose. Patients with rare hereditary problems of galactose intolerance,

the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Lecithin

Clopidogrel 75 mg Film-Coated Tablets contains lecithin (soya oil). If a patient is hypersensitive to peanut or soya, this

medicine should not be used.

The tablet container contains desiccant that should not be swallowed.

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.

Contraindications:

– Hypersensitivity to the active substance, soya oil, peanut oil or to any of the excipients.

– Severe hepatic impairment.

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

Pharmacokinetics:

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-oxoclopidogrel

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 C of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose as it is after four days of max

75-mg maintenance dose. C occurs approximately 30 to 60 minutes after dosing.

max

Elimination:

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

46% in the faeces in the 120-hour interval after dosing. After a single oral dose of 75mg, clopidogrel has a half-life of

approximately 6 hours. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated

administration.