Composition:

Each film-coated tablet contains Clopidogrel bisulphate USP equivalent to

Clopidogrel 75 mg.

Additional ingredients:

Mannitol, Povidone, Microcrystalline cellulose, Low substituted

Hydroxypropylcellulose, Hydrogenated castor oil, Iron oxide red, Isopropyl alcohol,

dichloromethane.

Tablet coating: Opadry Y-I-7000 white.

Indication

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

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

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

disease.

 Patients suffering from acute coronary syndrome:

 Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave

myocardial infarction), including patients undergoing a stent placement following

percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).

 ST segment elevation acute myocardial infarction, in combination with ASA in medically

treated patients eligible for thrombolytic therapy.

Administration & Dosage

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.

Side effects:

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 spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in

postmarketing 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.

In CURE, the major bleeding event rate for clopidogrel+ASA was dose-dependent on ASA

(<100mg: 2.6%; 100-200mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for

placebo+ASA (<100mg: 2.0%; 100-200mg: 2.3%; >200mg: 4.0%). The risk of bleeding

(life threatening, major, minor, other) decreased during the course of the trial: 0-1 months

(clopidogrel: 9.6%; placebo: 6.6%), 1-3 months (clopidogrel: 4.5%; placebo: 2.3%), 3-6 months

(clopidogrel: 3.8%; placebo: 1.6%), 6-9 months (clopidogrel: 3.2%; placebo: 1.5%), 9-12 months

(clopidogrel: 1.9%; placebo: 1.0%). There was no excess in major bleeds with clopidogrel +

ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more

than five days prior to surgery (4.4% clopidogrel+ASA vs. 5.3% placebo+ASA).

In patients who remained on therapy within five days of bypass graft surgery, the event rate was

9.6% for clopidogrel+ASA, and 6.3% for placebo+ASA.

In Clarity, there was an overall increase in bleeding in the clopidogrel + ASA group (17.4%) vs.

the placebo + ASA group (12.9%).The incidence of major bleeding was similar between groups

(1.3% versus 1.1% for the clopidogrel + ASA and the placebo + ASA groups, respectively). 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 (0.6% versus 0.5% in the clopidogrel + ASA and the placebo + ASA

groups, respectively).

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.

Blood and the lymphatic system disorders:

Uncommon:

Thrombocytopenia, leucopenia and eosinophilia.

Rare:

Neutropenia including severe neutropenia.

Very rare:

Thrombotic thrombocytopenic purpura (TTP) (see section 4.4), 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:

Vertigo

Vascular disorders:

Common:

Haematoma

Very rare:

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

Adverse Drug reaction*:

“Inform doctors about unexpected reactions after using drugs”

Drug Interactions

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.

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 medicinal products that inhibit

CYP2C19 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 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. 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 interactions. No clinically significant pharmacodynamic

interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or

both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not

significantly influenced by the co-administration of phenobarbital or oestrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the co administration of

clopidogrel. Antacids did not modify the extent of clopidogrel absorption.

Data from 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 tolbutamide and the

NSAIDs, which are metabolised by Cytochrome P450 2C9. Data from the CAPRIE study

indicate that phenytoin and tolbutamide can be safely co-administered with Clopidogrel.

Apart from the specific medicinal product interaction information described above, interaction

studies with clopidogrel and some medicinal products commonly administered in patients with

atherothrombotic disease have not been performed. However, patients entered into clinical trials

with clopidogrel received a variety of concomitant medicinal products including diuretics, beta

blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators,

antidiabetic agents (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without

evidence of clinically significant adverse interactions.

Precautions in usage

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 non-steroidal antiinflammatory

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 anaemia associated with 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):

Contradictions

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

• Severe liver impairment.

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

Overdosage

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.

Pharmaceutical Form: Film-coated tablet

Pharmacotherapeutic group: platelet aggregation inhibitors, ATC Code: B01AC 04.

Pharmacological properties:

Pharmacodynamics

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.

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 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.

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 954% 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 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.

Storage conditions

Store below 30 °C.

Shelf life

3 years

Package

Klopi Tablets are packed in Alu-Alu Blister pack of 14’s. 2 such blisters are packed in carton

along with the pack insert.

Manufacturer

Kusum Healthcare Private Limited

Address

SP 289 (A), RIICO Industrial Area, Chopanki, Bhiwadi, India