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.

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.
Prevention of atherothrombotic and thromboembolic events in atrial fibrillation.
 In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.
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 Effects
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:
Vertigo
Vascular disorders
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.
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.
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. 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.
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.
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
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 Klopi 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
Klopi 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.

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.
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.
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 condition
Store below 30°C.
Keep all medicines out of reach of children.
Dosage forms and packaging available
Alu-Alu blister of 14 tablets and 2 or 10 blisters in a carton.
Shelf-life
36 months
Name and address of manufacturer
Kusum Healthcare Pvt. Ltd.
SP 289(A), RIICO Industrial Area, Chopanki, Bhiwadi (Rajasthan), India
Date of revision of package insert
Not Applicable
MM Reg. No.: 1812AA7079