Plavix 75mg Tablet

PLAVIX is indicated for the reduction of atherothrombotic events as follows:

• Recent Myocardial Infarction (MI), Recent Stroke, or Established Peripheral Arterial Disease: Reduction of atherosclerotic events (myocardial infarction, stroke, death due to vascular causes) in patients with a history of symptomatic atherosclerotic disease defined by ischaemic stroke (from 7 days until less than 6 months), myocardial infarction (from a few days until less than 35 days) or established peripheral arterial disease.
• Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave myocardial infarction [MI]) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG (coronary artery bypass graft), PLAVIX in combination with ASA has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischaemia. For patients with ST-segment elevation acute myocardial infarction, PLAVIX in combination with ASA has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke.

The recommended daily dose of PLAVIX is 75 mg once daily.

Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), PLAVIX should be initiated with a single 300-mg loading dose and then continued at 75 mg once daily. Aspirin (75 mg u2013 325 mg once daily) should be initiated and continued in combination with PLAVIX. For patients with ST-segment elevation acute myocardial infarction, the recommended dose of PLAVIX is 75 mg once daily, administered in combination with aspirin, with or without thrombolytics. PLAVIX may be initiated with or without a loading dose. PLAVIX can be administered with or without food.

No dosage adjustment is necessary for elderly patients or patients with renal disease.

• Hypersensitivity to the active substance or any component of PLAVIX.
• Active pathological bleeding such as peptic ulcer and intracranial haemorrhage.
• Safety and efficacy in subjects below the age of 18 have not been established.
• Safety and efficacy in pregnancy and lactation have not been established (see HUMAN REPRODUCTION).
• PLAVIX is contraindicated in severe liver impairment.
• PLAVIX is contraindicated in thrombocytopenia and platelet dysfunction.
• Haemophilia, congenital or acquired, or history of acquired haemophilia related to clopidogrel.

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) HAS BEEN REPORTED TO OCCUR WITH PLAVIX DURING POST-MARKETING EXPERIENCE. MOST CASES WERE REPORTED IN THE FIRST TWO WEEKS OF TREATMENT. PRESCRIBERS SHOULD ALSO WARN PATIENTS ABOUT THE SIGNS AND SYMPTOMS OF THROMBOTIC THROMBOCYTOPENIC PURPURA.

Recent ischemic stroke: In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of aspirin and clopidogrel has been shown to increase major bleeding. Therefore, such addition should be undertaken with caution outside of clinical situations where the combination has proven to be beneficial.

In view of the lack of data, PLAVIX cannot be recommended in acute ischaemic stroke (less than 7 days).

Clopidogrel produces irreversible inhibition of platelet aggregation for the life of the platelet, which is 7-10 days. If a patient is to undergo elective surgery and an antiplatelet effect is not desired, PLAVIX should be discontinued 7 days prior to surgery. Spinal and epidural anaesthesia should not be administered to a patient taking clopidogrel or for 7 days thereafter. No lumber puncture should be done during these 7 days due to risk of haematoma formation following lumber puncture or spinal and epidural anaesthesia.

Bleeding and haematological disorders: Due to the risk of bleeding and haematological undesirable effects, blood cell count determination and/or other appropriate testing should be promptly considered whenever such suspected clinical symptoms arise during the course of treatment (see SIDE EFFECTS).

PLAVIX should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions associated with bleeding diathesis and in patients receiving treatment with acetylsalicylic acid, non-steroidal anti-inflammatory medicines including COX-2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs) or thrombolytics. Patients should be continuously followed carefully for any signs of bleeding including occult bleeding, especially but not limited to during the first weeks of treatment and/or after cardiac procedures or surgery.

PLAVIX prolongs bleeding time. PLAVIX should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intra-ocular). Medicines that might induce gastrointestinal lesions (such as acetylsalicylic acid and non-steroidal anti-inflammatory agents) should be used with caution in patients taking PLAVIX (see INTERACTIONS).

Patients should be told that it may take longer than usual to stop bleeding when they take PLAVIX, and that they should report any unusual bleeding (site or duration) to their physician. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicine is taken.

Because of the increased risk of bleeding, the concomitant administration of warfarin with PLAVIX should be undertaken with caution.

In view of the possible increased risk of bleeding, the concomitant administration of PLAVIX with ASA, heparin, or thrombolytics should be undertaken with caution (see INTERACTIONS).

Thrombotic Thrombocytopenic Purpura (TTP): Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of PLAVIX, sometimes after a short exposure (see WARNINGS). It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment, including plasmapharesis (plasma exchange).

Acquired haemophilia: Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel should be discontinued (see CONTRAINDICATIONS).

Cytochrome P450 2C19 (CYP2C19): Pharmacogenetics: Tests are available to identify a patientu2019s CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. (see Pharmacogenetics and DOSAGE AND DIRECTIONS FOR USE).

Cross-reactivity among thienopyridines: Patients should be evaluated for history of hypersensitivity to another thienopyridine (such as ticlopidine, prasugrel) since cross-reactivity among theinopyridines has been reported (see SIDE EFFECTS). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema or haematological reactions such as thrombocytopenia and neutropenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for cross-reactivity is advised.

Hepatic impairment: Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. PLAVIX should therefore be used with caution in this population.

Renal impairment: Therapeutic experience with clopidogrel is limited in patients with severe renal impairment. Therefore clopidogrel should be used with caution in these patients.

Acetylsalicylic acid: Acetylsalicylic acid (ASA) did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Concomitant administration of 500 mg of acetylsalicylic acid twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. Clopidogrel potentiated the effect of acetylsalicylic acid on collagen-induced platelet aggregation. As a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, concomitant use should be undertaken with caution (see Special Precautions). However, clopidogrel and ASA (75-325 mg once daily) have been administered together for up to one year.

Medicines associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of medicines associated with bleeding risk should be undertaken with caution.

Injectable anticoagulants: 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. As a pharmacodynamic interaction between clopidogrel and heparin is possible, 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 heparins are co-administered with acetylsalicylic acid. However, the concomitant use of clopidogrel with thrombolytic agents should be undertaken with caution.

Oral anticoagulants: Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution (see Special Precautions).

Glycoprotein IIb/IIIa inhibitors: As a pharmacodynamic interaction between clopidogrel and glycoprotein IIb/IIIa inhibitors is possible, concomitant use should be undertaken with caution.

Non-Steroidal Anti-Inflammatory Agents (NSAIDs): 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 and clopidogrel should be co-administered with caution (see Special Precautions).

Selective Serotonin Reuptake Inhibitors (SSRIs): Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.

Other concomitant therapy: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicine that inhibit the activity of this enzyme would be expected to result in reduced medicine levels of the active metabolite of clopidogrel and a reduction in clinical efficacy. Concomitant use of strong or moderate CYP2C19 inhibitors (e.g., omeprazole and esomeprazole) should be discouraged (see Special Precautions and Pharmacokinetics, Pharmacogenetics). If a proton pump inhibitor is to be used concomitantly with PLAVIX, consider using one with less CYP2C19 inhibitory activity.

No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. 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 clopidogrel could inhibit the activity of one of the Cytochrome P450 (CYP) enzymes (CYP 2C9). This could lead to increased plasma levels of medicines such as phenytoin, tolbutamide, torsemide, tamoxifen, fluvastatin and NSAIDu2019s which are metabolised by CYP 2C9. Data indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.

CYP2C8 substrate medicines: Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and medicines primarily cleared by CYP2C8 metabolism (e.g. repaglinide, paclitaxel) should be undertaken with caution.

In addition to the above specific interaction studies, patients entered into large clinical studies received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, anti-diabetic agents, anti-epileptic agents and hormone replacement therapy, without evidence of clinically significant adverse interactions.

Pregnancy: PLAVIX should not be used during pregnancy.

Breastfeeding mothers: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether clopidogrel is excreted in human breast milk. Mothers treated with PLAVIX should not breastfeed their infants.

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

Bleeding is the most common reaction reported both in clinical studies where frequencies varied from common to very common, as well as in post-marketing experience. Clinical studies adverse events: In the CAPRIE study, for patients treated with clopidogrel, the overall incidence of any bleeding was 9,3 %. The incidence of severe cases was 1,4 % and gastrointestinal bleeding occurred at a rate of 2,0 %, and required hospitalisation in 0,7 %. In the CURE study, the incidence of major and minor bleeding in the clopidogrel + ASA group was 3,7 % and 5,1 %, respectively. The principal sites for major bleeding included gastrointestinal and at arterial puncture sites. In an acute coronary syndrome study where clopidogrel was administered concomitantly with ASA, the major bleeding event rate for clopidogrel + ASA was dose-dependent on ASA (< 100 mg: 2,6 %; 100 u2013 200 mg: 3,5 %; > 200 mg: 4,9 %).

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). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9,6 % for clopidogrel + ASA.

Adverse reactions have been ranked under heading of system-organ class and frequency using the following convention: Very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1 000, < 1/100); rare (> 1/10 000, < 1/1 000); very rare (< 1/10 000).

Blood and the lymphatic system disorders: Uncommon : thrombocytopenia (sometimes severe), increased bleeding time, leucopenia, eosinophilia, neutropenia (sometimes severe) Very rare : aplastic anaemia These events related to myelotoxicity should be considered when a patient receiving PLAVIX demonstrates fever or other signs of infection.

Nervous system disorders: Uncommon : intracranial bleeding, headache, dizziness, paraesthesia Eye disorders: Uncommon : eye bleeding (mainly conjunctival) Ear and labyrinth disorders: Rare : vertigo Vascular disorders: Common : haematoma Respiratory, thoracic and mediastinal disorders: Common : epistaxis Gastrointestinal system disorders: Common : dyspepsia, abdominal pain, diarrhoea Uncommon : nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer, duodenal ulcer Skin and subcutaneous tissue disorders: Common : bruising Uncommon : rash, pruritus, purpura Renal and urinary disorders: Uncommon : haematuria General disorders and administrative site conditions: Common : bleeding at the puncture site

Post marketing experience Adverse reactions have been ranked under heading of system-organ class. Blood and the lymphatic system disorders: Serious cases of bleeding, mainly skin, musculoskeletal, eye (conjunctival, ocular, retinal) and respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), epistaxis, haematuria and haemorrhage of operative wound; cases of bleeding with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage). Thrombotic thrombocytopenic purpura (TTP) (see Special Precautions), aplastic anaemia/pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anaemia, acquired haemophilia A. Cardiac disorders: Kounis syndrome (vasospastic allergic angina) Immune system disorders: Anaphylactoid reactions, serum sickness, cross-reactive drug hypersensitivity among thienopyridines (such as ticlopidine, prasugrel) (see WARNINGS and SPECIAL PRECAUTIONS). Psychiatric disorders: Confusion, hallucinations Nervous system disorders: Taste disturbances, ageusia Vascular disorders: Vasculitis, hypotension Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia Gastrointestinal disorders: Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis Hepato-biliary disorders: Acute liver failure, hepatitis, abnormal liver function test Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis (AGEP)), drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, lichen planus Musculoskeletal, connective tissue and bone disorders: Arthralgia, arthritis, myalgia Renal and urinary disorders: Glomerulonephritis, blood creatinine increased Reproductive systems and breast disorders: Gynaecomastia General disorders and administration site conditions: Fever

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. Further treatment is symptomatic and supportive.