Rhea Clopidogrel Bisulfate

Clopidogrel bisulfate.

Each film-coated tablet contains Clopidogrel (as bisulfate) 75 mg.

Clopidogrel is indicated in adults for the prevention of atherothrombotic events in: Recent MI, Recent Stroke or Established Peripheral Arterial Disease: For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
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 medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, clopidogrel has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
For patients with ST-segment elevation acute myocardial infarction, clopidogrel 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.
Clopidogrel is indicated in adults for the prevention of atherothrombotic and thrombotic events in: Atrial Fibrillations: In patients with atrial fibrillation (AF) at increased risk of vascular events who can take vitamin K antagonist (VKA) therapy, VKA has been shown to be associated with a better clinical benefit than acetylsalicylic acid (ASA) alone or the combination of clopidogrel and ASA for the reduction of stroke.
In patients with atrial fibrillation who have at least one risk factor for vascular events and who cannot take VKA therapy (e.g., specific risk of bleeding, physician assessment that patient is unable to comply with INR (international normalised ratio) monitoring or that VKA use is inappropriate), clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke. Clopidogrel in combination with ASA has been shown to reduce the rate of the combined endpoint of stroke, myocardial infarction (MI), non-CNS systemic embolism, or vascular death, largely through a reduction in stroke.

General: Recent MI, Recent Stroke, or Established Peripheral Arterial Disease: Clopidogrel should be given as a single dose of 75 mg.
Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), clopidogrel should be initiated with a single 300-mg loading dose and then continued at 75 mg once daily. Acetylsalicylic acid (ASA) (75 mg up to 325 mg once daily) should be initiated and continued in combination with clopidogrel. In CURE, most patients with Acute Coronary Syndrome also received heparin.
For patients with ST-segment elevation acute myocardial infarction, the recommended dose of clopidogrel is 75 mg once daily, administered in combination with ASA, with or without thrombolytics. Clopidogrel may be initiated with or without a loading dose (300 mg was used in CLARITY).
Atrial Fibrillation: Clopidogrel should be given as a single dose of 75 mg. ASA (75-100 mg daily should be initiated and continued in combination with clopidogrel.
Pharmacogenetics: CYP2C19 poor metaboliser status is associated with diminished antiplatelet response to clopidogrel. A higher dose regimen (600-mg loading dose followed by 150 mg once daily) in poor metabolisers increases antiplatelet response. Consider the use of higher clopidogrel doses in patients who are poor CYP2C19 metabolisers. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.
Special Populations: Children: Safety and effectiveness in pediatric populations have not been established.
Elderly: No dosage adjustment is necessary in elderly patients.
Hepatic impairment: No dosage adjustment is necessary. See Precautions.
Renal impairment: No dosage adjustment is necessary. See Precautions.
Administration: Clopidogrel can be administered with or without food.

Signs and Symptoms: Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications.
Management: Appropriate therapy should be considered if bleeding is 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.

Hypersensitivity to the drug substance or any component of the product.
Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

Bleeding and haemotological 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 Adverse Reactions). Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution.
As with other anti-platelet 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 acetylsalicylic acid, heparin, glycoprotein IIb/IIIa inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), or selective serotonin reuptake inhibitors (SSRIs).
If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5 to 7 days prior to surgery. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular). Drugs that might induce gastrointestinal lesions (such as acetylsalicylic acid and Non-Steroidal Anti-Inflammatory Drugs) should be used with caution in patients taking clopidogrel. Patients should be told that it may 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 the physician. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken.
Recent ischemic stroke: In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of ASA 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.
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 (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.
Cytochrome P450 2C19 (CYP2C19): Pharmacogenetics: In patients who are CYP2C19 poor metabolisers clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Poor metabolisers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses may exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Consider the use of higher clopidogrel doses in patients who are known CYP2C19 poor metabolisers.
Cross-reactivity among thienopyridines: Patients should be evaluated for history of hypersensitivity to another thienopyridine (such as ticlopidine, prasurgel) since allergic cross-reactivity among thienopyridines has been reported (see Adverse Reactions). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological reactions such as thrombocytopaenia and neutropaenia (see Advere Reactions). 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.
Renal impairment: Experience with clopidogrel is limited in patients with severe renal impairment. Therefore, clopidogrel should be used with caution in this population.
Hepatic impairment: Experience is limited in patients with severe hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.
Excipients: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Driving a Vehicle or Performing Other Hazardous Tasks: No impairment of driving or psychometric performance was observed following clopidogrel administration.

Pregnancy: Reproduction studies have been performed in rats at doses up to 500 mg/kg per day and in rabbits at doses up to 300 mg/kg per day and have revealed no evidence of impaired fertility or harm to the foetus due to clopidogrel. There are, however, no adequate and well controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of a human response, this drug should not be used during pregnancy, unless, in the opinion of the physician, there is a clear need.
Lactation: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug. taking into account the importance of the drug to a nursing woman.

Clinical Studies Experience: Clopidogrel has been evaluated for safety in more than 44,000 patients, including over 12,000 patients treated for 1 year or more Clopidogrel 75 mg/day was well tolerated compared to acetylsalicylic acid (ASA) 325 mg/day in CAPRIE. The overall tolerability of clopidogrel in this study was similar to ASA regardless of age, gender and ethnicity. The clinically relevant adverse effects observed in CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A are discussed as follows.
Haemorrhagic disorders: In CAPRIE, the overall incidence of bleeding on clopidogrel and ASA was the same (9.3%). The incidence of severe cases was 1.4% and 1.6% in the clopidogrel and ASA groups, respectively.
In patients receiving clopidogrel, gastrointestinal bleeding occurred at a rate of 2.0% and required hospitalisation in 0.7%. In patients receiving ASA, the corresponding rates were 2.7% and 1.1%, respectively.
The overall incidence of other bleeding disorders was higher in the clopidogrel group (7.3%) compared to ASA (6.5%). However, the incidence of severe events was similar in both treatment groups (0.6% vs. 0.4%). The most frequent events reported were purpura/bruising and epistaxis. Other less frequently reported events were haematoma, haematuria and eye bleeding (mainly conjunctival).
The incidence of intracranial bleeding was 0.4% for clopidogrel compared to 0.5% for ASA.
In CURE, there was an increase in major and minor bleeding between the clopidogrel + ASA group compared with the placebo + ASA group (event rates 3.7% vs. 2.7%, for major, respectively, and 5.1% vs. 2.4% for minor). The principal sites for major bleeding included gastrointestinal and at arterial puncture sites.
The increase in life-threatening bleeding in the clopidogrel + ASA group compared to the placebo + ASA group was not statistically significant (2.2% vs. 1.8%). There was no difference between the two groups in the rate of fatal bleeding (0.2% in both groups). The rate of non-life-threatening major bleeding was significantly higher in the clopidogrel + ASA group compared with the placebo + ASA group (1.6% vs. 1%), and the incidence of intracranial bleeding was 0.1% in both groups.
The major bleeding event rate for clopidogrel + ASA was dose-dependent on MA (<100 mg: 2.6%, 100-200 mg. 3.5%; >200 mg: 4.9%) as was the major bleeding event rate for placebo + ASA (<100 mg: 2.0%; 100-200 mg: 2.3%; >200 mg: 4.0%).
There was no excess in major bleeds 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. The overall incidence of bleeding is described in Table 1 for patients receiving both clopidogrel and ASA in CURE.
Ninety-two percent (92%) of the patients in the CURE study received heparin/LMWH. and the rate of bleeding in these patients was similar to the overall results. (See Table 1.)

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In CLARITY, the incidence of major bleeding (defined as intracranial bleeding or bleeding associated with a fall in hemoglobin >5 g/dL) was similar between groups (1.3% versus 1.1% in the clopidogrel + ASA and in the placebo + ASA groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytics or heparin therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the clopidogrel + ASA and in the placebo + ASA groups, respectively) and intracranial haemorrhage (0.5% versus 0.7%. respectively) was low and similar in both groups.
The overall rate of noncerebral major bleeding or cerebral bleeding in COMMIT was low and similar in both groups as shown in Table 2 as follows. (See Table 2.)

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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 in 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 (see Table 3) and haemorrhagic stroke (0.8% and 0.6%, respectively) between groups. (See Table 3.)

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Haematological disorders: In CAPRIE, severe neutropaenia (<0.450G/L) was observed in 4 patients (0.04%) on clopidogrel and 2 patients (0.02%) on ASA.
Two of the 9599 patients who received clopidogrel and none of the 9586 patients who received ASA had neutrophils counts of zero. Although the risk of myelotoxicity with clopidogrel appears to be quite low, this possibility should be considered when a patient receiving clopidogrel demonstrates fever or other sign of infection.
One case of aplastic anaemia occurred on clopidogrel treatment. The incidence of severe thrombocytopaenia (<80 g/L.) was 0.2% on clopidogrel and 0.1% on ASA; very rare cases of platelet count ≤30 g/L have been reported. In CURE and CLARITY, the number of patients with thrombocytopenia or neutropenia was similar in both groups. Other clinically relevant adverse drug reactions pooled from CAPRIE and CURE, CLARITY, COMMIT and ACTIVE-A198 studies with an incidence <0.1% as well as all serious and relevant ADR with an incidence <0.1% are presented as follows.
The following CIOMS frequency rating is used, when applicable.
Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very rare <0.01%; Unknown (cannot be estimated from available data).
Central and peripheral nervous system disorders: Uncommon: headache, dizziness, paraesthesia. Rare: vertigo.
Gastrointestinal system disorders: Common: dyspepsia, abdominal pain, diarrhoea. Uncommon: nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer, duodenal ulcer.
Platelet, bleeding and clotting disorders: Uncommon: bleeding time increased, platelets decreased.
Skin and appendages disorders: Uncommon: rash, pruritus.
White cell and RES disorders: Uncommon: leucopenia, neutrophils decreased, eosinophilia.
Post-marketing experience: Adverse reactions have been ranked under heading of system-organ class. Frequencies for the following adverse reactions are not known (cannot be estimated from available data).
Blood and the lymphatic system disorders: Serious cases of bleeding, mainly skin, musculoskeletal, eye (conjunctival, ocular, retinal) and respiratory tract bleeding, epistaxis, haematuria and haemorrhage of operative wound; cases of bleeding with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage), agranulocytosis, aplastic anaemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired haemophilia A.
Immune system disorders: Anaphylactoid reactions, serum sickness; Cross-reactive drug hypersensitivity among thienopyridines (such as ticlopicline, prasugrel) (see Precautions).
Psychiatric disorders: Confusion, hallucinations.
Nervous system disorders: Taste disturbances.
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: Hepatitis (non-infectious), acute liver failure.
Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliatiye rash, urticaria, pruritus, angioederna, bultous dermatitis (erythema multitorme, Stevens Johnson syndrome, toxic epidermal necrolysis), 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: Glomerulopathy.
General disorders and administration site conditions: Fever.
Investigations: Abnormal liver function test, blood creatinine increase.

Thrombolytics: The safety of the concomitant administration of clopidogrel, thrombolytics and heparin was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytics and heparin are co-administered with acetylsalicylic acid.
Glycoprotein IIb/IIIa inhibitors: As a pharmacodynamic interaction between clopidogrel and glycoprotein IIb/IIIa inhibitors is possible, concomitant use should be undertaken with caution.
Injectable anticoagulants: 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. As a pharmacodynamic interaction between clopidogrel and heparin is possible, concomitant use 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.
Acetylsalicylic acid: Acetylsalicylic acid did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, 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. As a pharmacodynamic interaction between clopidogrel intake. As a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, concomitant use should be undertaken with caution. However clopidogrel and ASA (75-325 mg once daily) have been administered together for up to one year.
Non-Steroidal Anti-Inflammatory Drugs (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 and clopidogrel should be co-administered with caution.
Other concomitant therapy: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs 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. Concomitant use of strong or moderate CYP2C19 inhibitors (e.g., omeprazole) should be discouraged (see Precautions). If a proton pump inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19 inhibitory activity, such as pantoprazole.
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 5μM ADP was diminished by 39% (24 hours) and 21% (Day 5) when clopidogrel and omeprazole were administered together.
In a second interaction study with omeprazole 80 mg administered 12 hours apart from the clopidogrel standard regimen, the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19.
In a third interaction study with omeprazole 80 mg administered with a higher dose regimen of clopidogrel (600-mg loading dose followed by 150 mg/day), a degree of interaction was observed similar to that noted in the other omeprazole interaction studies. However, active metabolite formation and platelet aggregation were at the same level as clopidogrel administered alone at the standard dose regimen.
In a crossover clinical study, healthy subjects were administered clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with pantoprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 20% (Day 1) and 14% (Day 5) when clopidogrel and pantoprazole were administered together. Mean inhibition of platelet aggregation was diminished by 15% (24 hours) and 11% (Day 5) when clopidogrel and pantoprazole were administered together. These results indicate that clopidogrel can be administered with pantoprazole.
The CURRENT trial compared 2 dosing regimens of clopidogrel (600 mg loading dose, then 150 mg/day for 6 days followed by 75 mg/day up to 30 days vs. 300-mg loading dose followed by 75 mg/day up to 30 days). A subanalysis (n=18.432) correlated PPI use (mainly omeprazole and pantoprazole) at randomization and hospital discharge and demonstrated no interaction between clopidogrel and PPI use for the primary endpoint (CV death, MI or stroke) or any secondary endpoints, including stent thrombosis.
A number of other clinical studies have been conducted with clopidogrel and other concomitaot medications 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.
Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy. coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis.
However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. It is unlikely that clopidogrel may interfere with the metabolism of drugs such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by cytochrome P450 2C9 Data from the CAPRIE study indicate that phenvtoin and tolbutamide can be safely co-administered with clopidogrel.
In addition to the above specific interaction studies, patients entered into large clinical studies CAPRIE and CURE) 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 (including insulin), anti-epileptic agents. GPIIb/IIIa antagonists and hormone replacement therapy, without evidence of clinically significant adverse interactions.

Store at temperatures not exceeding 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AC04 - clopidogrel ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.

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