Clopistad

Clopistad

clopidogrel

Manufacturer:

Stellapharm

Distributor:

DCH Auriga

Marketer:

Stadpharm [MY]
Full Prescribing Info
Contents
Clopidogrel bisulfate.
Description
Active ingredient: One tablet contains clopidogrel (as clopidogrel bisufate) 75 mg.
Excipients/Inactive Ingredients: Hypromellose, Macrogol 6000, Red ferric oxide, Talc, Titanium dioxide, Colloidal anhydrous silica, Crospovidone, Hydrogenated caster oil, Lactose monohydrate, Maize starch, Microcrystalline cellulose, Povidone K30.
Action
Pharmacology: Pharmacodynamics: Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated. Clopidogrel also inhibits plalelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity.
Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan.
Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.
Pharmacokinetics: Clopidogrel is rapidly but incompletely absorbed after oral administration, absorption appears to be at least 50%. It is a prodrug and is extensively metabolised in the liver, mainly to the inactive carboxylic acid derivative. The active metabolite appears to be a thiol derivative but has not been identified in plasma. Clopidogrel and the carboxylic acid derivative are highly plasma protein bound. Clopidogrel and its metabolites are excreted in urine and in faeces, after oral administration, about 50% of a dose is recovered from the urine and about 46% from the faeces.
Indications/Uses
Prevention of atherothrombotic events.
Clopidogrel is indicated in: Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemlc stroke (from 7 days until less than 6 months) or established peripheral arterial disease.
Adult 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.
Dosage/Direction for Use
Adults and elderly.
Clopidogrel should be given as a single daily dose of 75 mg with or without food.
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 or 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.
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.
Contraindications
Hypersensitivity to clopidogrel or to any of the excipients.
Severe liver impairment.
Active pathological bleeding e.g, peptic ulcer or intracranial haemorrhage.
This drug product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug product.
Breastfeeding.
Special Precautions
Due to the risk of bleeding and haematological undesirable effects, 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 antiplalelet 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, non-steroidal anti-inflammatory drugs (NSAIDs) induding COX-2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors or thrombolytics. 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 GI 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) 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 either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresls. In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke.
Cytochrome P450 (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. 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.
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.
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.
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.
Effects on Ability to Drive and Use Machines: Clopidogrel has no or negligible influence on the ability to drive and use machines.
Use In Pregnancy & Lactation
Pregnancy: There are no adequate and well-controlled studies in pregnant women, clopidogrel should be used during pregnancy only if clearly needed.
Lactation: Not known whether the drug is distributed into milk in humans. Discontinue nursing or the drug because of potential for severe adverse effects in infants.
Adverse Reactions
Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the following. Their frequency is defined using the following conventions: Common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); 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), aplastic anaemia, pancytopoenia, agranulocytosis, severe thrombocytopoenia, granulocytopoenia and anaemia.
Immune system disorders: Very rare: Serum sickness and anaphylactoid reactions.
Psychiatric disorders: Very rare: Hallucinations and confusion.
Nervous system disorders: Uncommon: Intracranial bleeding (some cases were reported with fatal outcome), headache, paraesthesia and dizziness.
Very rare: Taste disturbances.
Eye disorders: Uncommon: Eye bleeding (conjunctival, ocular and 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 and interstitial pneumonitis.
Gastrointestinal disorders: Common: Gastrointestinal haemorrhage, diarrhoea, abdominal pain and dyspepsia.
Uncommon: Gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation and flatulence.
Rare: Retroperitoneal haemorrhage.
Very rare: Gastrointestinal and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis) and stomatitis.
Hepatobiliary disorders: Very rare: Acute liver failure, hepatitis and abnormal liver function test.
Skin and subcutaneous tissue disorders: Common: Bruising.
Uncommon: Rash, pruritus and skin bleeding (purpura).
Very rare: Bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme), angioedema, erythematous rash, urticaria, eczema and lichen planus.
Musculoskeletal, connective tissue and bone disorders: Very rare: Musculoskeletal bleeding (haemarthrosis), arthritis, arthralgia and myalgia.
Renal and urinary disorders: Uncommon: Haematuria.
Very rare: Glomerulonephritis and increased blood creatinine.
General disorders and administration site conditions: Common: Bleeding at puncture site.
Very rare: Fever.
Investigations: Uncommon: Prolonged bleeding time, decreased neutrophil count and decreased platelet count.
Drug Interactions
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 may be at risk of increased bleeding from trauma, surgery or other pathological conditions that 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 ASA 500 mg twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and ASA 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 1 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 MI. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with ASA.
Nonsteroidal anti-inflammatory drugs (NSAIDs): In a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult GI blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of GI 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 drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel and a reduction in clinical efficacy. Concomitant use of drugs that inhibit CYP2C19 should be discouraged. Drugs that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.
Proton pump inhibitors: Omeprazole 80 mg once daily administered at the same time as clopidogrel decreased the exposure of the active metabolite of clopidogrel by 45% (loading dose) and 40% (maintenance dose). Omeprazole, when administered 12 hours after clopidogrel resulted in similar reductions in exposure to the active metabolite.
The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction of 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 esomeprazole 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 drugs that reduce stomach acid such as H2 blockers (except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with antiplatelet activity of clopidogrel.
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, cimetidine 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 P-450 2C9. This could potentially lead to increased plasma levels of medicinal products eg, 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 safety co-administeredwith clopidogrel.
Apart from the specific medicinal product interaction information described previously, 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, β-blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.
CYP2C8 substrate drugs: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution.
Storage
Do not sore above 30°C.
ATC Classification
B01AC04 - clopidogrel ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
Presentation/Packing
FC tab 75 mg (pink, round-shaped, biconvex, engraved with "75" on one side and plain on the other) x 3 x 10's.
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