COMPOSITION :
Clopidogrel Bisulfate Film coated tablet 75 mg, each film coated tablet contains : Clopidogrel bisulfate equivalent to Clopidogrel 75 mg.
DESCRIPTION :
Clopidogrel Bisulfate containing Clopidogrel bisulfate (equivalent to Clopidogrel) is available in 75 mg film coated tablet.
INDICATIONS :
Clopidogrel Bisulfate is indicated 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). 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 AND ADMINISTRATION :
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 (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 – 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 or without a loading dose in combination with ASA and with or without thrombolytics. For patients greater than 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.
Children and adolescents :
There is no experience in children.
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 reversed the effects of Clopidogrel.
CONTRAINDICATIONS :
- Hypersensitivity to the active substance or to any of the excipients of the medical product.
- Severe liver impairment.
- Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.
- Breast-feeding.
WARNING AND 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 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, nonsteroidal anti-inflammatory drugs, including COX-2 inhibitors, heparin, or glycoprotein IIb/IIIa inhibitors. Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of the treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of Clopidogrel with warfarin is not recommended since it may increase the intensity of bleedings.
- If a patient is to undergo elective surgery and antiplatelet effect is not necessary, Clopidogrel should be discontinued 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).
- 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. Patients should inform physicians and dentist that they are taking Clopidogrel before any surgery is scheduled and before any new drug is taken. Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of Clopidogrel, sometimes after a short exposure. It is characterized by thrombocytopenia and microangiopathic hemolytic anemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.
- In view of the lack of data, Clopidogrel cannot be recommended in acute ischemic stroke (less than 7 days).
- Therapeutic experience with Clopidogrel is limited in patients with renal impairment. Therefore Clopidogrel should be used with caution in these patients.
- Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.
- Patient with rare hereditary problems of galactose intolerance, the Lapp lactase deficiencies or glucose galactose malabsorption should not take this medicine.
- Pregnancy : As no clinical data on exposed pregnancies are available, it is preferable not to use Clopidogrel during pregnancy as a precautionary measure. Animal studies do not indicate direct harmful effects, with respect to pregnancy, embryonic/foetal development, parturition or postnatal development.
- Lactation : Studies in rats have shown that Clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this medicinal product is excreted in human milk. Clopidogrel should not be administered in nursing mother.
DRUG INTERACTIONS :
- Warfarin : The concomitant administration of Clopidogrel with warfarin 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 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 ASA is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.
- 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 heparin 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 ASA. However, the concomitant use of the Clopidogrel with thrombolytic agents should be undertaken with caution.
- Nonsteroidal 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 including COX-2 inhibitors and Clopidogrel should be co-administered with caution.
- A number of other clinical studies have been conducted with Clopidogrel and other concomitant 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 co-administration of Phenobarbital, Cimetidine or Oestrogen.
- The pharmacokinetics of Digoxin or Theophylline was 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 drug such as Phenytoin and Tolbutamide and the NSAIDs, which are metabolized by Cytochrome P450 2C9. Data from CAPRIE study indicate that Phenytoin and Tolbutamide can be safely co-administered with Clopidogrel.
- Apart from the specific drug interaction information described above, interaction studies with Clopidogrel and some drugs commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with Clopidogrel received a variety of concomitant medications including diuretics, beta blockers, ACE inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy and GP IIb/IIIa antagonists without evidence of clinically significant adverse interactions.
ADVERSE REACTION :
- Bleeding : Some cases were reported with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage); serious cases of skin bleeding (purpura), musculoskeletal bleeding (haemarthrosis, haematoma), eye bleeding (conjunctival, ocular, retinal), epistaxis, respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), haematuria and haemorrhage of operative wound have been reported; cases of serious haemorrhage have been reported in patients taking Clopidogrel concomitantly with Acetylsalicylic acid or Clopidogrel with Acetylsalicylic acid with heparin.
- In addition to clinical studies experience, the following adverse reactions have been spontaneously reported. Within each system organ class (MedDRA classification), they are ranked under heading of frequency. “Very rare” corrensponds to < 1/10000, within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
- Blood and lymphatic system disorders : Very rare case of Thrombotic Thrombocytopenia Purpura (TTP) (1/200000 exposed patients), severe thrombocytopenia (platelet count ≤ 30 × 109/l), granulocytopenia, agranulocytosis, anaemia and aplastic anaemia/pancytopenia.
- Immune system disorders : Very rare case of anaphylactoid reactions and serum sickness.
- Psychiatric disorders : Very rare case of confusion and hallucinations.
- Nervous system disorders : Very rare case of taste disturbances.
- Vascular disorders : Very rare case of vasculitis and hypotension.
- Respiratory, thoracic and mediastinal disorders : Very rare case of bronchospasm and interstitial pneumonitis.
- Gastrointestinal disorders : Very rare case of pancreatitis, colitis (including ulcerative or lymphocytic colitis) and stomatitis.
- Hepato-biliary disorders : Very rare case of acute liver failure and hepatitis.
- Skin and subcutaneous tissue disorders : Very rare case of angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome), rash erythematosus, urticaria, eczema and lichen planus.
- Musculoskeletal, connective tissue and bone disorders : Very rare case of arthtralgia, arthritis and myalgia.
- Renal and urinary disorders : Very rare case of glomerulonephritis.
- General disorders and administration site condition : Very rare case of fever.
- Investigations : Very rare case of abnormal liver function test and blood creatinine increase.
PRESENTATION :
| Clopidogrel Bisulfate Film coated tablet 75 mg
Reg. No. GKL1702354217A1 |
Box, 10 blisters @ 10 film coated tablets |
| Clopidogrel Bisulfate Film coated tablet 75 mg
Reg. No. … |
Box, 10 strips @ 10 film coated tablets |
STORAGE :
STORE BELOW 30°C
ON MEDICAL PRESCRIPTION ONLY
Manufactured by :
BERNOFARM
Sidoarjo – Indonesia
