Therodel

Each film-coated tablet contains: Clopidogrel Bisulfate equivalent to 75 mg of Clopidogrel.

Pharmacology: Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor, and the subsequent ADP-mediated activation of the Glycoprotein (GP) IIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of Clopidogrel is necessary to produce inhibition of platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of the platelet activation by released ADP. Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to Clopidogrel are affected for the reminder of their lifespan and recovery of normal platelet function occurs at a rate consistent with platelet turnover.
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.

THERODEL 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 segments 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.

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 acetyl salicylic 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 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's no experience in children.

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 effect of Clopidogrel.

THERODEL is contra-indicated to patients: Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Severe liver impairment.
Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.
Pregnant and lactating women. As no clinical data on exposed pregnancies are available, it is preferable not to use Clopidogrel during pregnancy as a precautionary measure. Studies in rats have shown that Clopidogrel and/or its metabolites are excreted in the milk. Clopidogrel should not be administered in nursing mother.

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 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 used of Clopidogrel, sometimes after a short exposure. It is characterized by thrombocytopenia and microangiopathic 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 ischaemic 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 have may 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 taken this medicine.

Bleeding: Some cases were reported with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage); serious cases of skin bleeding (purpura), musculo-skeletal bleeding (haemarthrosis, haematoma), eye bleeding (conjuctival, 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 (ASA) or Clopidogrel with ASA and heparin.
Hematological disorders: Neutropenia, Thrombocytopenia, Aplastic anemia.
Central and peripheral nervous system disorders: Uncommon: Headache, Dizziness and Paraesthesia.
Rare: Vertigo.
Gastrointestinal system disorders: Common: Dyspepsia, Abdominal pain and Diarrhoea.
Uncommon: Gastric ulcer and Duodenal ulcer, Gastritis, Vomiting, Nausea, Constipation, Flatulence.
Platelet, bleeding and clotting disorders: Uncommon: Bleeding time increased and Platelets decreased.
Skin and appendages disorders: Uncommon: Rash and Pruritus.
White cell and RES disorders: Uncommon: Leucopenia, Eosinophilia, Neutrophils decreased.
Blood and lymphatic system disorders: Very rare: Thrombotic Thrombocytopenic Purpura (TTP) (1/200,000 exposed patients), severe Thrombocytopenia (platelet count ≤30 x 10⁹/L), Granulocytopenia, Agranulocytosis, Anaemia and Aplastic Anaemia/Pancytopenia.
Immune system disorders: Very rare: Anaphylactoid reactions, Serum sickness.
Psychiatric disorders: Very rare: Confusion, Hallucinations.
Nervous system disorders: Very rare: Taste disturbances.
Vascular disorders: Very rare: Vasculitis, Hypotension.
Respiratory, thoracic and mediastinal disorders: Very rare: Bronchospasm, Interstitial pneumonitis.
Gastrointestinal disorders: Very rare: Pancreatitis, Colitis (including ulcerative or lymphocytic colitis), Stomatitis.
Hepato-biliary disorders: Very rare: Acute liver failure, Hepatitis.
Skin and subcutaneous tissue disorders: Very rare: Angioderma, Bullous dermatitis (erythema multiforme, Stevens Johnson Syndrome), rash erythematous, urticaria, eczema and lichen planus.
Musculoskeletal, connective tissue and bone disorders: Very rare: Arthralgia, Arthritis, Myalgia.
Renal and urinary disorders: Very rare: Glomerulonephritis.
General disorders and administration site conditions: Very rare: Fever.
Investigations: Very rare: Abnormal liver function test, Blood creatinine increase.

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 acetylsalicylic acid 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 one year.
Heparin: 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 was similar to that observed when thrombolytic agents and heparins are co-administered with ASA. However, the concomitant use of Clopidogrel with thrombolytic agents should be undertaken with caution.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The concomitant administration of Clopidogrel and naproxen increase 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: No significant 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 influence 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.
Carboxylic acid metabolite of Clopidogrel could inhibit the activity of Cytochrome P450 2C9. This could potentially lead to increased plasma level of drugs such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by Cytochrome P450 2C9. Phenytoin and tolbutamide can be safely co-administered with Clopidogrel.
Apart from the specific drug interaction information described previously, 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, ACEI, calcium antagonist, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy and GPIIb/IIIa antagonist without evidence of clinically significant adverse interactions.

Store below 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

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

K