Norplat/Norplat-S

Norplat/Norplat-S

clopidogrel

Manufacturer:

Getz Pharma

Distributor:

Getz Bros
Full Prescribing Info
Contents
Norplat: Clopidogrel bisulfate.
Norplat-S: Clopidogrel bisulfate, aspirin.
Description
Norplat is an inhibitor of ADP-induced platelet aggregation. It reduces the chance of having a heart attack or a stroke in people who have already had a heart attack or a stroke.
Clopidogrel bisulfate is methyl (+)-(S)-α-(2-chlorophenyl)-6-7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). Its molecular formula is C16H16ClNO2S·H2SO4.
Norplat-S: Each enteric-coated tablet contains clopidogrel bisulfate 75 mg and aspirin 75 mg.
Norplat-S is a fixed-dose combination containing clopidogrel and aspirin.
Aspirin, also an antiplatelet agent, is 2-(acetyloxy) benzoic acid. Its molecular formula is C9H8O4.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Clopidogrel is an inhibitor of platelet aggregation ie, a drug that inhibits the ability of platelets to clump together as part of a blood clot.
Clopidogrel appears to act by blocking the adenosine phosphate (ADP) receptor, which prevents fibrinogen-binding to the receptor. This decreases the ability of platelet adhesion and aggregation. Clopidogrel is a prodrug and requires biotransformation to produce inhibition of platelet aggregation.
Norplat: The active metabolite of clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP.
Norplat-S: Aspirin: Acetylsalicylic acid inhibits the activity of the enzyme cyclooxygenase and thus, prostaglandins and thromboxane formation are decreased. By blocking thromboxane synthesis, acetylsalicylic acid inhibits rapidly the platelet aggregation, this action is irreversible. Acetylsalicylic acid may also inhibit formation of prostacyclin, a platelet aggregation inhibitor, this action is reversible.
Pharmacokinetics: Norplat: Clopidogrel, after administration, requires hepatic biotransformation to an active metabolite. Hepatic activation is thought to be mediated by the CYP P-450 1A subfamily. The uncharacterized active metabolite is labile and highly reactive.
Absorption: Following oral administration, clopidogrel is rapidly absorbed. Absorption is at least 50% and is not significantly affected by food. Peak plasma concentrations (roughly 3 mg/L) of the primary circulating metabolite occur at about 1 hr following multiple dosing of 75 mg/day. Plasma concentrations of the parent drug are undetectable 2 hrs after an oral dose.
Distribution: Clopidogrel and the main circulating metabolite bind reversibly to human plasma proteins (98% and 94%, respectively).
Metabolism: Clopidogrel is extensively metabolized in the liver. The main circulating metabolite is the carboxylic acid derivative, and it has no effect on platelet aggregation. The active metabolite appears to be thiol derivative but not has been identified in the plasma.
Elimination: Clopidogrel and its metabolites are excreted about equally in urine and feces. The t½ of the carboxylic acid derivative is about 8 hrs.
Norplat-S: Clopidogrel is rapidly absorbed after oral administration. Absorption is at least 50%. It is a prodrug and is extensively metabolized 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 derivatives are highly protein bound. Clopidogrel and its metabolites are excreted in the urine and feces. After oral administration, about 50% of a dose is recovered from the urine and 46% from the feces.
Aspirin: After oral doses, absorption of non-ionized aspirin occurs in the stomach and intestine. Some aspirin is hydrolyzed to salicylate in the gut wall. Once absorbed, aspirin is rapidly converted to salicylate but during the first 20 min after an oral dose, aspirin is the predominant form of the drug in the plasma. Aspirin is 80-90% bound to plasma proteins and is widely distributed; its volume of distribution is reported to be 170 mL/kg in adults. As plasma-drug concentrations increase, the binding sites on the proteins become saturated and the volume of distribution increases. Both aspirin and salicylate have pharmacological activity although only aspirin has an antiplatelet effect. Salicylate is extensively bound to plasma proteins and is rapidly distributed to all body parts. Salicylate appears in breast milk and crosses placenta, and is mainly eliminated by hepatic metabolism.
Salicylate is also excreted unchanged in the urine, the amount excreted by this route increase with increasing dose and also depends on urinary pH, about 30% of a dose being excreted in alkaline urine compared with 2% of a dose in acidic urine. Renal excretion involves glomerular filtration, active renal tubular secretion and passive tubular reabsorption.
Special Populations: Norplat/Norplat-S: Renal Insufficiency: After repeated doses of clopidogrel 75 mg/day plasma levels of the main circulating metabolite were lower in plasma impairment (CrCl from 5-15 mL/min) compared to subjects with moderate renal impairment (CrCl of 30-60 mL/min) or healthy subjects. However, the prolongation of bleeding time was similar. No dose adjustment is required in mild to moderate renal impairment patients.
Indications/Uses
Norplat: For the prevention of atherosclerotic events in peripheral arterial disease or within 35 days of myocardial infarction or within 6 months of ischemic stroke or in acute coronary syndrome without ST-segment elevation.
Norplat-S: Reduction of thrombotic events in patients with recent myocardial infarction, recent stroke or established peripheral arterial disease.
Prophylactically in patients at risk of thromboembolic disorders eg, myocardial infarction, peripheral arterial disease and stroke.
Acute coronary syndrome (unstable angina/non-Q wave myocardial infarction).
Dosage/Direction for Use
Norplat: Recent MI, Recent Stroke or Established Peripheral Arterial Disease: The recommended daily dose is 1 Norplat tab 75 mg daily.
Prophylactic Use in Patients at Risk of Thromboembolic Disorders eg, Myocardial Infarction, Peripheral Arterial Disease and Stroke: Recommended Daily Dose: 1 tab daily.
Acute Coronary Syndrome (Unstable Angina/Non-Q-wave MI): Dose should be initiated with a single 300-mg loading dose and then continued at 75 mg once daily (with aspirin 75-325 mg once daily).
Norplat-S: Recommended Dose: 1 tablet daily. Norplat-S has been administered for up to 1 year.
Norplat/Norplat-S can be administered with or without food.
Contraindications
Norplat: Hypersensitivity to clopidogrel or any component of Norplat.
Patients who suffer from active pathological bleeding eg, peptic ulcer or intracranial hemorrhage.
Norplat-S: History of hypersensitivity to clopidogrel, aspirin or any component of Norplat-S.
Patients with active gastroduodenal ulcers; hypersensitivity to salicylates (bronchospasm, anaphylactic reactions); hemorrhagic disease; severe hepatic function impairment.
Pregnancy and lactation.
Special Precautions
General: Clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions.
If a patient is to undergo elective surgery, consideration should be given to stopping clopidogrel 5 days before surgery.
Clopidogrel should be used with caution in patients who have lesions with a propensity to bleed (eg, ulcers). Drugs that might induce such lesions should be used with caution in patients taking clopidogrel.
Hematological: Full blood count should be performed before starting treatment and every 2 weeks during the first 3 months of therapy. If clopidogrel is discontinued during this period, a full blood count should be performed within 2 weeks of stopping treatment.
Norplat: Clopidogrel should not be administered to patients with hematopoietic disorders eg, neutropenia or thrombocytopenia, hemorrhagic diathesis or other hemorrhagic disorders associated with a prolonged bleeding time.
Norplat-S: Aspirin should be used with caution in children or teenagers with chickenpox, influenza or fever.
Patients allergic to ibuprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs). Patients with chronic or recurrent stomach or duodenal ulcers or digestive hemorrhages; severe renal disease; suffering from allergic diseases eg, asthma or urticaria and gout.
Patients with Hepatic Impairment: Experience is limited in patients with severe hepatic disease, who may have bleeding diatheses. Norplat/Norplat-S should be used with caution in such patients.
Patients with Renal Impairment: Experience is limited in patients with severe renal impairment. Norplat/Norplat-S should be used with caution in such patients.
Use in Pregnancy & Lactation: Norplat: Clopidogrel has not been studied in pregnant women. It should be used during pregnancy only if clearly needed.
It is not known if clopidogrel is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clopidogrel is given to nursing mother.
Use in Children: Norplat: Safety and effectiveness in the population have not been established.
Use In Pregnancy & Lactation
Norplat: Clopidogrel has not been studied in pregnant women. It should be used during pregnancy only if clearly needed.
It is not known if clopidogrel is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clopidogrel is given to nursing mother.
Norplat-S: Contraindicated during pregnancy and lactation.
Adverse Reactions
Clopidogrel is generally well tolerated. However, the following adverse effects have been reported during treatment.
Common: GI disturbances (diarrhea, abdominal pain, indigestion and nausea) and dermatological reactions (rash, pruritus).
Rare: GI bleeding, gastric ulcers, severe neutropenia or agranulocytosis, thrombocytopenia, thrombotic thrombocytopenic purpura, aplastic anemia, membranous nephropathy with nephrotic syndrome, loss of taste, acute arthritis.
Norplat: Less Common: Chest pain, nose bleeds.
Norplat-S: Gastrointestinal Disturbances: Heartburn.
Ephritic Ion Reactions: Edema, urticaria, asthma.
Rare: Increase bleeding tendency.
Drug Interactions
Warfarin: Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution.
Drugs Metabolized by Cytochrome P-450: At high concentrations in vitro, clopidogrel inhibits P-450 (2C9). Accordingly, it may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin and many NSAIDs, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is co-administered with clopidogrel.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Concomitant administration of Norplat-S may be associated with increased occult gastrointestinal blood loss. Norplat-S and NSAIDs should be co-administered with caution.
Norplat: Aspirin: A pharmacodynamic interaction between clopidogrel and aspirin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. However, clopidogrel and aspirin have been administered together for up to 1 year.
Heparin: A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.
Norplat-S: Anticoagulants, Coumarin, Heparin or Thrombolytic Agents: Norplat-S may cause hypoprothrombinemia leading to increased anticoagulation and risk of bleeding when given concomitantly with anticoagulants, coumarin, heparin or thrombolytic agents.
Methotrexate: Aspirin may decrease renal clearance of methotrexate leading to toxic methotrexate plasma concentrations. If they are used concurrently, methotrexate dosage should be decreased.
Antidiabetic Agents: Antidiabetic agents potentiate the effect of salicylates.
Uricosuric Agents: Although salicylates in larger doses are uricosuric agents, smaller amounts may decrease the uricosuric effects of probenecid, sulfinpyrazone and phenylbutazone.
Antacids: The effects of acetylsalicylic acid may be decreased by concurrent use of antacids.
Storage
Store below 30°C. Protect from sunlight and moisture.
MIMS Class
Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)
ATC Classification
B01AC04 - clopidogrel ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
B01AC30 - combinations ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
Presentation/Packing
Norplat: FC tab 75 mg x 28's.
Norplat-S: EC tab 10's.
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