Plasep Clopidogrel Bisulfate Tablets

PLASEP
Clopidogrel Tablets

 

COMPOSITION

PLASEP

Each film coated tablet contains:

Clopidogrel Bisulfate USP

Equivalent to Clopidogrel 75mg

PLASEP 300

Each film coated tablet contains:

Clopidogrel Bisulfate USP

Equivalent to Clopidogrel 300mg

 

CLINICAL PHARMACOLOGY

Mechanism of Action

Clopidogrel is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established cardiovascular atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, unstable angina or the need for vascular bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate.

Pharmacokinetics

Absorption and Distribution: Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75mg clopidogrel (base), with peak plasma levels (3 mg/L) of the main circulating metabolite occurring approximately 1 hour after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150mg of clopidogrel. Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites.
Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 ug/mL.

Metabolism and Elimination: In vitro and in vivo, clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.

 

Special Populations

Geriatric Patients: Plasma concentrations of the main circulating metabolite are significantly higher in elderly ( = 75 years) compared to young healthy volunteers but these higher plasma levels were not associated with differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.

Renally Impaired Patients: After repeated does of 75mg Clopidogrel Bisulfate per day, plasma levels of the main circulating metabolite were lower in patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) compared to subjects with moderate renal impairment (creatinine clearance 30 to 60 mL/min) or healthy subjects. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy volunteers, the prolongation of bleeding time was similar to healthy volunteers receiving 75mg of Clopidogrel Bisulfate per day.

Gender: No significant difference was observed in the plasma levels of the main circulating metabolite between males and females. In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time. In the large, controlled clinical study (Clopidogrel vs. Aspirin in Patients at Risk of lschemic Events; CAPRIE), the incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.

Race: Pharmacokinetic differences due to race have not been studied.

 

INDICATIONS

Clopidogrel Bisulfate is indicated for the reduction of atherothrombotic events as follows:

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 Bisulfate have 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 MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, Clopidogrel Bisulfate has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI, or stroke as well as the rate of a combined endpoint of cardiovascular death, MI stroke or refractory ischemia. For patients with ST-segment elevations myocardial infarction, Clopidogrel Bisulfate 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. This benefit is not known to pertain to patients who receive primary angioplasty.

 

DOSAGE AND ADMINISTRATION

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease.
The recommended daily dose of Clopidogrel Bisulfate is 75mg once daily.

Acute Coronary Syndrome

For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), Clopidogrel Bisulfate should be initiated with a single 300-mg loading dose and then continued at 75mg once daily. Aspirin (75 mg-325 mg once daily) should be initiated end continued in combination with Clopidogrel Bisulfate. In CURE, most patients with Acute Coronary Syndrome also received heparin acutel.

For patients with ST-segment elevation acute myocardial infarction, the recommended dose of Clopidogrel Bisulfate is 75 mg once daily, administered in combination with aspirin, with or without thrombolytics. Clopidogrel Bisulfate may be initiated with or without a loading dose 300mg was used in CLARITY.

Clopidogrel Bisulfate can be administered with or without food.

No dosage adjustment is necessary for elderly patients or patients with renal disease.

 

CONTRAINDICATIONS
The use of Clopidogrel Bisulfate is contraindicated In the following conditions:

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

 

PRECAUTIONS

Clopidogrel Bisulfate prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, Clopidogrel Bisulfate should be discontinued 5 days prior to surgery.

Due to the risk of bleeding and undesirable hematological 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.
In patients with recent TIA or stroke who are at high risk of recurrent ischemic events, the combination of aspirin and Clopidogrel Bisulfate has not been shown to be more effective than Clopidogrel Bisulfate alone, but the combination has been shown to increase major bleeding.

GI Bleeding: In CAPRIE, Clopidogrel Bisulfate was associated with a rate of gastrointestinal bleeding of 2.0%, vs. 2.7% on aspirin. In CURE, the incidence of major gastrointestinal bleeding was 1.3% vs. 0.7% (Clopidogrel Bisulfate + aspirin vs. placebo + aspirin, respectively). Clopidogrel Bisulfate should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions should be used with caution in patients taking Clopidogrel Bisulfate.

Use in Hepatically Impaired Patients: Experience is limited in patients with severe hepatic disease, who may have bleeding diatheses. Clopidogrel Bisulfate should be used with caution in this population.

Use in Renally-impaired Patients: Experience is limited in patients with severe renal impairment. Clopidogrel Bisulfate should be used with caution in this population.

 

DRUG INTERACTIONS

Study of specific drug interactions yielded the following results:

Aspirin: Aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Concomitant administration of 500mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by Clopidogrel Bisulfate. Clopidogrel Bisulfate potentiated the effect of aspirin on collagen-induced platelet aggregation. Clopidogrel Bisulfate and aspirin have been administered together for up to one year.

Heparin: In a study in healthy volunteers, Clopidogrel Bisulfate did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on inhibition of platelet aggregation induced by Clopidogrel Bisulfate.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs): In healthy volunteers receiving naproxen, concomitant administration of Clopidogrel Bisulfate was associated with increased occult gastrointestinal blood loss. NSAIDs and Clopidogrel Bisulfate should be coadministered with caution.

Warfarin: Because of the increased risk of bleeding, the concomitant administration of warfarin with Clopidogrel Bisulfate should be undertaken with caution.

Other Concomitant Therapy: No clinically significant pharmacodynamic interactions were observed when Clopidogrel Bisulfate was co administered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of Clopidogrel Bisulfate was also not significantly influenced by the co administration of Phenobarbital, cimetidine or estrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the co administration of Clopidogrel Bisulfate (clopidogrel bisulfate).

At high concentrations in vitro, clopidogrel inhibits P450 (2C9). Accordingly, Clopidogrel Bisulfate may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, 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 Bisulfate.

In addition to the above specific interaction studies, patients entered into clinical trials with Clopidogrel Bisulfate received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium< antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), thrombolytics, heparins (unfractionated and LMWH). GPllb/llla antagonists, antiepileptic agents and hormone replacement therapy without evidence of clinically significant adverse interactions.

There are no data on the concomitant use of oral anticoagulants, non study oral antiplatelet drugs and chronic NSAIDs with clopidogrel.

 

OVERDOSE

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting (in baboons), prostration, difficult breathing, and gastrointestinal hemorrhage in all species.

Recommendations About Specific Treatment

Based on biological plausibility, platelet transfusion may be appropriate to reverse the pharmacological effects of Clopidogrel Bisulfate if quick reversal is required.

 

STORAGE

Do not store above 30oC. Protect from light and moisture.

Keep out of reach of children

 

PACKING INFORMATION

PLASEP-Alu-Alu Blister Pack of 10 Tablets

PLASEP 300-Alu-Alu Blister Pack of 10 Tablets

NAFDAC Reg. No. B4-3948

 

Manufactured by

MSN Laboratories Private Limited

Plot No 42, Anrich Industrial Estate,

Bollaram, Medak Dist – 502 325, INDIA.

 

Marketed and Distributed by

Phillips Pharmaceuticals (Nigeria) Ltd,

122-132 Afprint Industrial Estate,

Isolo, Lagos, Nigeria.

Advertisements