Plagerine Clopidogrel Bisulfate Tablets

Plagerine

CLOPIDOGREL TABLETS USP 75 mg

 

COMPOSITION

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

 

CHEMISTRY

methyl (+)-(S)-(2- chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetatesulfate (1:1).

 

PHARMACOLOGICAL CATEGORY

Antiplatelet Agent.

 

PHARMACOLOGY

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 atherosclerotic cardiovascular disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, or need for 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.

 

Pharmacodynamics

Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent A.P. mediated activation of the glycoprotein GPllb/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 platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released A.P. Clopidogrel does not inhibit phosphodiesterase activity.

 

Pharmacokinetics

Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, and it too has no effect on platelet aggregation. It represents about 85% of the circulating drug related compounds in plasma.

The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days. Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg 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 150 mg of clopidogrel.

Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites.

Clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative.

 

INDICATIONS AND USES

Clopidogrel bisulfate is indicated for the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease.

 

CONTRAINDICATIONS

The use of CLOPIDOGREL is contraindicated to Hypersensitivity and active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

 

SIDE EFFECTS/ADVERSE REACTIONS

Body as a Whole General Disorders

Chest Pain, Accidental Injury, Influenza- like symptoms, Pain, Fatigue.

 

Cardiovascular disorders, general

Edema, Hypertension.

 

Central & peripheral peripheral nervous system disorders

Headache, Dizziness.

 

Gastrointestinal system disorders

Abdominal pain, Dyspepsia, Diarrhea, Nausea.

 

Metabolic & nutritional disorders

Hypercholesterolemia

 

Musculo-skeletal system disorders

Arthralgia, Back Pain.

 

Platelet, bleeding & clotting disorders

Purpura, Epistaxis

 

Psychiatric disorders

Depression

 

Respiratory system disorders

Upper respiratory tract infection, Dyspnea, Rhinitis, Bronchitis, Coughing.

 

Skin & appendage disorders

Rash, Pruritus.

 

Urinary system disorders

Urinary tract infection.

 

PRECAUTIONS/WARNINGS

As with other anti-platelet agents, 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 and an antiplatelet effect is not desired,
CLOPIDOGREL should be discontinued 7 days prior to surgery.

 

DRUG INTERACTIONS

Aspirin did not modify the clopidogrel- mediated inhibition of A.P. induced platelet aggregation. Co-administration of heparin had no effect on inhibition of platelet aggregation induced by Clopidogrel.

Clopidogrel should be co-administered with caution in Nonsteroidal Anti-Inflammatory Drugs.

 

USE IN PREGNANCY AND LACTATION

No adequate and well-controlled studies in pregnant women. Clopidogrel should be used during pregnancy only if clearly needed.

 

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.

 

DOSAGE AND ADMINISTRATION

Hypertension

The recommended dose of CLOPIDOGREL is 75 mg once daily with or without food. No dosage adjustment is necessary for elderly patients or patients with renal disease.

 

OVERDOSAGE, SYMPTOMS AND ANTIDOTE

One case of deliberate overdosage with CLOPIDOGREL was reported in the large, controlled clinical study. A 34- year- old woman took a single 1,050- mg dose of CLOPIDOGREL (equivalent to 14 standard 75- mg tablets). There were no associated adverse events. No special therapy was instituted, and she recovered without sequelae. Based on biological plausibility, platelet transfusion may be appropriate to reverse the pharmacological effects of CLOPIDOGREL if quick reversal is required.

 

STORAGE

Store below 30oC.

 

DATE OF PUBLICATION: MAR. 2002

 

NAFDAC Reg. No.: A4-5107

 

Manufactured by

MICRO LABS LIMITED

92, SIPCOT, HOSUR-635 126, INDIA.

Pladox Clopidogrel Bisulfate Tablets

PLADOX™
Clopidogrel Tablets USP 75 mg

 

Each film-coated tablet contains:

Clopidogrel Bisulfate U.S.P.

Equivalent to Clopidogrel 75 mg

Excipients q.s.

Approved colours are used.

 

PLADOX (Clopidogrel Bisulfate) is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors. Chemically it is methyl (+)-(S)-ᾳ-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridhie- 5(4H)-acetate sulfate(1:1) 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. 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.

 

INDICATIONS AND USAGE

PLADOX 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 (Ml), recent stroke, or established peripheral arterial disease, dopidogrel bisulfate has 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 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, clopidogel bisulfate has been shown to decrease the rate of a combined endpoint of cardiovasular death as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.

 

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.

 

WARNINGS

Thrombotic thrombocytopenic purpura (TTP).

TTP has been reported rarely following use of clopidogrel bisulfate, sometimes after a short exposure (<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

 

PRECAUTIONS

General

PLADOX (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.

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. Pladox should be used with caution in this population.

 

Drug Interactions

Aspirin

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

Heparin

In a study in healthy volunteers, PLADOX did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration 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 PLADOX was associated with increased occult gastrointestinal blood loss. NSAIDs and Pladox should be co-administered with caution.

 

ADVERSE REACTIONS

The overall tolerability of Clopidogrel Bisulfate in CAPRIE was similar to that of aspirin regardless of age, gender and race, with an approximately equal incidence (13%) of patient withdrawing from treatment because of adverse reactions.

Hemorrhagic

In CAPRIE patients receiving clopidogrel bisulfate, gastrointestinal hemorrhage occurred at a rate of 2%, and required hospitalization in 0.7%. In patients receiving aspirin, the corresponding rates were 2.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin. In CURE, PLADOX (Clopidogrel bisulfate) use with aspirin was associated with an increase in bleeding compared to placebo with aspirin. There was an excess in major bleeding in patients receiving clopidogrel bisulfate plus aspirin compared with placebo plus aspirin, primarily gastrointestinal and at puncture sites.

 

OVERDOSAGE

Overdose following PLADOX (Clopidogrel bisulfate) 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, difficulty breathing, and gastrointestinal hemorrhage in all species.

Nursing Mothers

Studies in rats have shown that PLADOX (Clopidogrel bisulfate) and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

 

DOSAGE AND ADMINISTRATION

Recent MI, Recent Stroke or Established Peripheral Arterial Disease

The recommended daily dose of PLADOX (Clopidogrel bisulfate) tablets is 75 mg once daily.

Acute Coronary Syndrome

For patients with acute coronary syndrome (unstable angina/non-Q-wave MI), PLADOX should be initiated with a single 300 mg loading dose and then continued at 75 mg once daily. Aspirin (75 mg to 325 mg once daily) should be initiated and continued in combination with PLADOX (clopidogrel bisulfate). In CURE, most patients with Acute Coronary Syndrome also received heparin acutely. Clopidogrel tablets can be administered with or without food.

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

 

STORAGE

Store below 30°C. Protect from direct sun light.

Keep out of reach of children.

 

Presentation

3 strips of 10 tablets each.

 

NAFDAC Reg. No.: A4-5967

 

Marketed by

Fidson Healthcare Plc.

268, Ikorodu Road,

Obanikoro, Lagos, Nigeria.

info@fidson.com

www.fidson.com

 

Manufactured by

V. S. International Pvt. Ltd.

Plot No.: 17&18, Golden Indl. Estate,

Somnath Road, Dabhei, Daman- 396215, India.

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.