Plixx

(Clopidogrel Tablets U.S.P.)

COMPOSITION :

Clopidogrel Bisulphate BP

equivalent to Clopidogrel 75 mg

DESCRIPTION :

Plixx is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of subsequent ADP-mediated activation of the glycoprotein GP IIb/IIIa complex. Chemically, it is methyl (+)-(S)_α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c] pyridine-5 (4H)-acetate sulfate (1:1).

CLINICAL PHARMACOLOGY :

  • Mechanism of Action After activation by cytochrome P450 (CYP)-mediated hepatic metabolism, Plixx selectively and irreversibly inhibits ADP-induced platelet aggregation. At a clinically relevant dosage (75 mg/day), Plixx prevented ADP-induced inhibition of adenylate cyclase and binding of fi brinogen without modifying the glycoprotein (GP) IIb/IIIa complex in platelets obtained from healthy volunteers. The drug also abolished cyclic AMP-dependent phosphorylation of vasodilator-simulated phosphoprotein, an event associated with activation of the GP IIb/IIIa complex.

  • Pharmacokinetics Plixx is rapidly converted to an inactive carboxylic acid metabolite (SR 26334) after absorption from the gastrointestinal tract. Administrations of Plixx with food and antacids doesnot signifi cantly alter the bioavailabilit y. Plasma concentrations of SR 26334 increase linearly in proportion to the dose after single dose of administration of 50-150 mg Plixx. Plixx and SR 26334 are irreversibly and avidly (98 and 94% respectively) bound in a nonsaturable manner to human plasma proteins in vitro. Plixx and its metabolite do not distribute in the red blood cells to a substantial extent. The elimination half-life of SR 26334 is about 7-8 hours after both single and multiple dose administration. Approximately 50 and 46% of radiolabeled Plixx is eliminated in the urine and faces, respectively, within 5 days of oral administration.

  • INDICATIONS :

    Plixx 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 DEPLATT 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 hemorrh

  • WARNINGS :

    Patients should be told that it might take them longer than usual to stop bleeding when they take Plixx and that they should report any unusual bleeding to their physician. Patients should inform physicians and dentists that they are taking Plixx before any surgery is scheduled and before any new drug is taken.

PRECAUTIONS

  • General As with other antiplatelet agents, Plixx should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions or drug therapy. If a patient is to undergo elective surgery and an antiplatelet effect is not desired, Plixx should be discontinued 7 days prior to surgery

  • GI Bleeding DEPLATT prolongs the bleeding time. In CAPRIE, Plixx was associated with a rate of gastrointestinal bleeding of 2.0%, vs. 2.7% on aspirin. Plixx should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions (such as aspirin and other nonsteroidal antiinflammatorydrugs [NSAIDs]) should be used with caution in patients taking Plixx.

  • Use in Hepatic Impaired Patients Experience

    is limited in patients with severe hepatic disease, who may have bleeding diatheses. DEPLATT should be used with caution in this population.

  • CARCINOGENESIS, MUTAGENESIS, IM PAIRMENT OF FERTILITY :There was no evidence of tumorigenicity when Plixx was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures >25 times that in humans at the recommended daily dose of 75 mg.

    Plixx was not genotoxic in four in vitro tests and in one in vivo test.

    Plixx was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis).

  • PREGNANCY CATEGOR Y B :Plixx should be used during pregnancy only if clearly needed.

  • Nursing Mothers Animal studies do not show that Plixx 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.

DRUG INTERACTIONS :

  • Aspirin Aspirin did not modify the Plixx-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 Plixx Plixx potentiated the effect of aspirin on collagen-induced platelet aggregation. The safety of chronic concomitant administration of aspirin and Plixx has not been established.

  • Heparin Plixx 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 Plixx The safety of this combination has not been established, however, and concomitant use should be undertaken with caution.

  • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)Concomitant administration of Plixx was associated with increased occult gastrointestinal blood loss in healthy volunteers receiving naproxen. NSAIDs and Plixx should be co-administered with caution.

  • Warfarin The safety of the co-administration of Plixx with warfarin has not been established. Consequently, concomitant administration of these two agents should be undertaken with caution.

  • Other Concomitant Therapy No clinically significant pharmacodynamic interactions were observed when Plixx was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of Plixx was also not signifi cantly influenced by the co-administration of phenobarbital, cimetidine or estrogen.

    The pharmacokinetics of digoxin or theophylline was not modified by the co-administration of Plixx).

    At high concentrations in vitro, Plixx inhibits P450(2C9). Accordingly, Plixx 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 Coad ministered with Plixx.

    In addition to the above specific interaction studies, patients entered into CAPRIE received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents, antiepileptic agents and hormone replacement therapy without evidence of clinically significant adverse interactions.

OVERDOSAGE ;

One case of deliberate over dosage with Plixx was reported in the large, controlled clinical stud y. A 34-year-old woman took a single 1,050-mg dose of Plixx (equivalent to 14 standard 75-mg tablets). There were no associated adverse events. No special therapy was instituted, and she recovered without sequelae.

No adverse events were reported after single oral administration of 600 mg (equivalent to 8 standard 75-mg tablets) of Plixx in healthy volunteers. The bleeding time was prolonged by a factor of 1.7, which is similar to that typically observed with the therapeutic dose of 75 mg of Plixx per day.

A single oral dose of Plixx at 1500 or 2000 mg/kg was lethal to mice, 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.

ADVERSE EFFECTS :

In CAPRIE, the Most Common clinically impotant side effects with plixx were pruritus, purpura, diarrhoea and rash; infrequent events included intracranial hemorrhage (0.4%) and severe neutropenia (0.04%).

The worldwide post marketing experience with Plixx reported thrombotic thrombocytopenic purpura (TTP) at the rate of 4 cases per million patients.

DOSAGE AND ADMINISTRATION :

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

Pediatric Use

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

EXPIRY DATE :

Do not use later than the date of expiry.

STORAGE :

Store below 30oC, protected from light and moisture

PRESENTATION AND AVAILABILITY :

Plixx is available as light pink coloured, round, biconvex,film coated tablets, in strips & Blister strips of 10 tablets.