Plavix has been evaluated for safety in more than 42,000 patients, including over 9,000 patients treated for 1 year or more. The clinically important adverse events observed in CAPRIE, CURE, CLARITY and COMMIT are discussed below.

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

Hemorrhagic: In CAPRIE patients receiving Plavix, gastrointestinal hemorrhage occurred at a rate of 2.0%, 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 Plavix compared to 0.5% for aspirin.

In CURE, Plavix use with aspirin was associated with an increase in bleeding compared to placebo with aspirin (see Table 5). There was an excess in major bleeding in patients receiving Plavix plus aspirin compared with placebo plus aspirin, primarily gastrointestinal and at puncture sites. The incidence of intracranial hemorrhage (0.1%), and fatal bleeding (0.2%), were the same in both groups.

The overall incidence of bleeding is described in Table 5 for patients receiving both Plavix and aspirin in CURE.

Table 5: CURE Incidence of bleeding complications (% patients)

Ninety-two percent (92%) of the patients in the CURE study received heparin/LMWH, and the rate of bleeding in these patients was similar to the overall results.

There was no excess in major bleeds within seven days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (event rate 4.4% Plavix + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for Plavix + aspirin, and 6.3% for placebo + aspirin.

In CLARITY, the incidence of major bleeding (defined as intracranial bleeding or bleeding associated with a fall in hemoglobin > 5 g/dL) was similar between groups (1.3% versus 1.1% in the Plavix + aspirin and in the placebo + aspirin groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytics or heparin therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the Plavix + aspirin and in the placebo + aspirin groups, respectively) and intracranial hemorrhage (0.5% versus 0.7%, respectively) was low and similar in both groups.

The overall rate of noncerebral major bleeding or cerebral bleeding in COMMIT was low and similar in both groups as shown in Table 6 below.

Table 6: Number (%) of Patients with Bleeding Events in COMMIT

Adverse events occurring in ≥ 2.5% of patients on Plavix in the CAPRIE controlled clinical trial are shown below regardless of relationship to Plavix. The median duration of therapy was 20 months, with a maximum of 3 years.

Table 7: Adverse Events Occurring in ≥ 2.5% of Plavix Patients in CAPRIE

No additional clinically relevant events to those observed in CAPRIE with a frequency ≥ 2.5%, have been reported during the CURE and CLARITY controlled studies. COMMIT collected only limited safety data.

Other adverse experiences of potential importance occurring in 1% to 2.5% of patients receiving Plavix (clopidogrel bisulfate) in the controlled clinical trials are listed below regardless of relationship to Plavix. In general, the incidence of these events was similar to that in patients receiving aspirin (in CAPRIE) or placebo + aspirin (in the other clinical trials).

Autonomic Nervous System Disorders: Syncope, Palpitation. Body as a Whole-general disorders: Asthenia, Fever, Hernia. Cardiovascular disorders: Cardiac failure. Central and peripheral nervous system disorders: Cramps legs, Hypoaesthesia, Neuralgia, Paraesthesia, Vertigo. Gastrointestinal system disorders: Constipation, Vomiting. Heart rate and rhythm disorders: Fibrillation atrial. Liver and biliary system disorders: Hepatic enzymes increased. Metabolic and nutritional disorders: Gout, hyperuricemia, non-protein nitrogen (NPN) increased. Musculo-skeletal system disorders: Arthritis, Arthrosis. Platelet, bleeding & clotting disorders: GI hemorrhage, hematoma, platelets decreased. Psychiatric disorders: Anxiety, Insomnia. Red blood cell disorders: Anemia. Respiratory system disorders: Pneumonia, Sinusitis. Skin and appendage disorders: Eczema, Skin ulceration. Urinary system disorders: Cystitis. Vision disorders: Cataract, Conjunctivitis.

Other potentially serious adverse events which may be of clinical interest but were rarely reported ( < 1%) in patients who received Plavix in the controlled clinical trials are listed below regardless of relationship to Plavix. In general, the incidence of these events was similar to that in patients receiving aspirin (in CAPRIE) or placebo + aspirin (in the other clinical trials).

Body as a whole: Allergic reaction, necrosis ischemic. Cardiovascular disorders: Edema generalized. Gastrointestinal system disorders: Peptic, gastric or duodenal ulcer, gastritis, gastric ulcer perforated, gastritis hemorrhagic, upper GI ulcer hemorrhagic. Liver and Biliary system disorders: Bilirubinemia, hepatitis infectious, liver fatty. Platelet, bleeding and clotting disorders: hemarthrosis, hematuria, hemoptysis, hemorrhage intracranial, hemorrhage retroperitoneal, hemorrhage of operative wound, ocular hemorrhage, pulmonary hemorrhage, purpura allergic, thrombocytopenia. Red blood cell disorders: Anemia aplastic, anemia hypochromic. Reproductive disorders, female: Menorrhagia. Respiratory system disorders: Hemothorax. Skin and appendage disorders: Bullous eruption, rash erythematous, rash maculopapular, urticaria. Urinary system disorders: Abnormal renal function, acute renal failure. White cell and reticuloendothelial system disorders: Agranulocytosis, granulocytopenia, leukemia, leukopenia, neutropenia.

Postmarketing Experience

The following events have been reported spontaneously from worldwide postmarketing experience:

• Body as a whole:
  • - hypersensitivity reactions, anaphylactoid reactions, serum sickness
• Central and Peripheral Nervous System disorders:
  • - confusion, hallucinations, taste disorders
• Hepato-biliary disorders:
  • - abnormal liver function test, hepatitis (non-infectious), acute liver failure
• Platelet, Bleeding and Clotting disorders:
  • - cases of bleeding with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal hemorrhage)
  • -  thrombotic thrombocytopenic purpura (TTP) - some cases with fatal outcome - (see WARNINGS)
  • -  agranulocytosis, aplastic anemia/pancytopenia
  • - conjunctival, ocular and retinal bleeding
• Respiratory, thoracic and mediastinal disorders:
  • - bronchospasm, interstitial pneumonitis
• Skin and subcutaneous tissue disorders:
  • - angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, lichen planus
• Renal and urinary disorders:
  • - glomerulopathy, increased creatinine levels
• Vascular disorders:
  • - vasculitis, hypotension
• Gastrointestinal disorders:
  • - colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis
• Musculoskeletal, connective tissue and bone disorders:
  • - myalgia

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 500 mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by Plavix. Plavix potentiated the effect of aspirin on collagen-induced platelet aggregation. Plavix and aspirin have been administered together for up to one year.

Heparin: In a study in healthy volunteers, Plavix 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 Plavix.

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

Warfarin: Because of the increased risk of bleeding, the concomitant administration of warfarin with Plavix should be undertaken with caution. (See PRECAUTIONS - General.)

Other Concomitant Therapy: No clinically significant pharmacodynamic interactions were observed when Plavix was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of Plavix was also not significantly influenced by the coadministration of phenobarbital, cimetidine or estrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of Plavix (clopidogrel bisulfate).

At high concentrations in vitro, clopidogrel inhibits P₄₅₀ (2C9). Accordingly, Plavix 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 coadministered with Plavix.

In addition to the above specific interaction studies, patients entered into clinical trials with Plavix 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), GPIIb/IIIa 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 anti-platelet drugs and chronic NSAIDs with clopidogrel.

Drug/Laboratory Test Interactions

None known.

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