"March 11, 2010 - The FDA has put a new "black box" warning on the anti-clotting drug Plavix, the second best-selling drug in the world.
The new label warns that normal doses of Plavix have a potentially deadly lack of effect in 2% "...
The following serious adverse reactions are discussed below and elsewhere in the labeling:
- Bleeding [see WARNINGS AND PRECAUTIONS]
- Thrombotic thrombocytopenic purpura [see WARNINGS AND PRECAUTIONS]
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Plavix has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing Plavix plus aspirin to placebo plus aspirin and trials comparing Plavix alone to aspirin alone are discussed below.
In CURE, Plavix use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise.
The overall incidence of bleeding is described in Table 1.
Table 1: CURE Incidence of Bleeding Complications (%
|Event||Plavix (+ aspirin)*
|Placebo (+ aspirin)*
|Major bleeding †||3.7 ‡||2.7 §|
|5 g/dL hemoglobin drop||0.9||0.9|
|Requiring surgical intervention||0.7||0.7|
|Requiring transfusion ( > 4 units)||1.2||1.0|
|Other major bleeding||1.6||1.0|
|Intraocular bleeding with significant loss of vision||0.05||0.03|
|Requiring 2-3 units of blood||1.3||0.9|
|* Other standard therapies were
used as appropriate.
† Life-threatening and other major bleeding.
‡ Major bleeding event rate for Plavix + aspirin was dose-dependent on aspirin: < 100 mg = 2.6%; 100-200 mg = 3.5%; > 200 mg = 4.9% Major bleeding event rates for Plavix + aspirin by age were: < 65 years = 2.5%, ≥ 65 to < 75 years = 4.1%, ≥ 75 years = 5.9%
§ Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: < 100 mg = 2.0%; 100-200 mg = 2.3%; > 200 mg = 4.0% Major bleeding event rates for placebo + aspirin by age were: < 65 years = 2.1%, ≥ 65 to < 75 years = 3.1%, ≥ 75 years = 3.6%
¶ Led to interruption of study medication.
Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.
In COMMIT, similar rates of major bleeding were observed in the Plavix and placebo groups, both of which also received aspirin (see Table 2).
Table 2: Incidence of Bleeding Events in COMMIT (%
|Type of bleeding||Plavix (+ aspirin)
|Placebo (+ aspirin)
|Major* noncerebral or cerebral bleeding**||0.6||0.5||0.59|
|Other noncerebral bleeding (non-major)||3.6||3.1||0.005|
|Any noncerebral bleeding||3.9||3.4||0.004|
|* Major bleeds were cerebral
bleeds or non-cerebral bleeds thought to have caused death or that required
** The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for Plavix + aspirin by age were: < 60 years = 0.3%, ≥ 60 to < 70 years = 0.7%, ≥ 70 years = 0.8%. Event rates for placebo + aspirin by age were: < 60 years = 0.4%, ≥ 60 to < 70 years = 0.6%, ≥ 70 years = 0.7%.
CAPRIE (Plavix vs. Aspirin)
In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking Plavix vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Plavix compared to 0.5% for aspirin.
Other bleeding events that were reported more frequently in the Plavix group were epistaxis and hematoma.
Other Adverse Events
In CURE and CHARISMA, which compared Plavix plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between Plavix and placebo.
In CAPRIE, which compared Plavix to aspirin, pruritus was more frequently reported in those taking Plavix. No other difference in the rate of adverse events (other than bleeding) was reported.
The following adverse reactions have been identified during post-approval use of Plavix. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A
- Eye disorders: Eye (conjunctival, ocular, retinal) bleeding
- Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea
- General disorders and administration site condition: Fever, hemorrhage of operative wound
- Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test
- Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness
- Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, myalgia, arthralgia, arthritis
- Nervous system disorders: Taste disorders, fatal intracranial bleeding, headache
- Psychiatric disorders: Confusion, hallucinations
- Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding, eosinophilic pneumonia
- Renal and urinary disorders: Increased creatinine levels
- Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding, lichen planus, generalized pruritus
- Vascular disorders: Vasculitis, hypotension
Read the Plavix (clopidogrel bisulfate) Side Effects Center for a complete guide to possible side effects
Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].
Proton Pump Inhibitors (PPI)
Avoid concomitant use of Plavix with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of Plavix when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with Plavix. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of Plavix than did omeprazole or esomeprazole [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Coadministration of Plavix and NSAIDs increases the risk of gastrointestinal bleeding.
Warfarin (CYP2C9 Substrates)
Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of Plavix with warfarin increases the risk of bleeding because of independent effects on hemostasis.
However, at high concentrations in vitro, clopidogrel inhibits CYP2C9.
SSRIs And SNRIs
Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.
Read the Plavix Drug Interactions Center for a complete guide to possible interactions
Prescribing Document Revised: December 2013This monograph has been modified to include the generic and brand name in many instances.
Additional Plavix Information
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