Plavix Side Effects

Generic Name: clopidogrel

Please note - some side effects for Plavix may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Plavix - for the Consumer

Plavix

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Plavix:

Easy bruising; minor bleeding.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bleeding in the eye; change in vision; change in the amount of urine; chest pain; dark or bloody urine; black, tarry stools, unusual or severe bleeding (eg, excessive bleeding from cuts, increased menstrual bleeding, unexplained vaginal bleeding, unusual bleeding from the gums when brushing); loss of appetite; pale skin; seizures; severe, persistent headache; sore throat or fever; speech problems; unusual bruising; weakness; unexplained weight loss; yellowing of the skin or eyes.

Plavix Side Effects - for the Professional

Plavix

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. 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 6 for patients receiving both Plavix and aspirin in CURE.

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 7 below.

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.

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:

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  hypersensitivity reactions, anaphylactoid reactions, serum sickness

• Central and Peripheral Nervous System disorders:

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  confusion, hallucinations, taste disorders

• Hepato-biliary disorders:

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  abnormal liver function test, hepatitis (non-infectious), acute liver failure

• Platelet, Bleeding and Clotting disorders:

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  cases of bleeding with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal hemorrhage)

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  thrombotic thrombocytopenic purpura (TTP) – some cases with fatal outcome –

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  agranulocytosis, aplastic anemia/pancytopenia

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  conjunctival, ocular and retinal bleeding

• Respiratory, thoracic and mediastinal disorders:

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  bronchospasm, interstitial pneumonitis

• Skin and subcutaneous tissue disorders:

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  angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, lichen planus

• Renal and urinary disorders:

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  glomerulopathy, increased creatinine levels

• Vascular disorders:

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  vasculitis, hypotension

• Gastrointestinal disorders:

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  colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis

• Musculoskeletal, connective tissue and bone disorders:

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  myalgia

Side Effects by Body System

General

Clopidogrel has been evaluated for safety in more than 17,500 patients, including over 9,000 patients treated for 1 year or more. The overall tolerability of clopidogrel 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.

General complaints among at least 2.5% of treated patients in controlled trials have included chest pain, influenza-like syndrome, general body pain, or fatigue. A causal relationship has not been clearly demonstrated.

Hematologic

Hematologic side effects appear to be less commonly associated with clopidogrel when compared with ticlopidine. Hemorrhage has been the most commonly reported and potentially serious, or fatal, side effect. Safety evaluation data from large clinical trials have shown that gastrointestinal hemorrhage occurred in 2.0% of patients 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 associated with the use of clopidogrel and aspirin was 0.4% and 0.5%, respectively. Purpura and epistaxis have been reported in 5.3% and 2.9% of patients, respectively. Similar incidences were observed among patients treated with aspirin in comparative trials.

Results from the CURE study (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events) showed the use of clopidogrel 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 plus aspirin compared with placebo plus aspirin (primarily gastrointestinal and at puncture sites). The incidence of fatal bleeding (0.2%) and intracranial hemorrhage (0.1%) was the same in both groups.

Rare incidences of granulocytopenia, leukemia, leukopenia, and a decrease in neutrophils have also been reported.

Thrombotic thrombocytopenic purpura (TTP), not noted during clinical trials, has been reported. A potentially life threatening event, the incidence of TTP usually occurred within 2 weeks of initiation of clopidogrel. Plasma exchange resulted in resolution of symptoms and laboratory abnormalities.

Agranulocytosis, aplastic anemia/pancytopenia, retroperitoneal hematoma, and conjunctival, ocular and retinal bleeding have been reported during postmarketing experience.

Severe neutropenia (less than 450 neutrophils/mcL) has occurred in approximately 4/10,000 patients. Although the risk of myelosuppression appears to be quite low, it is recommended in cases of fever or other signs of infection that possible neutropenia be evaluated. Gastrointestinal hemorrhage has been observed in approximately 1.0% to 2.5% of patients. Hemarthrosis, hematuria, hemoptysis, retroperitoneal hemorrhage, operative wound hemorrhage, ocular hemorrhage, pulmonary hemorrhage, allergic purpura, menorrhagia, thrombocytopenia, agranulocytosis, granulocytopenia, leukemia, leukopenia, neutropenia, aplastic anemia, and hypochromic anemia have occurred in less than 1% of patients. These adverse events were observed at similar rates among patients treated with aspirin in controlled trials.

Subarachnoid hemorrhage has been reported in a patient receiving clopidogrel and aspirin following lumbar puncture. Several attempts were required in order to reach the intrathecal space.

Gastrointestinal

Rare GI adverse events included perforated gastric ulcer, hemorrhagic gastritis, and upper GI hemorrhage. Similar incidences were observed among patients treated with aspirin in comparative trials.

A randomized trial studied patients in Hong Kong who took aspirin to prevent vascular diseases. The patients were randomized to clopidogrel 75 mg daily plus placebo twice daily or aspirin 80 mg daily plus esomeprazole 20 mg twice daily for 12 months. The study found that recurrent ulcer bleeding occurred in 8.1% of the clopidogrel/placebo group compared to 0.6% of the aspirin/esomeprazole group. There were no differences in rates of lower gastrointestinal bleeding (4.3% vs. 4.4%) or recurrent ischemic events (5.6% vs. 6.9%).

Gastrointestinal (GI) discomfort has occurred in 27.1% of patients (compared with 29.8% of patients who were treated with aspirin in comparative trials). Other GI side effects have included diarrhea in 4.5%, dyspepsia in 5.2%, nausea in 3.4%, and abdominal pain in 5.6% of patients. Colitis, pancreatitis, and stomatitis have also been reported during postmarketing experience. Rarely, gastritis and constipation have been reported.

The development of ulcers have also been associated with the use of this drug. Results from a randomized trial in Hong Kong showed that patients taking clopidogrel may experience more than 12 times as many ulcers as patients who take aspirin plus esomeprazole.

Hypersensitivity

Hypersensitivity reactions have been reported in less than 1% of patients. In addition, hypersensitivity reactions as well as anaphylactoid reactions and serum sickness have been reported in postmarketing experience.

Clopidogrel-induced hypersensitivity syndrome has been associated with febrile pancytopenia, elevated liver enzymes, tachycardia, nausea, vomiting, rash, pruritus, fever, and neutropenia. In at least one case, hypersensitivity syndrome resolved with dechallenge and recurred upon rechallenge.

Cardiovascular

Cardiovascular side effects have included chest pain (8.3%), edema (4.1%), and hypertension (4.3%) in treated patients during controlled trials (compared with 8.3%, 4.5% and 5.1%, respectively, in patients who were given aspirin). Cardiovascular adverse events that have occurred in 1.0% to 2.5% of patients included syncope, palpitations, atrial fibrillation, and heart failure. Generalized edema has been reported in less than 1% of treated patients. A relationship between these adverse events and clopidogrel administration has not been clearly defined. Similar rates were observed among patients treated with aspirin in controlled trials.

Rarely, heart failure has been associated with the use of clopidogrel. Vasculitis, angioedema, and hypotension have also been reported during postmarketing experience.

Nervous system

Nervous system side effects have included headache (7.6%) and dizziness (6.2%). Similar incidences were observed among patients treated with aspirin in comparative trials. Rarely, hypoesthesia, neuralgia, paresthesia, and vertigo like symptoms have been reported. Confusion and hallucinations were also reported during postmarketing experience.

Musculoskeletal

Musculoskeletal side effects including arthralgias and back pain have been reported in approximately 6% of patients. A similar incidence was observed in patients treated with aspirin in comparative trials. Myalgia has been reported during postmarketing experience.

Psychiatric

Psychiatric side effects including depression (3.6%), anxiety, and insomnia have been reported. The incidence of depression among patients treated with aspirin in comparative trials was 3.9%. The baseline incidence among patients prior to drug therapy was not reported. Less than 0.1% of patients discontinued therapy due to depression. Anxiety and insomnia were observed at similar rates among patients treated with aspirin in controlled trials.

Respiratory

Respiratory tract side effects have included upper respiratory tract infection (8.7%), dyspnea (4.5%), rhinitis (4.2%), bronchitis (3.7%), and cough (3.1%). Less than 0.1% of patients discontinued therapy due to these symptoms. Bronchospasm and interstitial pneumonitis have been reported in postmarketing experience.

Dermatologic

Dermatologic adverse events that occurred in 1.0% to 2.5% of patients included eczema and skin ulceration. Rare cases of serious skin eruptions, such as bullous eruptions, erythematous or maculopapular rashes, or urticaria have occurred in less than 1.0% of patients. These adverse events were observed at similar rates among patients treated with aspirin in controlled trials.

Two case reports of patients developing maculopapular pruritic rashes following administration of clopidogrel have been reported. The rash recurred in both patients after switching to ticlopidine. In one patient, rechallenge resulted in recurrence of the rash. These two cases illustrate the possibility of cross-sensitivity between thienopyridines.

Dermatologic side effects have manifested primarily as hypersensitivity reactions. Rash and pruritus have occurred in 4.2% and 3.3% of patients, respectively. However, the incidence of rash and all skin disorders has been as high as 16% (0.7% serious). The incidence of patient withdrawal due to skin and appendage adverse reactions has been 1.5%.

Erythema multiforme, lichen planus, Stevens-Johnson syndrome, and toxic epidermal necrolysis have also been reported during postmarketing experience. At least one case of suberythrodermic pustular psoriasis has been reported following administration of clopidogrel.

Hepatic

Hepatic side effects including elevated hepatic enzymes have occurred in 1.0% to 2.5% of patients. Hyperbilirubinemia, hepatitis, and fatty liver have been reported in fewer than 1% of patients. A relationship between these adverse events and clopidogrel is not clear and the incidences were similar among patients treated with aspirin in controlled trials. Abnormal liver function tests, hepatitis (non-infectious), and acute liver failure have been reported in postmarketing experience.

A patient experienced elevated liver enzymes and fever within days of initiating treatment with clopidogrel. Following discontinuation of clopidogrel, liver enzymes returned to normal and fever disappeared. Upon rechallenge, these signs and symptoms returned. However, the patient was able to tolerate treatment with ticlopidine without adverse effects.

Metabolic

Metabolic side effects have occurred at an incidence of 1.0% to 2.5%, however, their relationship to clopidogrel has not been clearly defined. Adverse effects included hyperuricemia, gout, and increased plasma concentrations of nonprotein nitrogen.

Genitourinary

Genitourinary side effects have been extremely rare. Cystitis has been reported among 1.0% to 2.5% of patients in controlled trials, although the relationship to drug therapy is questionable. Cystitis occurred at similar rates among patients treated with aspirin in controlled trials. Glomerulopathy and elevated creatinine levels have also been reported during postmarketing experience.

Ocular

Ocular side effects have been extremely rare. Cataracts or conjunctivitis have been reported in 1.0% to 2.5% of patients, although the relationship to drug therapy has not been established. These adverse events occurred at similar rates in patients treated with aspirin in controlled trials.

Other

Other side effects reported during clinical trials have included accidental injury (7.9%), influenza-like symptoms (7.5%), pain (6.4%), and fatigue (3.3%). The incidence of these effects was similar to that reported with aspirin use. Taste disorders have also been reported during postmarketing experience.

Renal

Renal side effects including glomerulonephropathy and increased creatinine levels have been reported during postmarketing experience. In addition, membranous nephropathy has been associated with clopidogrel use.

Immunologic

Immunologic side effects including a possible link between autoimmune acquired hemophilia and clopidogrel has been reported. Systemic inflammatory response syndrome has also been associated with clopidogrel use.

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