Clopidogrel (clopidogrel bisulfate 75 mg) Dailymed

• Reduced effectiveness in impaired CYP2C19 function: Avoid concomitant use with omeprazole or esomeprazole. (5.1)
• Bleeding: Clopidogrel increases risk of bleeding. Discontinue 5 days prior to elective surgery. (5.2)
• Discontinuation of clopidogrel: Premature discontinuation increases risk of cardiovascular events. (5.3)
• Recent transient ischemic attack or stroke: Combination use of clopidogrel and aspirin in these patients was not shown to be more effective than clopidogrel alone, but was shown to increase major bleeding. (5.4)
• Thrombotic thrombocytopenic purpura (TTP): TTP has been reported with clopidogrel, including fatal cases. (5.5)

5.1 Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 [see Boxed Warning ] and by concomitant medications that interfere with CYP2C19.

Proton Pump Inhibitors

Avoid concomitant use of clopidogrel with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel [see Drug Interactions (7.1) and Dosage and Administration (2.4)].

5.2 General Risk of Bleeding

Thienopyridines, including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel five days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event rate 4.4% clopidogrel + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel + aspirin, and 6.3% for placebo + aspirin.

Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

5.3 Discontinuation of Clopidogrel

Avoid lapses in therapy, and if clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel may increase the risk of cardiovascular events.

5.4 Patients With Recent Transient Ischemic Attack (TIA) or Stroke

In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.

5.5 Thrombotic Thrombocytopenic Purpura (TTP)

TTP, sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (< 2 weeks). TTP is a serious condition that 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 [see Adverse Reactions (6.2)].

6 Adverse Reactions

The following serious adverse reactions are discussed below and elsewhere in the labeling:

• Bleeding [see Warnings and Precautions (5.2)]
• Thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.5)]

Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-888-838-2872, X6351 or drug.safety@tevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

Clopidogrel 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 clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel alone to aspirin alone are discussed below.

Bleeding

CURE

In CURE, clopidogrel 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 (% Patients)

Event	Clopidogrel (+ aspirin)Other standard therapies were used as appropriate. (n = 6259)	Placebo (+ aspirin) (n = 6303)
Major bleedingLife-threatening and other major bleeding.	3.7Major bleeding event rate for clopidogrel + aspirin was dose-dependent on aspirin: < 100 mg = 2.6%; 100 to 200 mg = 3.5%; > 200 mg = 4.9% Major bleeding event rates for clopidogrel + aspirin by age were: < 65 years = 2.5%, ≥ 65 to < 75 years = 4.1%, ≥ 75 years = 5.9%	2.7Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: < 100 mg = 2.0%; 100 to 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%
Life-threatening bleeding	2.2	1.8
Fatal	0.2	0.2
5 g/dL hemoglobin drop	0.9	0.9
Requiring surgical intervention	0.7	0.7
Hemorrhagic strokes	0.1	0.1
Requiring inotropes	0.5	0.5
Requiring transfusion (≥ 4 units)	1.2	1.0
Other major bleeding	1.6	1.0
Significantly disabling	0.4	0.3
Intraocular bleeding with significant            loss of vision	0.05	0.03
Requiring 2 to 3 units of blood	1.3	0.9
Minor bleedingLed to interruption of study medication.	5.1	2.4

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.

COMMIT

In COMMIT, similar rates of major bleeding were observed in the clopidogrel and placebo groups, both of which also received aspirin (see Table 2).

Table 2: Incidence of Bleeding Events in COMMIT (% Patients)

Type of bleeding	Clopidogrel (+ aspirin) (n = 22961)	Placebo (+ aspirin) (n = 22891)	p-value
MajorMajor bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion. noncerebral or cerebral bleedingThe relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for clopidogrel + 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%.	0.6	0.5	0.59
Major noncerebral	0.4	0.3	0.48
Fatal	0.2	0.2	0.90
Hemorrhagic stroke	0.2	0.2	0.91
Fatal	0.2	0.2	0.81
Other noncerebral bleeding (non-major)	3.6	3.1	0.005
Any noncerebral bleeding	3.9	3.4	0.004

CAPRIE (Clopidogrel vs. Aspirin)

In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel 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 clopidogrel compared to 0.5% for aspirin.

Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis and hematoma.

Other Adverse Events

In CURE and CHARISMA, which compared clopidogrel plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel and placebo.

In CAPRIE, which compared clopidogrel to aspirin, pruritus was more frequently reported in those taking clopidogrel. No other difference in the rate of adverse events (other than bleeding) was reported.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clopidogrel. 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)
• 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
• Renal and urinary disorders: Increased creatinine levels
• Skin and subcutaneous tissue disorders: Maculopapular or erythematous rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, skin bleeding, lichen planus, generalized pruritus
• Vascular disorders: Vasculitis, hypotension