Clopidogrel (Page 2 of 8)

5.4 Thrombotic Thrombocytopenic Purpura (TTP)

TTP, sometimes fatal, has been reported following use of clopidogrel bisulfate, 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)].

5.5 Cross-Reactivity among Thienopyridines

Hypersensitivity including rash, angioedema or hematologic reaction has been reported in patients receiving clopidogrel bisulfate, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines [see Contraindications(4.2) and Adverse Reactions(6.2)].

6 ADVERSE REACTIONS

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

6.1 Clinical Trials 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 bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for one year or more. The clinically important adverse reactions observed in trials comparing clopidogrel bisulfate plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below.

Bleeding

CURE

In CURE, clopidogrel bisulfate 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 Bisulfate (+ aspirin) (n=6259) Placebo (+ aspirin) (n=6303)
* Life-threatening and other major bleeding. Led to interruption of study medication.
Major bleeding * 3.7 2.7
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 bleeding 5.1 2.4

COMMIT

In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate 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 bisulfate (+ aspirin) (n=22961) Placebo (+ aspirin) (n=22891) p-value
*
Major bleeds were cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion.
Major * noncerebral or cerebral bleeding 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 (nonmajor) 3.6 3.1 0.005
Any noncerebral bleeding 3.9 3.4 0.004

CAPRIE (clopidogrel bisulfate vs Aspirin)

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

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

Other Adverse Events

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

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

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