PLAVIX (clopidogrel bisulfate) is indicated for the secondary prevention of atherothrombotic events (myocardial infarction, stroke and vascular death) in patients with atherosclerosis documented by stroke, myocardial infarction, or established peripheral arterial disease.

• PLAVIX, in combination with acetylsalicylic acid (ASA), is indicated for the early and long-term secondary prevention of atherothrombotic events (myocardial infarction, ischemic stroke, cardiovascular death and/or refractory ischemia) in patients with acute coronary syndromes- without ST segment elevation (ie. unstable angina or non-Q-wave myocardial infarction). These benefits of PLAVIX have been shown only when these patients were concomitantly treated with ASA in addition to other standard therapies. These benefits were also seen in patients who were managed medically and those who were managed with percutaneous coronary intervention (with or without stent) or CABG (coronary artery bypass graft).

  
  

• For patients with ST-segment elevation acute myocardial infarction, PLAVIX has been shown to reduce the rate of an endpoint of all-cause mortality and the rate of a combined endpoint of death, re-infarction or stroke.

  
  

No data available.

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.

  
  

• Active bleeding such as peptic ulcer and intracranial hemorrhage.

  
  

• Significant liver impairment or cholestatic jaundice.

  
  

As with other antiplatelet agents, when considering prescribing PLAVIX (clopidogrel bisulfate), physicians should inquire whether the patient has a history of bleeding. Clopidogrel should be used with caution in patients who may be at risk of increased bleeding from recent trauma, surgery or other pathological condition(s).

Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution (see Drug Interactions).

In patients with recent transient ischaemic attack (TIA) or stroke who are at high risk of recurrent ischemic events, the combination of aspirin and PLAVIX has not been shown to be more effective than PLAVIX alone, but the combination has been shown to increase major bleeding (see Drug Interactions).

If a patient is to undergo elective surgery, consideration should be given to discontinue PLAVIX 5 to 7 days prior to surgery to allow for the reversal of the effect.

Platelet transfusion may be used to reverse the pharmacological effects of PLAVIX when quick reversal is required.

PLAVIX (clopidogrel bisulfate) prolongs bleeding time. Although PLAVIX has shown a lower incidence of gastrointestinal bleeding compared to ASA in a large controlled clinical trial (CAPRIE), PLAVIX should not be used in patients who have lesions with a propensity to bleed. In CURE, the incidence of major GI bleeding was 1.3% versus 0.7% (PLAVIX+ASA versus placebo+ASA, respectively).

In patients taking PLAVIX, drugs that might induce GI lesions should be used with caution.

Thrombotic thrombocytopenic purpura (TTP) has been reported rarely following the use of PLAVIX, but it can occur anytime during the first year of exposure. Few cases have been reported after more than one year of exposure. TTP is a potentially fatal condition requiring prompt treatment with plasmapheresis. It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBC's] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

Experience is limited in patients with moderate hepatic impairment who may have bleeding diatheses. As with any patient exhibiting hepatic impairment, liver function should be carefully monitored and PLAVIX should be used with caution.

In the CAPRIE study, there were 344 hepatically impaired patients (Alkaline phosphatase >300 U/L, or ALT >120 U/L, or AST >75 U/L) and 168 received clopidogrel for a mean duration of 18 months. The adverse events were more common in this population, compared to the rest of the CAPRIE population, and more common in the clopidogrel (N=168) than in the ASA (N=176) group (any bleeding disorders, N=17 vs N=14; any rash, N=11 vs N=6; diarrhea, N=8 vs N=3, respectively).

If a patient is to undergo elective surgery, consideration should be given to discontinue PLAVIX 5 to 7 days prior to surgery to allow for a reversal of its effect.

Clopidogrel should be used with caution in patients who may be at risk of increased bleeding from recent surgery.

Therapeutic experience with clopidogrel is limited in patients with severe and moderate renal impairment. Therefore, PLAVIX should be used with caution in these patients.

There are no adequate and well-controlled studies in pregnant women.

Reproduction studies have been performed in rats at doses up to 500 mg/kg per day and in rabbits at doses up to 300 mg/kg per day and have revealed no evidence of impaired fertility or harm to the fetus due to clopidogrel. Because animal reproduction studies are not always predictive of a human response, PLAVIX should be used during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in milk. It is not known whether this drug is excreted in human milk. Therefore, clopidogrel should not be used by lactating women.

Safety and effectiveness in subjects below the age of 18 have not been established.

The safety profile of clopidogrel has been evaluated in clinical trials in more than 42 000 patients and further assessed during post-marketing experience.

Of the patients who participated in the CAPRIE, CURE and CLARITY double-blind international clinical trials, approximately 50% were elderly patients (>65 years) and 15% were 75 years and older. 9000 patients were treated for one year or more. In COMMIT, approximately 58% of the patients treated with PLAVIX were 60 years and older, 26% of whom were 70 years and older.

The most frequent adverse drug reactions (≥1%) with PLAVIX (with or without associated ASA) in controlled clinical trials were hemorrhage and bleeding disorders including purpura, any rash, dyspepsia, abdominal pain and diarrhea (see Clinical Trial Adverse Drug Reactions).

The most serious adverse drug reactions from controlled clinical trials rarely reported (<1%) were bleeding and clotting disorders including gastrointestinal hemorrhage, hemorrhagic ulcer and hemothorax.

agranulocytosis/granulocytopenia, aplastic anemia, neutropenia and thrombocytopenia.

duodenal, gastric or peptic ulcer, gastritis.

any rash and bullous eruption.

The overall incidence of study drug discontinuation because of adverse events was similar in both groups in CAPRIE (PLAVIX 11.9% and ASA 11.9%). In CURE, study drug discontinuation occurred in 5.8 % of patients with PLAVIX plus ASA and 3.9% of patients with placebo plus ASA. In CLARITY, study drug discontinuation was greater in the placebo group (8.6%) compared with the clopidogrel group (6.9%). In COMMIT, the overall incidence of discontinuations was similar between the two treatment groups (2.4% in the clopidogrel group versus 2.2% in the placebo group).

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

With few exceptions (see Table 1) the overall tolerability of PLAVIX was similar regardless of age, sex and race. However, in women there was a slightly higher incidence of bleeding disorders in the clopidogrel group (11.36% vs 9.88%).

The clinically important adverse events observed in CAPRIE were the following:

One case of Henoch-Schönlein purpura (acute visceral symptoms: vomiting, diarrhea, abdominal distension, hematuria, renal colic) was reported in a patient taking PLAVIX. The patient recovered without sequellae within one month. Rare cases of platelet count ≤30 000/mm³ have been reported. The overall incidence of bleeding on clopidogrel and ASA was the same (9.3%). The incidence of severe cases was 1.4% and 1.6% in the clopidogrel and ASA groups respectively. The overall incidence of other bleeding disorders was higher in the clopidogrel group (7.3%) compared to ASA (6.5%). However, the incidence of severe events was similar in both treatment groups (0.6% vs 0.4%).

Overall, the incidence of gastrointestinal events (e.g. abdominal pain, dyspepsia, gastritis and constipation) in patients receiving PLAVIX (clopidogrel bisulfate) was 27.1%, compared to 29.8% in those receiving ASA. The incidence of patients withdrawing from treatment because of gastrointestinal adverse reactions was 3.2% for PLAVIX and 4.0% for ASA.

The overall incidence of hepatic and biliary disorders was similar in patients treated with clopidogrel (3.5%) compared to ASA (3.4%). The most frequent events were increased liver enzymes and bilirubinemia.

The incidence of skin and appendage disorders in patients receiving PLAVIX was 15.8% (0.7% serious); the corresponding rate in ASA patients was 13.1% (0.5% serious). There was no notable difference between treatment groups in the incidence of bullous eruptions (0.23% PLAVIX versus 0.16% ASA). One case of a severe bullous eruption was reported in a patient taking PLAVIX. The overall incidence of patients withdrawing from treatment because of skin and appendage disorders adverse reactions was 1.5% for PLAVIX and 0.8% for ASA.

A summary of the clinically relevant adverse effects observed in CAPRIE are presented in Table 1. In CAPRIE, patients with a known intolerance to ASA were excluded from the study.

Table 1: PLAVIX

Summary of Adverse Events Occurring in ≥ 1% of PLAVIX Patients in CAPRIE—CAPRIE Trial

^a. Statistically significant difference between treatments (p≤0.05).
^b. Patients may be included in more than 1 category.

No clinically relevant events other than those observed in CAPRIE have been reported with a frequency ≥2.5% during the CURE, CLARITY and COMMIT controlled studies.

The number of patients discontinuing due to adverse reactions in CAPRIE are shown in Table 2.

Table 2: PLAVIX

Patients Discontinued Because of Adverse Experiences in CAPRIE (number and percentage of patients)

Adverse Experience	Study Drug Permanently Discontinued
	PLAVIX N=9599 (%)	ASA N=9586 (%)
Rash	0.90	0.41a
Diarrhea	0.42	0.27
Indigestion/Nausea/Vomiting	1.9	2.41a
Any Bleeding Disorder	1.20	1.37
Intracranial Hemorrhage	0.21	0.33
Gastrointestinal Hemorrhage	0.52	0.93a
Abnormal Liver Function	0.23	0.29

^a. Statistically significant, p<0.05.

In CURE, PLAVIX was given with ASA and was not associated with a significant increase in life-threatening or fatal bleeds compared to placebo given with ASA; the incidences of non-life threatening major bleeding and minor bleeding were significantly larger in the PLAVIX+ASA group. The incidence of intracranial hemorrhage was 0.1% in both groups. The principal sites for major bleeding were primarily gastrointestinal and at arterial puncture sites. In patients receiving both PLAVIX and ASA in CURE, the incidence of bleeding is described in Table 3.

Table 3: PLAVIX

Incidence of Bleeding Complications (% patients)—CURE Trial

Event	PLAVIX+ASAa (N=6259)	Placebo+ASAa (N=6303)	p-value
Life-threatening Bleeding	2.2	1.8	0.13
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 Transfusions (≥4 units)	1.2	1
Other Major Bleeding	1.6	1	0.005
Significantly Disabling	0.4	0.3
Intraocular Bleeding with Significant Loss of Vision	0.05	0.03
Requiring 2–3 Units of Blood	1.3	0.9
Major Bleedingb	3.7c	2.7d	0.001
Minor Bleedinge	5.1	2.4	<0.001
Total with Bleeding Complications	8.5	5.0	<0.001

^a. Other standard therapies were used as appropriate. All patients received ASA 75–325 mg daily (mean=160 mg).
^b. Life threatening and other major bleeding necessitating transfusion of ≥2 units of blood.
^c. Major bleeding event rate for PLAVIX+ASA was dose-dependent on ASA: <100 mg=2.6%; 100-200 mg=3.5%; >200 mg=4.9%.
^d. Major bleeding event rate for placebo+ASA was dose-dependent on ASA: <100 mg=2.0%; 100-200 mg=2.3%; >200 mg=4.0%.
^e. Led to interruption of study medication.

The number of patients with bleeding that met the criteria for major bleeding established by the Thrombolysis in Myocardial Infarction (TIMI) trial was 68 (1.09%) in the clopidogrel group and 73 (1.16%) in the placebo group (relative risk, 0.94; p=0.70). The number with bleeding that met the criteria for life-threatening or severe bleeding established by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUST) trial was 78 in the clopidogrel group and 70 in the placebo group (relative risk, 1.12; p=0.48). Some patients had more than one bleeding episode.

Ninety-two percent (92%) of the patients in the CURE study received unfractionated or low molecular weight heparin, 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+ASA; 5.3% placebo+ASA). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for PLAVIX+ASA, and 6.3% for placebo+ASA, which was not significantly different.

Other potentially serious adverse events which may be of clinical interest but were rarely reported (<1%) in patients who received PLAVIX in the CAPRIE or CURE 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 CURE).

allergic reaction and necrosis ischemic.

edema generalized.

gastric ulcer perforated, gastritis hemorrhagic and upper GI ulcer hemorrhagic.

bilirubinemia, hepatitis infectious and liver fatty.

hemarthrosis, hematuria, hemoptysis, hemorrhage intracranial, hemorrhage retroperitoneal, hemorrhage of operative wound, ocular hemorrhage, pulmonary embolism, pulmonary hemorrhage, purpura allergic.

anemia aplastic, anemia hypochromic.

menorrhagia.

hemothorax.

bullous eruption, rash erythematous, rash maculopapular, urticaria.

abnormal renal function, acute renal failure.

agranulocytosis, granulocytopenia, leukemia.

Other clinically relevant adverse drug reactions pooled from CAPRIE and CURE studies, or observed in other studies, with an incidence >0.1% as well as serious and relevant adverse drug reactions with an incidence <0.1% are presented below:

Uncommon: dizziness and paraesthesia. Rare: vertigo.

Common: dyspepsia, abdominal pain, diarrhea. Uncommon: nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer, duodenal ulcer.

Uncommon: bleeding time increased, platelets decreased. Very rare: thrombotic thrombocytopenic purpura (TTP).

Uncommon: rash, pruritus.

Uncommon: leucopenia, neutrophils decreased, eosinophilia.