Plavix 75 mg

In view of the possible increased risk of bleeding, anticoagulant drugs should be used with caution as tolerance and safety of simultaneous administration with clopidogrel has not been established. Risk factors should be assessed for individual patients before using clopidogrel.

Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution.

Clinically significant adverse interactions were not detected in clinical trials with PLAVIX where patients received a variety of concomitant medications including ASA, diuretics, beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, lipid-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), thrombolytics, unfractionated and/or LMW heparin, glycoprotein IIb/IIIa inhibitors, antiepileptic agents, and hormone replacement therapy (however, see Table 5 regarding ASA and glycoprotein IIb/IIIa inhibitors). A review of the clinical trial data indicates that there is no evidence of an interaction between PLAVIX and atorvastatin. In CAPRIE, patients on HMG CoA reductase inhibitors and clopidogrel experienced a higher incidence of bleeding events (primarily epistaxis). Patients on HMG CoA reductase inhibitors and ASA experienced a higher incidence of intracranial hemorrhage. There is no known pathophysiological or pharmacological explanation for this observation.

Data from studies with human liver microsomes indicated that the carboxylic acid metabolite of clopidogrel could inhibit the activity of cytochrome P450 2C9. However, in vivo, clopidogrel does not modify the pharmacokinetics of S-warfarin (typical CYP2C9 substrate). Accordingly, it is unlikely that clopidogrel may interfere with the metabolism of drugs such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely coadministered with clopidogrel.

No clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered in clinical studies to investigate drug interaction with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of PLAVIX was slightly enhanced by the coadministration of phenobarbital, however this was not considered to be clinically significant. Pharmacodynamic activity of PLAVIX was not changed with the coadministration of cimetidine. Pharmacodynamic activity of PLAVIX was not significantly influenced by the coadministration of estrogen.

None known.

There is no interaction of PLAVIX with food since administration of PLAVIX with meals did not significantly modify the bioavailability of clopidogrel. Interactions with herbal products have not been established.

For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), PLAVIX should be initiated with a 300 mg loading dose and continued long term at 75 mg once a day with ASA (80 mg-325 mg daily).

For patients with ST-segment elevation acute myocardial infarction, the recommended dose of PLAVIX is 75 mg once daily, administered in combination with aspirin, with or without thrombolytics. PLAVIX may be initiated with or without a loading dose (300 mg was used in CLARITY).

No dosage adjustment is necessary for elderly patients or patients with renal impairment (see Action and Clinical Pharmacology, Special Populations and Conditions).

The recommended dose of PLAVIX is 75 mg once daily long term with or without food.

If a dose of PLAVIX is missed, it should be taken as soon as possible. However, if it is close to the time of the next dose, disregard the missed dose and return to the regular dosing schedule. Do not double doses.

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 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).

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%).

Very rare: hepatitis, abnormal liver function test, acute liver failure.

Very rare: bronchospasm, interstitial pneumonitis.

Very rare: taste disturbances.

Uncommon: rash, pruritus.

allergic reaction and necrosis ischemic.

Very rare: maculopapular or erythematous rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme), Stevens-Johnson syndrome, toxic epidermal necrolysis, eczema, lichen planus.

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%).

abnormal renal function, acute renal failure.

Uncommon: leucopenia, neutrophils decreased, eosinophilia.

anemia aplastic, anemia hypochromic.

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).

Very rare: vasculitis.

menorrhagia.

Very rare: agranulocytosis, aplastic anemia/pancytopenia; cases of bleeding with fatal outcome (especially gastrointestinal, intracranial and retroperitoneal hemorrhage); serious cases of bleeding, mainly eye (conjuctival, ocular, retinal), musculoskeletal, respiratory tract and skin bleeding, epistaxis, hematuria and hemorrhage of operative wound, hematoma; thrombotic thrombocytopenic purpura (TTP). Some cases of TTP resulted in fatal outcomes (see Warnings and Precautions).

Very rare: confusion, hallucinations.

Very rare: colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis.

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

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

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.

hemothorax.

The following additional adverse reactions were reported in marketed use, however a causal relationship with clopidogrel has not been clearly established.

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.

Very rare: hypotension, often related to bleeding or allergic reaction.

Very rare: fever.

Uncommon: dizziness and paraesthesia. Rare: vertigo.

Very rare: glomerulopathy, elevated blood creatinine.

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.

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

bullous eruption, rash erythematous, rash maculopapular, urticaria.

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

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:

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.

bilirubinemia, hepatitis infectious and liver fatty.

agranulocytosis/granulocytopenia, aplastic anemia, neutropenia and thrombocytopenia.

Very rare: anaphylactoid reactions, serum sickness.

Very rare: arthralgia, arthritis, myalgia.

No data available.

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).

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.

No antidote to the pharmacological activity of clopidogrel has been found. Platelet transfusion may be used to reverse the pharmacological effects of PLAVIX when quick reversal is required.

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

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.

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.

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.

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

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.

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.

Although plasma concentrations of the main circulating metabolite are significantly higher in elderly (75 years) as compared to young healthy subjects, there were no differences in platelet aggregation and bleeding time (see Dosage and Administration).

Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is non saturable in vitro up to a concentration of 100 μg/mL.

Following repeated 75 mg oral doses of clopidogrel (base), plasma concentrations of the parent compound are very low and generally below the quantification limit (0.00025 mg/mL) beyond 2 hours after dosing. Accordingly the standard pharmacokinetic parameters of clopidogrel were not evaluable. The mean pharmacokinetic parameters of the main circulating compound (carboxylic acid derivative) after single oral administration of 75 mg clopidogrel are summarized below:

Clopidogrel is rapidly absorbed after oral administration of repeated 75 mg clopidogrel (base), with peak plasma levels (approx. 3 mg/L) of the main circulating metabolite occurring at approximately 1 hour after dosing. The pharmacokinetics of the carboxylic acid metabolite are linear (plasma concentrations increase in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel. Absorption is at least 50%, based on urinary excretion of clopidogrel-related metabolites. Administration of PLAVIX with meals did not significantly modify the bioavailability of clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite.

The role of platelets in the pathophysiology of atherosclerotic disease and atherothrombotic events has been established. Long-term prophylactic use of antiplatelet drugs has shown consistent benefit in the prevention of ischemic stroke, myocardial infarction, unstable angina, peripheral arterial disease, need for vascular bypass or angioplasty, and vascular death in patients at increased risk of such outcomes, including those with established atherosclerosis or a history of atherothrombosis. PLAVIX (clopidogrel bisulfate) is a specific inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation.

Following an oral dose of ¹⁴C-labeled clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the feces in the 5 days after dosing. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration. Covalent binding to platelets accounted for 2% of the radiolabel with a half-life of 11 days.

After repeated doses of 75 mg per day, plasma levels of the main circulating metabolite were significantly lower in subjects with severe renal impairment (creatinine clearance from 5 to 15 mL/min) compared to subjects with moderate renal impairment (creatinine clearance 30 to 60 mL/min). Since no differences in C_max, for both clopidogrel and the main circulating metabolite were observed, a compensatory phenomenon i.e. biliary excretion, which has been observed in animals, may explain the lower values of AUC observed in subjects with severe chronic renal failure. The inhibition of ADP-induced platelet aggregation was lower (to 25%) than what was observed in healthy subjects in other clinical studies (see Dosage and Administration).

No significant difference was observed in the plasma levels of the main circulating metabolite between males and females. In a small study comparing men and women (N=10 males and 10 females), less inhibition of ADP-induced platelet aggregation was observed in women. In the CAPRIE study (Clopidogrel versus ASA in Patients at Risk of Ischemic Events; for details see below), the incidence of clinical outcome events was similar in men and women.

Clopidogrel is extensively metabolized by the liver to a pharmacodynamically active chemical moiety. The main circulating metabolite (the carboxylic acid derivative) is inactive and represents about 85% of the circulating metabolites in plasma. The relationship between platelet aggregation and the concentration of the main circulating metabolite has not been established.

Clopidogrel inhibits selectively the binding of ADP to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein IIb-IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation. An active metabolite responsible for the activity of the drug has been identified. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity. Acetylsalicylic acid (ASA) inhibits the cyclooxygenase enzyme pathway preventing the production of prostaglandin and thus, the synthesis of thromboxane A2 which induces platelet aggregation. Clopidogrel acts on the ADP receptor and ASA acts on a separate receptor thereby inhibiting different pathways of platelet activation and aggregation. Therefore, there is potential for synergy between the two agents.

Clopidogrel acts by modifying irreversibly the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan and recovery of normal platelet function occurs at a rate consistent with platelet turnover (approximately 7 days). Single administration is not sufficient to reach a desired therapeutic effect. Statistically significant and dose-dependent inhibition of platelet aggregation was noted 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg per day produced inhibition of ADP-induced platelet aggregation from the first day. Steady state was reached between Day 3 and Day 7. At steady state, with a dose of 75 mg per day, the average inhibition level observed was between 40% and 60%. The aggregation level and bleeding time gradually returned to baseline values within 5-7 days after treatment was discontinued. The precise correlation between inhibition of platelet aggregation, prolongation of bleeding time and prevention of atherothrombotic events has not been established. The effect of a loading dose has been clinically evaluated in the CURE study (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events). The benefits of clopidogrel with concomitant ASA were apparent within 24 hours after randomization in the CURE trial.