CLOPIVAS Film-coated tablet Ref.[50463] Active ingredients: Clopidogrel

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 and by concomitant medications that interfere with CYP2C19.

Proton Pump Inhibitors

Avoid concomitant use of CLOPIVAS with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel.

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 CLOPIVAS five days prior to surgery. In patients who stopped therapy more than five days prior to coronary artery bypass graft (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 (7-10 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.

Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with aspirin), and that they should report any unusual bleeding (site or duration) to their physician.

Discontinuation of Clopidogrel

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

Patients with Recent Transient Ischemic Attack or Stroke

In patients with recent transient ischemic attack (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.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (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 red blood cells (RBCs)] seen on peripheral smear}, neurological findings, renal dysfunction, and fever.

Acquired Hemophilia

Acquired hemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated partial thromboplastin time (aPTT) prolongation with or without bleeding, acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be managed and treated by specialists, and clopidogrel should be discontinued.

Cross-Reactivity among Thienopyridines

Hypersensitivity, including rash, angioedema or hematologic reaction, has been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines.

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

• Bleeding
• TTP

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

In the CURE trial, use of clopidogrel with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (Table 2). 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.

Table 2. Incidence of bleeding complications (% patients) in the CURE trial:

^* Other standard therapies were used as appropriate.
^**/* Life-threatening and other major bleeding.
^& Major 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%
^§ Major 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%
^¶ Led to interruption of study medication

Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecularweight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

In the COMMIT trial, similar rates of major bleeding were observed in the clopidogrel and placebo groups, both of which also received aspirin (Table 3).

Table 3. Incidence of bleeding events in COMMIT (% patients):

^* Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion.
^**/* The 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%.

In the CAPRIE trial comparing clopidogrel with aspirin, 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 the CAPRIE trial that 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.

Some adverse events that were reported include – thrombocytopenia, leucopenia, neutropenia (including severe neutropenia), granulocytopenia, anemia, cross-reactive drug hypersensitivity among thienopyridines (such as ticlopidine, prasugrel), paresthesia, dizziness, vertigo, abdominal pain, dyspepsia, gastritis, vomiting, nausea, constipation, flatulence, gynecomastia, glomerulonephritis, hematuria.

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, TTP, acquired hemophilia A

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 Conditions: 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, eosinophilic pneumonia

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, druginduced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding, lichen planus, generalized pruritus

Vascular Disorders: Vasculitis, hypotension

CYP2C19 Inhibitors

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

Proton Pump Inhibitors

Avoid concomitant use of CLOPIVAS with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole.

Nonsteroidal Anti-Inflammatory Drugs

Coadministration of clopidogrel and nonsteroidal antiinflammatory drugs (NSAIDs) increases the risk of gastrointestinal bleeding.

Glycoprotein IIb/IIIa Inhibitors

Clopidogrel should be used with caution in patients who receive concomitant GP IIb/IIIa inhibitors.

Acetylsalicylic Acid

Aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of aspirin on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of aspirin twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. However, clopidogrel and aspirin have been administered together for up to one year.

Heparin

In a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.

Oral Anticoagulants [eg: Warfarin (CYP2C9 Substrates)]

The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleeding. Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or international normalized ratio (INR) in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9.

Thrombolytics

The safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute MI. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with aspirin.

Selective Serotonin-Reuptake Inhibitors and Serotonin Norepinephrine-Reuptake Inhibitors

Since selective serotonin-reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.

Other Medicinal Products

A number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine.

Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co-administration of phenobarbital or oestrogen. The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption. Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by CYP2C9 can be safely co-administered with clopidogrel. Apart from the specific medicinal product interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and GP IIb/IIIa antagonists without evidence of clinically significant adverse interactions.

Category B.

Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m² basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies with clopidogrel in pregnant women. Because animal reproduction studies are not always predictive of a human response, CLOPIVAS should be used during pregnancy only if clearly needed.

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether clopidogrel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue CLOPIVAS, taking into account the importance of the drug to the mother.

Safety and effectiveness in the pediatric population have not been established.

A randomized, placebo-controlled trial (CLARINET) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemicto-pulmonary arterial shunt. Possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin and the late initiation of therapy following shunt palliation. It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population.

Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were aged 65 years and older, and 15% were aged 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were aged 60 years and older, 26% of whom were aged 70 years and older. No dosage adjustment is necessary in elderly patients.

Experience is limited in patients with severe and moderate renal impairment.

No dosage adjustment is necessary in patients with hepatic impairment.