Clopidogrel Bisulfate: Package Insert and Label Information
CLOPIDOGREL BISULFATE — clopidogrel bisulfate tablet, film coated
Physicians Total Care, Inc.
WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
The effectiveness of clopidogrel is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1)]. Clopidogrel at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient’s CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy [see Clinical Pharmacology (12.5)]. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers [see Dosage and Administration (2.3)].
1 INDICATIONS AND USAGE
1.1 Acute Coronary Syndrome (ACS)
- For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], including patients who are to be managed medically and those who are to be managed with coronary revascularization, clopidogrel tablets have been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
- For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets have been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is unknown.
The optimal duration of clopidogrel tablet therapy in ACS is unknown.
1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel tablets has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
2 DOSAGE AND ADMINISTRATION
2.1 Acute Coronary Syndrome
Clopidogrel tablets can be administered with or without food [see Clinical Pharmacology (12.3)]
- For patients with non-ST-elevation ACS (UA/NSTEMI), initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75-325 mg once daily) and continue in combination with clopidogrel tablets [see Clinical Studies (14.1)].
- For patients with STEMI, the recommended dose of clopidogrel tablets is 75 mg once daily orally, administered in combination with aspirin (75-325 mg once daily), with or without thrombolytics. Clopidogrel tablets may be initiated with or without a loading dose [see Clinical Studies (14.1)].
2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
The recommended daily dose of clopidogrel tablets is 75 mg once daily orally, with or without food [see Clinical Pharmacology (12.3)].
2.3 CYP2C19 Poor Metabolizers
CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response [see Clinical Pharmacology (12.5)], an appropriate dose regimen for this patient population has not been established.
2.4 Use with Proton Pump Inhibitors (PPI)
Avoid using omeprazole or esomeprazole with clopidogrel tablets. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel tablets. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite [see Warnings and Precautions (5.1), Drug Interactions (7.1) and Clinical Pharmacology ( 12.3) ].
3 DOSAGE FORMS AND STRENGTHS
Clopidogrel tablets USP, 75 mg are white, film coated, round, biconvex tablets debossed with “R” on one side and “196” on other side.
4.1 Active Bleeding
Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions (6.2)].
5 WARNINGS AND PRECAUTIONS
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 (7-10 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)]
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.
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)
|(+ aspirin)*||(+ aspirin)*|
|Major bleeding †||3.7 ‡||2.7 §|
|5 g/dL hemoglobin drop||0.9||0.9|
|Requiring surgical intervention||0.7||0.7|
|Requiring transfusion (≥4 units)||1.2||1.0|
|Other major bleeding||1.6||1.0|
|Intraocular bleeding with||0.05||0.03|
|significant loss of vision|
|Requiring 2-3 units of blood||1.3||0.9|
|Minor bleeding ¶||5.1||2.4|
* 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%; 100-200 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%; 100-200 mg= 2.3%; >200 mg=4%
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 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)||Placebo (+ aspirin)||P-value|
|Major* noncerebral or cerebral bleeding**||0.6||0.5||0.59|
|Other noncerebral bleeding (non-major)||3.6||3.1||0.005|
|Any noncerebral bleeding||3.9||3.4||0.004|
* 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%.
CAPRIE (clopidogrel vs. Aspirin)
In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2 % 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
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