Clopidogrel

American Health Packaging

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use clopidogrel safely and effectively. See full prescribing information for clopidogrel. Clopidogrel Tablets, USPInitial U.S. Approval: 1997BOXED WARNINGWARNING: DIMINISHED EFFECTIVEN ESS IN POOR METABOLIZERS See full prescribing information for complete boxed warning. • Effectiveness of clopidogrel depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1) • Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. (12.5) • Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. (12.5) • Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. (2.3, 5.1) RECENT MAJOR CHANGESDosage and Administration (2.4)                                12/2011 Warnings and Precautions (5.1)                                  12/2011INDICATIONS AND USAGEClopidogrel is a P2Y12 platelet inhibitor indicated for: ●     Acute coronary syndrome •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 has 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. (1.1) •For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets has 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 PCI is unknown. (1.1) ●        Recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease. Clopidogrel tablets has been shown to reduce the combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death. (1.2)DOSAGE AND ADMINISTRATION●    Acute coronary syndrome (2.1) •Non-ST-segment elevation ACS (UA/NSTEMI): 300 mg loading dose followed by 75 mg once daily, in combination with aspirin (75-325 mg once daily) •STEMI: 75 mg once daily, in combination with aspirin (75-325 mg once daily), with or without a loading dose and with or without thrombolytics ●   Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily (2.2)DOSAGE FORMS AND STRENGTHSTablets: 75 mg, 300 mg (3) CONTRAINDICATIONS •Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage (4.1) •Hypersensitivity to clopidogrel or any component of the product (4.2) WARNINGS AND PRECAUTIONS •Reduced effectiveness in impaired CYP2C19 function: Avoid concomitant use with omeprazole or esomeprazole. (5.1) •Bleeding: Clopidogrel increases risk of bleeding. Discontinue 5 days prior to elective surgery. (5.2) •Discontinuation of clopidogrel: Premature discontinuation increases risk of cardiovascular events. (5.3) •Recent transient ischemic attack or stroke: Combination use of clopidogrel and aspirin in these patients was not shown to be more effective than clopidogrel alone, but was shown to increase major bleeding. (5.4) •Thrombotic thrombocytopenic purpura (TTP): TTP has been reported with clopidogrel, including fatal cases. (5.5) Side EffectsBleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Wockhardt USA LLC. at 1-800-346-6854 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •Nonsteroidal anti-inflammatory drugs (NSAIDs): Combination use increases risk of gastrointestinal bleeding. (7.2) •Warfarin: Combination use increases risk of bleeding. (7.3) USE IN SPECIFIC POPULATIONSNursing mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother. (8.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
• 1. CLOPIDOGREL INDICATIONS AND USAGE
  • 1.1 Acute Coronary Syndrome (ACS)
  • 1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
• 2. CLOPIDOGREL DOSAGE AND ADMINISTRATION
  • 2.1 Acute Coronary Syndrome
  • 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
  • 2.3 CYP2C19 Poor Metabolizers
  • 2.4 Use with Proton Pump Inhibitors (PPI)
• 3. DOSAGE FORMS AND STRENGTHS
• 4. CLOPIDOGREL CONTRAINDICATIONS
  • 4.1 Active Bleeding
  • 4.2 Hypersensitivity
• 5. WARNINGS AND PRECAUTIONS
  • 5.1 Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function
  • 5.2 General Risk of Bleeding
  • 5.3 Discontinuation of Clopidogrel
  • 5.4 Patients with Recent Transient Ischemic Attack (TIA) or Stroke
  • 5.5 Thrombotic Thrombocytopenic Purpura (TTP)
• 6. CLOPIDOGREL ADVERSE REACTIONS
  • 6.1 Clinical Studies Experience
  • 6.2 Postmarketing Experience
• 7. DRUG INTERACTIONS
  • 7.1 CYP2C19 Inhibitors
  • 7.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
  • 7.3 Warfarin (CYP2C9 Substrates)
• 8. USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 10. OVERDOSAGE
• 11. CLOPIDOGREL DESCRIPTION
• 12. CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.5 Pharmacogenomics
• 13. NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
• 14. CLINICAL STUDIES
  • 14.1 Acute Coronary Syndrome
  • 14.2 Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease
  • 14.3 Lack of Established Benefit of Clopidogrel plus Aspirin in Patients with Multiple Risk Factors or Established Vascular Disease
• 16. HOW SUPPLIED/STORAGE AND HANDLING
• 17. PATIENT COUNSELING INFORMATION
  • 17.1 Benefits and Risks
  • 17.2 Bleeding
  • 17.3 Other Signs and Symptoms Requiring Medical Attention
  • 17.4 Invasive Procedures
  • 17.5 Concomitant Medications
  • 17.6 Medication Guide
• Package/Label Display Panel

FULL PRESCRIBING INFORMATION

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 tablet has 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 tablet has 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 tablets 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 tablet 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 tablet 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 tablet 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. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel. 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

• •75 mg tablets: Pink, round, biconvex, film-coated tablets debossed with "W 314" on one side and plain on other.
• •300 mg tablets: Pink, modified capsule shaped, biconvex, film-coated tablets debossed with "W 315" on one side and plain on other.

4. CONTRAINDICATIONS

4.1 Active Bleeding

Clopidogrel is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

4.2 Hypersensitivity

Clopidogrel is 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.

Bleeding

CURE

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.

* 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 = 2.0%; 100-200 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 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).

* 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 2.0% 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 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

7. DRUG INTERACTIONS

7.1 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 [see Warnings and Precautions (5.1) and Dosage and Administration (2.4)].

Proton Pump Inhibitors (PPI)

Avoid concomitant use of clopidogrel 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 [see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Coadministration of clopidogrel and NSAIDs increases the risk of gastrointestinal bleeding.

7.3 Warfarin (CYP2C9 Substrates)

Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or 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.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy 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 in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug 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 the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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

Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older.

The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively [see Adverse Reactions (6.1)]. No dosage adjustment is necessary in elderly patients.

8.6 Renal Impairment

Experience is limited in patients with severe and moderate renal impairment [see Clinical Pharmacology (12.2)].

8.7 Hepatic Impairment

No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.2)].

10. OVERDOSAGE

Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals.

Based on biological plausibility, platelet transfusion may restore clotting ability.

11. DESCRIPTION

Clopidogrel  bisulfate is a thienopyridine class inhibitor of P2Y₁₂ ADP platelet receptors. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H) acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C₁₆H₁₆ClNO₂S•H₂SO₄ and its molecular weight is 419.9.

The structural formula is as follows: