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Clopidogrel Bisulfate

FDA Drug Information • Also known as: Clopidogrel, Clopidogrel Bisulfate

Brand Names
Clopidogrel, Clopidogrel Bisulfate
Route
ORAL
Dosage Form
TABLET, FILM COATED
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE See full prescribing information for complete boxed warning.

  • Effectiveness of clopidogrel tablets depends on conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. ( 5.1, 12.3 )
  • Tests are available to identify patients who are CYP2C19 poor metabolizers. ( 12.5 )
  • Consider use of another platelet P2Y 12 inhibitor in patients identified as CYP2C19 poor metabolizers. ( 5.1 ) The effectiveness of clopidogrel tablets results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 )] . Clopidogrel tablets at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed "CYP2C19 poor metabolizers"). Tests are available to identify patients who are CYP2C19 poor metabolizers [see Clinical Pharmacology ( 12.5 )] . Consider use of another platelet P2Y 12 inhibitor in patients identified as CYP2C19 poor metabolizers.

    • Description

    11 DESCRIPTION Clopidogrel tablets, USP is a thienopyridine class inhibitor of P2Y 12 ADP platelet receptors. Chemically it is methyl (+)-( S )-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4 H )-acetate sulfate (1:1). The molecular formula of clopidogrel bisulfate is C 16 H 16 ClNO 2 S

  • H 2 SO 4 and its molecular weight is 419.9. The structural formula is as follows: Clopidogrel bisulfate, USP is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°. Clopidogrel tablets, USP 75 mg for oral administration are provided as pink, round, biconvex, film coated tablets, engraved “APO” on one side, “CL” over “75” on the other side. The tablets contain 97.875 mg of clopidogrel bisulfate, which is the molar equivalent of 75 mg of clopidogrel base. Clopidogrel tablets, USP 300 mg for oral administration are provided as pink, oblong, biconvex, film coated tablets engraved "APO" on one side and "CL 300" on the other side. The tablets contain 392 mg of clopidogrel bisulfate, which is the molar equivalent of 300 mg of clopidogrel base. Each tablet contains anhydrous lactose, colloidal silicon dioxide, crospovidone, methylcellulose and zinc stearate as inactive ingredients. The pink film coating contains ferric oxide red, hydroxypropyl cellulose, hypromellose, polyethylene glycol and titanium dioxide. clopiodgrel-01.jpg

    • What Is Clopidogrel Bisulfate Used For?

    1 INDICATIONS AND USAGE Clopidogrel tablets are a P2Y 12 platelet inhibitor indicated for:

  • Acute coronary syndrome - For patients with non-ST-segment elevation ACS (unstable angina [UA]/non-ST-elevation myocardial infarction [NSTEMI]), clopidogrel tablets has been shown to reduce the rate of myocardial infarction (MI) and stroke. ( 1.1 ) - For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets has been shown to reduce the rate of MI and stroke. ( 1.1 )
  • Recent MI, recent stroke, or established peripheral arterial disease. Clopidogrel tablets has been shown to reduce the rate of MI and stroke. ( 1.2 ) 1.1 Acute Coronary Syndrome (ACS)
  • Clopidogrel tablets are indicated to reduce the rate of myocardial infarction (MI) and stroke in 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 should be administered in conjunction with aspirin.
  • Clopidogrel tablets are indicated to reduce the rate of myocardial infarction and stroke in patients with acute ST-elevation myocardial infarction (STEMI) who are to be managed medically. Clopidogrel tablets should be administered in conjunction with aspirin. 1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke clopidogrel tablets are indicated to reduce the rate of MI and stroke.

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Acute coronary syndrome ( 2.1 ) o Initiate clopidogrel with a single 300 mg oral loading dose and then continue at 75 mg once daily. o Initiating clopidogrel without a loading dose will delay establishment of an antiplatelet effect by several days.
  • Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily orally without a loading dose. ( 2.2 ) 2.1 Acute Coronary Syndrome In patients who need an antiplatelet effect within hours, initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiating clopidogrel without a loading dose will delay establishment of an antiplatelet effect by several days [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.1 )] . 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease 75 mg once daily orally without a loading dose [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )] .

    • Side Effects (Adverse Reactions)

    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 ( 5.4 )] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Inc. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 tablets has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for one 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. Table 1 : CURE Incidence of Bleeding Complications (% patients) Event Clopidogrel (+aspirin) (n=6,259) Placebo (+ aspirin) (n=6,303) Major bleeding* 3.7 2.7 Life-threatening bleeding 2.2 1.8 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 transfusion (≥4 units) 1.2 1 Other major bleeding 1.6 1 Significantly disabling 0.4 0.3 Intraocular bleeding with significant loss of vision 0.05 0.03 Requiring 2 to 3 units of blood 1.3 0.9 Minor bleeding † 5.1 2.4 *Life-threatening and other major bleeding. † Led to interruption of study medication. 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) (n=22,961) Placebo (+ aspirin) (n=22,891) p-value Major* noncerebral or cerebral bleeding 0.6 0.5 0.59 Major noncerebral 0.4 0.3 0.48 Fatal 0.2 0.2 0.90 Hemorrhagic stroke 0.2 0.2 0.91 Fatal 0.2 0.2 0.81 Other noncerebral bleeding (nonmajor) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 * Major bleeds were cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion. CAPRIE (Clopidogrel vs Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2% in those taking clopidogrel versus 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 postapproval use of clopidogrel tablets. Because these reactions are reported voluntarily from a population of an...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • CYP2C19 inducers: Increases levels of clopidogrel active metabolite and increases platelet inhibition. ( 7.1 )
  • Opioids: Decreased exposure to clopidogrel. Consider use of parenteral antiplatelet agent. ( 7.3 )
  • Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. ( 7.4 , 7.5 , 7.6 )
  • Other Antiplatelet Agents: Increases the risk of bleeding due to an additive effect. ( 7.7 )
  • Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations. ( 7.8 ) 7.1 CYP2C19 Inducers Since clopidogrel is metabolized to its active metabolite partly by CYP2C19, use of drugs that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel. Rifampin strongly induces CYP2C19 resulting to both an increase level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, avoid concomitant use of strong CYP2C19 inducers [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] . 7.2 CYP2C19 Inhibitors Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of 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 )]. Omeprazole or Esomeprazole Avoid concomitant use of clopidogrel with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel. Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 7.3 Opioids As with other oral P2Y 12 inhibitors, coadministration of opioid agonists delay and reduce the absorption of clopidogrel, presumably because of slowed gastric emptying, resulting in reduced exposure to its metabolites [see Clinical Pharmacology ( 12.3 )] . Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists. 7.4 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Coadministration of clopidogrel and NSAIDs increases the risk of gastrointestinal bleeding. 7.5 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,...

    • Contraindications

    4 CONTRAINDICATIONS

  • Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage ( 4.1 )
  • Hypersensitivity to clopidogrel or any component of the product ( 4.2 ) 4.1 Active Bleeding Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. 4.2 Hypersensitivity Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions ( 6.2 )] .

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Available data from cases reported in published literature and postmarketing surveillance with clopidogrel use in pregnant women have not identified any drug-associated risks for major birth defects or miscarriage [see Data] . There are risks to the pregnant woman and fetus associated with myocardial infarction and stroke [see Clinical Considerations] . No evidence of fetotoxicity was observed when clopidogrel was administered to pregnant rats and rabbits during organogenesis at doses corresponding to 65 and 78 times the recommended daily human dose [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Myocardial infarction and stroke are medical emergencies. Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of clopidogrel on the fetus. Labor or delivery Clopidogrel use during labor or delivery will increase the risk of maternal bleeding and hemorrhage. Avoid neuraxial blockade during clopidogrel use because of the risk of spinal hematoma. When possible, discontinue clopidogrel 5 to 7 days prior to labor, delivery, or neuraxial blockade. Data Human data The available data from published case reports over two decades of postmarketing use have not identified an association with clopidogrel use in pregnancy and major birth defects, miscarriage, or adverse fetal outcomes. Animal data Embryo-fetal developmental toxicology studies were performed in pregnant rats and rabbits with doses up to 500 and 300 mg/kg/day, respectively, administered during organogenesis. These doses,...

    Overdosage

    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 1,500 or 2,000 mg/kg was lethal to mice and to rats and at 3,000 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.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Clopidogrel tablets, USP 300 mg are pink, oblong, biconvex, film coated tablets, engraved "APO" on one side and "CL 300" on the other side. They are supplied as follows: Cartons of 20 film coated tablets (10 film coated tablets each blister pack x 2), NDC 0904-6467-10 Cartons of 30 film coated tablets (10 film coated tablets each blister pack x 3), NDC 0904-6467-07 WARNING: These Unit Dose packages are not child resistant and are Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Store at 25°C(77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight container [see USP]. Protect from moisture.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.