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  • CLASSES

    ADP (adenosine Diphosphate) Receptor Antagonist Platelet Aggregation Inhibitors

    BOXED WARNING

    Poor metabolizers

    Clopidogrel has a reduced effect on platelet function in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene (i.e., poor metabolizers). Consider another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers. Data have shown that poor metabolizers have a higher risk of mortality, myocardial infarction, and stroke compared to normal metabolizers. Clopidogrel metabolism and, subsequently, platelet inhibition can also be reduced by drugs that significantly inhibit CYP2C19, such as omeprazole and esomeprazole; concomitant use should be avoided. Dexlansoprazole, lansoprazole, and pantoprazole have less effect on antiplatelet activity. Some data indicate patients may have a higher risk of reinfarction and revascularization after acute coronary syndrome when taking clopidogrel in combination with a proton pump inhibitor.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, P2Y12 platelet inhibitor
    Used for rate reduction of myocardial infarction (MI) and stroke in patients with non-ST-elevation acute coronary syndromes, STEMI, established peripheral arterial disease, or recent MI or stroke
    Associated with diminished antiplatelet effect in CYP2C19 poor metabolizers

    COMMON BRAND NAMES

    Plavix

    HOW SUPPLIED

    Clopidogrel/Clopidogrel Bisulfate/Plavix Oral Tab: 75mg, 300mg

    DOSAGE & INDICATIONS

    For arterial thromboembolism prophylaxis (i.e., myocardial infarction prophylaxis, stroke prophylaxis, thrombosis prophylaxis).
    For patients with established peripheral arterial disease or coronary artery disease.
    Oral dosage
    Adults

    75 mg PO once daily. Guidelines recommend long-term single antiplatelet therapy, including clopidogrel, for patients with established coronary artery disease.

    For patients with unstable angina or acute myocardial infarction, NSTEMI (non-ST-elevation myocardial infarction).
    Oral dosage
    Adults

    300 mg PO once, followed by 75 mg PO once daily in combination with aspirin. Initiating therapy without a loading dose will delay establishment of an antiplatelet effect by several days. Guidelines recommend clopidogrel for up to 12 months and aspirin indefinitely in patients with either early invasive or initial ischemia-guided strategy. In patients with an aspirin allergy, clopidogrel monotherapy can be used. In patients who undergo coronary artery bypass grafting (CABG), resume clopidogrel after CABG to complete 12 months of therapy.

    For patients with acute myocardial infarction, STEMI (ST-elevation myocardial infarction).
    Oral dosage
    Adults

    300 mg PO once, followed by 75 mg PO once daily in combination with aspirin. Initiating therapy without a loading dose will delay establishment of an antiplatelet effect by several days.[28435] Guidelines recommend patients who are managed with thrombolytics receive adjunctive antiplatelet therapy, including clopidogrel for 14 days to 12 months and aspirin indefinitely.[55688] In patients who undergo coronary artery bypass grafting (CABG), resume clopidogrel after CABG to complete 12 months of therapy.

    Geriatrics older than 75 years

    75 mg PO once daily in combination with aspirin.[28435] Guidelines recommend patients who are managed with thrombolytics receive adjunctive antiplatelet therapy, including clopidogrel for 14 days to 12 months and aspirin indefinitely. A loading dose is not recommended in patients older than 75 years.[55688] In patients who undergo coronary artery bypass grafting (CABG), resume clopidogrel after CABG to complete 12 months of therapy.

    For pediatric arterial thromboembolism prophylaxis† (i.e., thrombosis prophylaxis† or stroke prophylaxis†, including in other cardiac conditions with a risk for arterial thrombosis (e.g., Kawasaki disease†).
    Oral dosage
    Children and Adolescents 3 to 17 years

    1 mg/kg/day PO titrated to response (Max: 75 mg/day).[32219] [54129] [54130] [54134] [54145] [54151] In a cohort of 90 pediatric patients (11 days to 17.9 years, median 6.7 years), the median dose administered was 1.3 mg/kg/day PO. Some studies have reported lower doses of 0.2 to 0.3 mg/kg/day in children.[54148] [54130] In a prospective study in 14 children (0.7 to 84 months), 0.2 mg/kg/day resulted in effective platelet inhibition (40% to 50% inhibition of platelet aggregation) in 2 of the 3 children who were older than 2 years.[54148] In another study, dosing was initiated with 0.5 to 1 mg/kg/day with subsequent doses titrated down to 0.2 to 0.3 mg/kg/day.[54130] Higher doses (more than 2 to 6 mg/kg/day) have been reported and were tolerated in a few reported cases; however, the risk of bleeding may be higher with increasing doses.[54129] [54134] In children with recurrent arterial ischemic stroke or TIAs who fail or are intolerant of aspirin, clopidogrel is recommended as an alternative antiplatelet agent.[49232] [52706] [54145] [54134] In children with Kawasaki disease who have severe coronary involvement, clopidogrel is recommended in combination with aspirin.[32219]

    Neonates, Infants, and Children 1 to 2 years

    0.2 mg/kg/day PO provides platelet inhibition concentrations similar to those achieved by the standard adult dose based on limited data. In the PICOLO study, which included 34 neonates (35 weeks or more gestational age and weight 2 kg or more) and 39 infants/children 30 days to 24 months, 0.2 mg/kg/day achieved the target ADP-induced platelet aggregation inhibition (30% to 50% inhibition of platelet aggregation) for both the maximum extent and the rate of platelet aggregation. Of the patients randomized, 73.3% had undergone placement of a systemic-to-pulmonary artery shunt, 24.4% had an intracardiac or intravascular stent placed, 1.2% had Kawasaki disease, and the remainder had an arterial graft in place. The majority of patients were also taking aspirin 81 mg/day or less. In another prospective study in 14 children (0.7 to 84 months; 11 children 2 years or younger), 93% of patients achieved effective platelet inhibition (30% to 50% inhibition of platelet aggregation) with a dose of 0.2 mg/kg/day. In children with recurrent arterial ischemic stroke or TIAs who fail or are intolerant of aspirin, clopidogrel is recommended as an alternative antiplatelet agent. In children with Kawasaki disease who have severe coronary involvement, clopidogrel is recommended in combination with aspirin.

    For patients with stable ischemic heart disease undergoing percutaneous coronary intervention (PCI).
    Oral dosage
    Adults

    300 or 600 mg PO once, followed by 75 mg PO once daily in patients receiving a stent in combination with aspirin. Guidelines recommend 300 mg loading dose within 24 hours of fibrinolytic and 600 mg if more than 24 hours since fibrinolytic. Treat for at least 6 months in patients receiving a drug-eluting stent (DES) and for at least 1 month in patients receiving a bare metal stent (BMS). If a patient receiving a BMS is at increased risk of bleeding, treat for at least 2 weeks. Continuing clopidogrel for longer may be reasonable in patients who have not experienced a bleeding complication and are not a high bleeding risk. Earlier clopidogrel discontinuation is reasonable if the bleeding risks outweigh the benefits; in patients with a DES, discontinuation after 3 months may be reasonable.  However, premature discontinuation of dual antiplatelet therapy is discouraged, including in the setting of elective procedures. Delay elective surgery for 6 months after DES and 1 month after bare metal stent placement. If the procedure cannot be delayed, continue aspirin if possible and restart clopidogrel as soon as possible.

    For patients with acute coronary syndrome (ACS) undergoing PCI.
    Oral dosage
    Adults

    300 or 600 mg PO once, followed by 75 mg PO once daily for at least 12 months in patients receiving a stent in combination with aspirin. Guidelines recommend 300 mg loading dose within 24 hours of fibrinolytic and 600 mg if more than 24 hours since fibrinolytic. Continuing clopidogrel for more than 12 months may be reasonable in patients who have not experienced a bleeding complication and are not a high bleeding risk. Earlier clopidogrel discontinuation after 6 months is reasonable if the bleeding risks outweigh the benefits. However, premature discontinuation of dual antiplatelet therapy is discouraged, including in the setting of elective procedures. Delay elective surgery for 6 months after DES and 1 month after bare metal stent placement. If the procedure cannot be delayed, continue aspirin if possible and restart clopidogrel as soon as possible.

    For patients with minor noncardioembolic stroke who did not receive IV alteplase.
    Oral dosage
    Adults

    300 or 600 mg PO once, followed by 75 mg PO once daily for a total of 90 days in combination with aspirin for the first 21 days. Guidelines suggest clopidogrel within 24 hours of symptom onset in patients presenting with National Institutes of Health Stroke Scale (NIHSS) score of 3 or less.[64716]

    MAXIMUM DOSAGE

    Adults

    75 mg/day PO chronic treatment (up to 600 mg PO for single loading dose).

    Geriatric

    75 mg/day PO chronic treatment (up to 600 mg PO for single loading dose).

    Adolescents

    Safety and efficacy have not been established; doses up to 6 mg/kg/day (Max: 75 mg/day) PO have been used off-label.

    Children

    3 to 12 years: Safety and efficacy have not been established; doses up to 6 mg/kg/day (Max: 75 mg/day) PO have been used off-label.
    1 to 2 years: Safety and efficacy have not been established; however, doses of 0.2 mg/kg/day PO have been used off-label.

    Infants

    Safety and efficacy have not been established; however, doses of 0.2 mg/kg/day PO have been used off-label.

    Neonates

    Safety and efficacy have not been established; however, doses of 0.2 mg/kg/day PO have been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Experience is limited in patients with severe and moderate renal impairment; specific guidelines for dosage adjustments in renal impairment are not available.

    ADMINISTRATION

    Oral Administration

    May be administered with or without food.

    STORAGE

    Generic:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Plavix:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Clopidogrel is contraindicated in patients with a known hypersensitivity to clopidogrel or any component of the product.

    Bleeding, GI bleeding, intracranial bleeding, peptic ulcer disease, surgery, trauma

    Clopidogrel increases the risk of bleeding and is contraindicated in patients with active pathological bleeding including GI bleeding and intracranial bleeding. As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions including peptic ulcer disease. When possible, interrupt clopidogrel therapy for 5 days prior to surgery; resume as soon as hemostasis is achieved. Clopidogrel inhibits platelet aggregation for the lifetime of the platelet (7 to 10 days). It may be possible to restore hemostasis by transfusing platelets because the half-life of clopidogrel's active metabolite is short; however, platelets transfused within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective. Use clopidogrel and other drugs that may promote bleeding (e.g., NSAIDs) together with caution.

    Hepatic disease

    The manufacturer states no dosage adjustment is necessary in patients with hepatic disease. However, a bleeding diathesis may exist in these patients, especially in those with severe liver disease, which may increase the risk of bleeding associated with clopidogrel. In addition, severe hepatic disease may impair the conversion of clopidogrel, the prodrug, to its active form.

    Renal disease, renal failure, renal impairment

    Experience is limited in patients with severe renal disease or renal failure. Use clopidogrel cautiously in patients with renal impairment.

    Poor metabolizers

    Clopidogrel has a reduced effect on platelet function in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene (i.e., poor metabolizers). Consider another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers. Data have shown that poor metabolizers have a higher risk of mortality, myocardial infarction, and stroke compared to normal metabolizers. Clopidogrel metabolism and, subsequently, platelet inhibition can also be reduced by drugs that significantly inhibit CYP2C19, such as omeprazole and esomeprazole; concomitant use should be avoided. Dexlansoprazole, lansoprazole, and pantoprazole have less effect on antiplatelet activity. Some data indicate patients may have a higher risk of reinfarction and revascularization after acute coronary syndrome when taking clopidogrel in combination with a proton pump inhibitor.

    Epidural anesthesia, labor, obstetric delivery, pregnancy, spinal anesthesia

    Available data from published cases and postmarketing reports with clopidogrel use during human pregnancy have not identified any drug-associated risks for major birth defects, miscarriage, or adverse fetal outcomes. No evidence of fetotoxicity was observed when clopidogrel was administered to rats and rabbits during organogenesis at doses corresponding to 65 and 78 times the recommended daily human dose. There are risks to the pregnant woman and fetus associated with myocardial infarction and stroke. Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of clopidogrel on the fetus. Clopidogrel use during labor or obstetric delivery will increase the risk of maternal bleeding and hemorrhage. Avoid neuraxial blockade (i.e., epidural anesthesia, spinal anesthesia) during clopidogrel use due to the risk of spinal hematoma. When possible, discontinue clopidogrel 5 to 7 days prior to labor, delivery, or neuraxial blockade.[28435]

    Breast-feeding

    There are no data on the presence of clopidogrel in human breast milk or the effects on milk production. No adverse effects on breast-fed infants have been observed with maternal clopidogrel use during lactation in a small number of postmarketing cases. Clopidogrel and/or its metabolites are excreted into the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for clopidogrel and any potential adverse effects on the breast-fed infant from clopidogrel or from the underlying maternal condition.[28435]

    Geriatric

    Of the total number of subjects in controlled clinical studies, approximately 50% of patients treated with clopidogrel were geriatric (i.e., 65 years of age and older). Approximately 16% of patients treated with clopidogrel were 75 years of age and over. During clinical trials, the incidence of major bleeding increased with increasing age; the incidence of bleeding was higher in patients treated with combination clopidogrel and aspirin. If bleeding is a potential concern and combination therapy is desired, geriatric patients and their prescribers should be encouraged to use a low dose of aspirin with clopidogrel. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, platelet inhibitors may cause thrombocytopenia and increase the risk of bleeding. Common side effects of platelet inhibitors include headache, dizziness, and vomiting. Concurrent use with aspirin, warfarin, or NSAIDs may increase the risk of bleeding.

    Children, infants, neonates

    Safe and effective use of clopidogrel has not been established in children, infants and neonates.

    Abrupt discontinuation

    In an effort to minimize the risk of cardiovascular events, avoid premature discontinuation or lapses in therapy (i.e., abrupt discontinuation) with clopidogrel. Premature discontinuation may increase the risk for cardiovascular events. If clopidogrel must be temporarily discontinued, restart therapy as soon as possible.

    Thrombotic thrombocytopenic purpura (TTP)

    Thrombotic thrombocytopenic purpura (TTP), sometimes fatal, has been reported rarely in patients receiving clopidogrel, sometimes after short exposure (less than 2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange). Thrombocytopenia, microangiopathic hemolytic anemia (schistocytes seen on peripheral smear), neurological findings, renal dysfunction, and fever characterize TTP.

    Thienopyridine hypersensitivity

    Clopidogrel is contraindicated in patients with a known hypersensitivity to clopidogrel or any component of the product. Evaluate patients receiving clopidogrel for a history of thienopyridine hypersensitivity. Hypersensitivity reactions including rash, angioedema, or hematologic reactions have been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines (e.g., ticlopidine, prasugrel).

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 2.0-2.0
    peptic ulcer / Delayed / 0.7-0.7
    intracranial bleeding / Delayed / 0.1-0.4
    thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-0.1
    ocular hemorrhage / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    serum sickness / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    insulin autoimmune syndrome / Delayed / Incidence not known

    Moderate

    hematoma / Early / 3.7-5.1
    bleeding / Early / 3.7-5.1
    hypertension / Early / 4.3-4.3
    constipation / Delayed / 2.4-2.4
    peripheral edema / Delayed / 1.2-1.2
    gastritis / Delayed / 0.8-0.8
    platelet dysfunction / Delayed / Incidence not known
    melena / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    confusion / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    hypoglycemia / Early / Incidence not known

    Mild

    headache / Early / 7.6-7.6
    dizziness / Early / 6.2-6.2
    rash / Early / 6.0-6.0
    abdominal pain / Early / 5.6-5.6
    purpura / Delayed / 5.3-5.3
    dyspepsia / Early / 5.2-5.2
    epistaxis / Delayed / 3.7-5.1
    diarrhea / Early / 4.5-4.5
    pruritus / Rapid / 3.3-3.3
    vertigo / Early / 2.2-2.2
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    fever / Early / Incidence not known
    dysgeusia / Early / Incidence not known
    myalgia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Coadministration of opioid agonists, such as dihydrocodeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Acetaminophen; Codeine: (Moderate) Coadministration of opioid agonists, such as codeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Acetaminophen; Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Acetaminophen; Oxycodone: (Moderate) Coadministration of opioid agonists, such as oxycodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Acetaminophen; Propoxyphene: (Moderate) Coadministration of opioid agonists delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Alfentanil: (Moderate) Coadministration of opioid agonists, such as alfentanil, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Aliskiren; Amlodipine: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Alogliptin; Pioglitazone: (Major) Do not exceed 15 mg/day of pioglitazone when coadministered with clopidogrel. Coadministration may increase the exposure of pioglitazone, increasing the risk for hypoglycemia. Pioglitazone is a CYP2C8 substrate and clopidogrel is a strong CYP2C8 inhibitor. Coadministration with another strong CYP2C8 inhibitor increased the exposure of pioglitazone by approximately 3.2-fold.
    Altretamine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors is used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as altretamine.
    Aminolevulinic Acid: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Amlodipine: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Amlodipine; Atorvastatin: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Amlodipine; Benazepril: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Amlodipine; Celecoxib: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Amlodipine; Olmesartan: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Amlodipine; Valsartan: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of clopidogrel and omeprazole as it significantly reduces the antiplatelet activity of clopidogrel. If necessary, consider using a PPI medication with less pronounced effects on antiplatelet activity, such as rabeprazole, pantoprazole, lansoprazole, or dexlansoprazole. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Omeprazole is an inhibitor of CYP2C19. In clinical studies, use of omeprazole significantly reduced the antiplatelet activity of clopidogrel when administered concomitantly or 12 hours apart.
    Anagrelide: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Antithrombin III: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants.
    Antithymocyte Globulin: (Moderate) An increased risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia, such as antithymocyte globulin. Platelet inhibitors should be used cautiously in patients with thrombocytopenia following the administration of antithymocyte globulin or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding.
    Apalutamide: (Major) Avoid concomitant use of clopidogrel and apalutamide due to the risk of bleeding. If use together is necessary, monitor for bleeding and apalutamide-related toxicity; consider dose reduction based on tolerability in patients experiencing grade 3 or higher adverse reactions or toxicities. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19 and is also a strong CYP2C8 inhibitor; apalutamide is a strong CYP2C19 inducer and a substrate of CYP2C8.
    Apixaban: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Argatroban: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Armodafinil: (Major) Armodafinil may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and armodafinil together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Armodafinil is an inhibitor of CYP2C19.
    Arsenic Trioxide: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other drugs that affect hemostasis. Clopidogrel should be used cautiously in patients with thrombocytopenia following the administration of myelosuppressive antineoplastic agents or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding.
    Aspirin, ASA: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy. (Moderate) Coadministration of opioid agonists, such as codeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Aspirin, ASA; Caffeine: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy. (Moderate) Coadministration of opioid agonists, such as dihydrocodeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Carisoprodol: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy. (Moderate) Coadministration of opioid agonists, such as codeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Dipyridamole: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy. (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Aspirin, ASA; Omeprazole: (Major) Avoid concomitant use of clopidogrel and omeprazole as it significantly reduces the antiplatelet activity of clopidogrel. If necessary, consider using a PPI medication with less pronounced effects on antiplatelet activity, such as rabeprazole, pantoprazole, lansoprazole, or dexlansoprazole. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Omeprazole is an inhibitor of CYP2C19. In clinical studies, use of omeprazole significantly reduced the antiplatelet activity of clopidogrel when administered concomitantly or 12 hours apart. (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Oxycodone: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy. (Moderate) Coadministration of opioid agonists, such as oxycodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Aspirin, ASA; Pravastatin: (Moderate) Although aspirin may be used in combination with clopidogrel, both drugs are associated with bleeding. In clinical trials, bleeding rates with concomitant use of aspirin and clopidogrel vs. placebo vary from similar to increased bleeding with coadministration. Monitor for bleeding during concomitant therapy.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of clopidogrel with cobicistat due to the potential for decreased clopidogrel efficacy. Prasugrel may be preferred to clopidogrel if coadministration with cobicistat is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Cobicistat is a strong CYP3A4 inhibitor.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Coadministration of opioid agonists delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Belladonna; Opium: (Moderate) Coadministration of opioid agonists delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration. (Moderate) Coadministration of opioid agonists, such as opium, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Benzhydrocodone; Acetaminophen: (Moderate) Coadministration of opioid agonists, such as benzhydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and platelet inhibitors are used concomitantly. Coadministration of betrixaban and platelet inhibitors may increase the risk of bleeding.
    Bexarotene: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including bexarotene.
    Bivalirudin: (Moderate) When used as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), bivalirudin is intended for use with aspirin (300 to 325 mg/day PO) and has been studied only in patients receiving concomitant aspirin. Generally, an additive risk of bleeding may be seen in patients receiving other platelet inhibitors (other than aspirin). In clinical trials in patients undergoing PTCA, patients receiving bivalirudin with heparin, warfarin, or thrombolytics had increased risks of major bleeding events compared to those receiving bivalirudin alone. According to the manufacturer, the safety and effectiveness of bivalirudin have not been established when used in conjunction with platelet inhibitors other than aspirin. However, bivalirudin has been safely used as an alternative to heparin in combination with provisional use of platelet glycoprotein IIb/IIIa inhibitors during angioplasty (REPLACE-2). In addition, two major clinical trials have evaluated the use of bivalirudin in patients receiving streptokinase following acute myocardial infarction (HERO-1, HERO-2). Based on the these trials, bivalirudin may be considered an alternative to heparin therapy for use in combination with streptokinase for ST-elevation MI. Bivalirudin has not been sufficiently studied in combination with other more specific thrombolytics.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Bupropion: (Moderate) Dosage adjustment of bupropion may be necessary during coadministration with clopidogrel. Concomitant use may increase bupropion exposure but decrease hydroxybupropion exposure. Bupropion is primarily metabolized to hydroxybupropion via CYP2B6; clopidogrel is a weak CYP2B6 inhibitor.
    Bupropion; Naltrexone: (Moderate) Dosage adjustment of bupropion may be necessary during coadministration with clopidogrel. Concomitant use may increase bupropion exposure but decrease hydroxybupropion exposure. Bupropion is primarily metabolized to hydroxybupropion via CYP2B6; clopidogrel is a weak CYP2B6 inhibitor.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Coadministration of opioid agonists, such as codeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Cangrelor: (Major) Do not administer clopidogrel until the cangrelor infusion is discontinued. The expected antiplatelet effect of a 600 mg loading dose of clopidogrel will be blocked if administered during the cangrelor infusion. Clopidogrel therapy should be initiated immediately after cangrelor discontinuation.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Chlorambucil: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Chloramphenicol: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of chloramphenicol. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; chloramphenicol is a CYP2C19 inhibitor.
    Chlorpheniramine; Codeine: (Moderate) Coadministration of opioid agonists, such as codeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Coadministration of opioid agonists, such as dihydrocodeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as dihydrocodeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Chlorpheniramine; Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Cilostazol: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of cilostazol and clopidogrel. Both agents are platelet inhibitors; therefore, concomitant use may increase the risk of bleeding. Platelet aggregation returns to normal within 96 hours of discontinuing cilostazol.
    Cimetidine: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of cimetidine. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; cimetidine is a CYP2C19 inhibitor.
    Citalopram: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of citalopram and clopidogrel. Selective serotonin reuptake inhibitors (SSRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Cladribine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Cobicistat: (Major) Avoid coadministration of clopidogrel with cobicistat due to the potential for decreased clopidogrel efficacy. Prasugrel may be preferred to clopidogrel if coadministration with cobicistat is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Cobicistat is a strong CYP3A4 inhibitor.
    Codeine: (Moderate) Coadministration of opioid agonists, such as codeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Codeine; Guaifenesin: (Moderate) Coadministration of opioid agonists, such as codeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as codeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Codeine; Phenylephrine; Promethazine: (Moderate) Coadministration of opioid agonists, such as codeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Codeine; Promethazine: (Moderate) Coadministration of opioid agonists, such as codeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Dabigatran: (Moderate) Coadministration of dabigatran and clopidogrel (300 mg or 600 mg loading dose) resulted in an increase in dabigatran AUC and Cmax of 30% and 40%, respectively; however capillary bleeding times were not further prolonged compared to clopidogrel monotherapy. In addition, coagulation measures for dabigatran's effect (aPTT, ECT, and TT) were unchanged, and inhibition of platelet aggregation (IPA), a measure of clopidogrel's effect, was unchanged. However, the manufacturer notes that the concomitant use of dabitatran and platelet inhibiting agents may increase the risk of bleeding. Monitor patients closely for signs of bleeding if dabigatran is given concomitantly with any platelet inhibiting agents.
    Dabrafenib: (Major) Avoid the concomitant use of dabrafenib and clopidogrel; dabrafenib concentrations may increase resulting in increased toxicity. Use of an alternate agent is recommended. If concomitant use is necessary, monitor patients for dabrafenib toxicity (e.g., skin toxicity, ocular toxicity, and cardiotoxicity). The clopidogrel manufacturer states that a dose adjustment of the CYP2C8 substrate may be necessary. Dabrafenib is a CYP2C8 substrate; the glucuronide metabolite of clopidogrel is a strong CYP2C8 inhibitor. The dabrafenib AUC value increased by 47% when dabrafenib was administered with another strong CYP2C8 inhibitor in a drug interaction study.
    Dalteparin: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants.
    Danaparoid: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants.
    Darunavir: (Major) Avoid coadministration of clopidogrel with darunavir. Concomitant use may reduce concentrations of the active metabolite of clopidogrel, therefore decreasing the antiplatelet activity of clopidogrel.
    Darunavir; Cobicistat: (Major) Avoid coadministration of clopidogrel with cobicistat due to the potential for decreased clopidogrel efficacy. Prasugrel may be preferred to clopidogrel if coadministration with cobicistat is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Cobicistat is a strong CYP3A4 inhibitor. (Major) Avoid coadministration of clopidogrel with darunavir. Concomitant use may reduce concentrations of the active metabolite of clopidogrel, therefore decreasing the antiplatelet activity of clopidogrel.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of clopidogrel with cobicistat due to the potential for decreased clopidogrel efficacy. Prasugrel may be preferred to clopidogrel if coadministration with cobicistat is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Cobicistat is a strong CYP3A4 inhibitor. (Major) Avoid coadministration of clopidogrel with darunavir. Concomitant use may reduce concentrations of the active metabolite of clopidogrel, therefore decreasing the antiplatelet activity of clopidogrel.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with clopidogrel is contraindicated due to the potential for dasabuvir-induced QT prolongation. Dasabuvir is primarily metabolized by CYP2C8; clopidogrel is a potent CY2C8 inhibitor. (Major) Avoid coadministration of clopidogrel with ritonavir due to the potential for decreased clopidogrel efficacy. Prasugrel is preferred to clopidogrel if coadministration with ritonavir is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Ritonavir is a strong CYP3A4 inhibitor.
    Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and clopidogrel is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant platelet inhibitors may increase the risk of hemorrhage.
    Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
    Desirudin: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants.
    Desvenlafaxine: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of desvenlafaxine and clopidogrel. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as dihydrocodeine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Dipyridamole: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Doxercalciferol: (Moderate) Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors including clopidogrel may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if clopidogrel is coadministered with doxercalciferol.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any platelet inhibitors within 7 days. These patients are at increased risk of bleeding during drotrecogin alfa therapy.
    Duloxetine: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of duloxetine and clopidogrel. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Edoxaban: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of clopidogrel with cobicistat due to the potential for decreased clopidogrel efficacy. Prasugrel may be preferred to clopidogrel if coadministration with cobicistat is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Cobicistat is a strong CYP3A4 inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of clopidogrel with cobicistat due to the potential for decreased clopidogrel efficacy. Prasugrel may be preferred to clopidogrel if coadministration with cobicistat is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Cobicistat is a strong CYP3A4 inhibitor.
    Enoxaparin: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants.
    Enzalutamide: (Major) Avoid coadministration of clopidogrel with enzalutamide if possible due to increased enzalutamide exposure. If concomitant use is unavoidable, reduce the dose of enzalutamide to 80 mg once daily; the original dose of enzalutamide may be resumed when clopidogrel is discontinued. Enzalutamide is a CYP2C8 substrate and the acyl-beta-glucuronide metabolite of clopidogrel is a strong CYP2C8 inhibitor. Coadministration with another strong CYP2C8 inhibitor increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold.
    Eptifibatide: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
    Escitalopram: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of escitalopram and clopidogrel. Selective serotonin reuptake inhibitors (SSRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Eslicarbazepine: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of eslicarbazepine. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; eslicarbazepine is a CYP2C19 inhibitor.
    Esomeprazole: (Major) Avoid concomitant use of clopidogrel and esomeprazole as it significantly reduces the antiplatelet activity of clopidogrel. If necessary, consider using a PPI medication with less pronounced effects on antiplatelet activity, such as rabeprazole, pantoprazole, lansoprazole, or dexlansoprazole. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Esomeprazole is an inhibitor of CYP2C19. In clinical studies, use of esomeprazole significantly reduced the antiplatelet activity of clopidogrel.
    Etravirine: (Major) Etravirine may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and etravirine together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Etravirine is an inhibitor of CYP2C19.
    Fedratinib: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of fedratinib. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; fedratinib is a moderate CYP2C19 inhibitor.
    Felbamate: (Major) Felbamate may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and felbamate together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Felbamate is a potent inhibitor of CYP2C19.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as clopidogrel, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of clopidogrel during coadministration with fenofibric acid.
    Fentanyl: (Moderate) Coadministration of opioid agonists, such as fentanyl, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
    Fluconazole: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of fluconazole. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; fluconazole is a potent CYP2C19 inhibitor.
    Fludarabine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Fluoxetine: (Major) Consider an alternative antidepressant to fluoxetine if possible in patients receiving clopidogrel. If coadministration is necessary, monitor patients for reduced clopidogrel effectiveness and signs and symptoms of bleeding. Fluoxetine may reduce the antiplatelet activity of clopidogrel through potent inhibition of the CYP2C19 metabolism of clopidogrel to its active metabolite. Additionally, selective serotonin reuptake inhibitors (SSRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Fluvoxamine: (Major) Consider an alternative antidepressant to fluvoxamine if possible in patients receiving clopidogrel. If coadministration is necessary, monitor patients for reduced clopidogrel effectiveness and signs and symptoms of bleeding. Fluvoxamine may reduce the antiplatelet activity of clopidogrel through potent inhibition of the CYP2C19 metabolism of clopidogrel to its active metabolite. Additionally, selective serotonin reuptake inhibitors (SSRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Fondaparinux: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants.
    Garlic, Allium sativum: (Moderate) Use together with caution. Garlic produces clinically significant antiplatelet effects, and a risk for bleeding may occur if platelet inhibitors are given in combination with garlic.
    Ginger, Zingiber officinale: (Moderate) Ginger inhibits thromboxane synthetase, a platelet aggregation inducer, and is a prostacyclin agonist so additive bleeding may occur if platelet inhibitors are given in combination with ginger, zingiber officinale.
    Ginkgo, Ginkgo biloba: (Major) Use Ginkgo biloba with caution in patients taking platelet inhibitors, as it can produce clinically-significant antiplatelet effects. A compound found in Ginkgo biloba, ginkgolide-B, may act as a selective antagonist of platelet activating factor (PAF). Although a review of Ginkgo biloba in 1992 stated that no known drug interactions exist, spontaneous hyphema has been reported in an elderly male who began taking Ginkgo while stabilized on daily aspirin. After ginkgo was stopped, no further bleeding was noted despite continuing the aspirin therapy. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic Ginkgo biloba ingestion.
    Glimepiride; Rosiglitazone: (Moderate) Coadministration of clopidogrel and rosiglitazone may result in increased serum concentrations of rosiglitazone and therefore increased risk for hypoglycemia. The dose of rosiglitazone may require adjustment during concurrent use based on clinical response. Rosiglitazone is metabolized by CYP2C8 and clopidogrel is a strong CYP2C8 inhibitor.
    Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co administered with aspirin. Caution and careful monitoring of clinical and/or laboratory parameters are warranted with this combination.
    Guaifenesin; Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Heparin: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants. In healthy volunteers receiving heparin, clopidogrel does not alter the effect of heparin on coagulation parameters or require adjustment of the heparin dose. In addition, heparin has no effect on inhibition of platelet aggregation induced by clopidogrel. Nevertheless, the safety of this combination has not been established and concomitant administration of clopidogrel with heparin should be undertaken with caution.
    Homatropine; Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Hydrocodone; Ibuprofen: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Hydrocodone; Phenylephrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Hydromorphone: (Moderate) Coadministration of opioid agonists, such as hydromorphone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with platelet function such as platelet inhibitors; the risk of bleeding may be increased. If coadministration with platelet inhibitors is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
    Ibrutinib: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as clopidogrel may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Ibuprofen; Oxycodone: (Moderate) Coadministration of opioid agonists, such as oxycodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Iloprost: (Moderate) When used concurrently with platelet inhibitors, inhaled iloprost may increase the risk of bleeding.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and ADP receptor antagonists due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of ADP receptor antagonists in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
    Intravenous Lipid Emulsions: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
    Isoniazid, INH: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of isoniazid. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; isoniazid is a CYP2C19 inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of clopidogrel and rifampin due to the risk of bleeding. Concomitant use results in increased plasma concentrations of clopidogrel's active metabolite and an increase in platelet inhibition. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; rifampin is a strong CYP2C19 inducer. (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of isoniazid. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; isoniazid is a CYP2C19 inhibitor.
    Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of clopidogrel and rifampin due to the risk of bleeding. Concomitant use results in increased plasma concentrations of clopidogrel's active metabolite and an increase in platelet inhibition. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; rifampin is a strong CYP2C19 inducer. (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of isoniazid. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; isoniazid is a CYP2C19 inhibitor.
    Ketoconazole: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of ketoconazole. In a drug interaction study, ketoconazole decreased the active metabolite of clopidogrel.
    Lepirudin: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with lepirudin.
    Levamlodipine: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Levomethadyl: (Moderate) Coadministration of opioid agonists delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Levomilnacipran: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of levomilnacipran and platelet inhibitors. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Levorphanol: (Moderate) Coadministration of opioid agonists, such as levorphanol, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Lomustine, CCNU: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as lomustine.
    Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest) during coadministration with clopidogrel. Clopidogrel is an inhibitor of CYP2C8 (potent) and CYP2B6 (weak); in vitro studies indicated loperamide is primarily metabolized by CYP2C8 and CYP3A4, with a CYP2B6 playing a minor role.
    Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest) during coadministration with clopidogrel. Clopidogrel is an inhibitor of CYP2C8 (potent) and CYP2B6 (weak); in vitro studies indicated loperamide is primarily metabolized by CYP2C8 and CYP3A4, with a CYP2B6 playing a minor role.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of clopidogrel with ritonavir due to the potential for decreased clopidogrel efficacy. Prasugrel is preferred to clopidogrel if coadministration with ritonavir is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Ritonavir is a strong CYP3A4 inhibitor.
    Luliconazole: (Minor) Monitor for reduced clopidogrel efficacy during concomitant use of luliconazole. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19. In vitro, luliconazole is a CYP2C19 inhibitor and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. However, no in vivo drug interaction trials have been conducted to evaluate the effect of luliconazole on drugs that are substrates of CYP2C19.
    Meperidine: (Moderate) Coadministration of opioid agonists, such as meperidine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Meperidine; Promethazine: (Moderate) Coadministration of opioid agonists, such as meperidine, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Mercaptopurine, 6-MP: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Metformin; Repaglinide: (Major) Avoid concomitant use of clopidogrel and repaglinide. If coadministration cannot be avoided, initiate repaglinide at 0.5 mg PO before each meal, and do not exceed a total daily dose of 4 mg. Increased glucose monitoring may be required. Concomitant administration of clopidogrel and repaglinide increased the systemic exposure of repaglinide 5.1-fold after a clopidogrel 300 mg loading dose and 3.9-fold on day 3 of clopidogrel 75 mg/day. The acyl-beta-gluconuride metabolite of clopidogrel is a strong CYP2C8 inhibitor, and repaglinide is primarily metabolized by CYP2C8.
    Metformin; Rosiglitazone: (Moderate) Coadministration of clopidogrel and rosiglitazone may result in increased serum concentrations of rosiglitazone and therefore increased risk for hypoglycemia. The dose of rosiglitazone may require adjustment during concurrent use based on clinical response. Rosiglitazone is metabolized by CYP2C8 and clopidogrel is a strong CYP2C8 inhibitor.
    Methadone: (Moderate) Coadministration of opioid agonists, such as methadone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Methoxsalen: (Minor) Agents that affect platelet function, such as platelet inhibitors, could decrease the efficacy of methoxsalen when used during photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs including increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants or antiplatelets including clopidogrel until data confirming the safety of these drug combinations are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving clopidogrel should be observed for increased bleeding.
    Milnacipran: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of milnacipran and platelet inhibitors. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Modafinil: (Major) Modafinil may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and modafinil together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Modafinil is an inhibitor of CYP2C19.
    Morphine: (Moderate) Coadministration of opioid agonists delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Morphine; Naltrexone: (Moderate) Coadministration of opioid agonists delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Mycophenolate: (Moderate) Platelet Inhibitors inhibit platelet aggregation and should be used cautiously in patients with thrombocytopenia, as mycophenolate can also cause thrombocytopenia.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with clopidogrel is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP2C8 substrate and clopidogrel is a strong CYP2C8 inhibitor. In vitro, the metabolism of paclitaxel to 6-alpha-hydroxypaclitaxel was inhibited by another inhibitor of CYP2C8.
    Naproxen; Esomeprazole: (Major) Avoid concomitant use of clopidogrel and esomeprazole as it significantly reduces the antiplatelet activity of clopidogrel. If necessary, consider using a PPI medication with less pronounced effects on antiplatelet activity, such as rabeprazole, pantoprazole, lansoprazole, or dexlansoprazole. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Esomeprazole is an inhibitor of CYP2C19. In clinical studies, use of esomeprazole significantly reduced the antiplatelet activity of clopidogrel.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Nicardipine: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of nicardipine. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; nicardipine is a CYP2C19 inhibitor.
    Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Olanzapine; Fluoxetine: (Major) Consider an alternative antidepressant to fluoxetine if possible in patients receiving clopidogrel. If coadministration is necessary, monitor patients for reduced clopidogrel effectiveness and signs and symptoms of bleeding. Fluoxetine may reduce the antiplatelet activity of clopidogrel through potent inhibition of the CYP2C19 metabolism of clopidogrel to its active metabolite. Additionally, selective serotonin reuptake inhibitors (SSRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of clopidogrel with ritonavir due to the potential for decreased clopidogrel efficacy. Prasugrel is preferred to clopidogrel if coadministration with ritonavir is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Ritonavir is a strong CYP3A4 inhibitor.
    Omeprazole: (Major) Avoid concomitant use of clopidogrel and omeprazole as it significantly reduces the antiplatelet activity of clopidogrel. If necessary, consider using a PPI medication with less pronounced effects on antiplatelet activity, such as rabeprazole, pantoprazole, lansoprazole, or dexlansoprazole. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Omeprazole is an inhibitor of CYP2C19. In clinical studies, use of omeprazole significantly reduced the antiplatelet activity of clopidogrel when administered concomitantly or 12 hours apart.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of clopidogrel and omeprazole as it significantly reduces the antiplatelet activity of clopidogrel. If necessary, consider using a PPI medication with less pronounced effects on antiplatelet activity, such as rabeprazole, pantoprazole, lansoprazole, or dexlansoprazole. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Omeprazole is an inhibitor of CYP2C19. In clinical studies, use of omeprazole significantly reduced the antiplatelet activity of clopidogrel when administered concomitantly or 12 hours apart.
    Omeprazole; Sodium Bicarbonate: (Major) Avoid concomitant use of clopidogrel and omeprazole as it significantly reduces the antiplatelet activity of clopidogrel. If necessary, consider using a PPI medication with less pronounced effects on antiplatelet activity, such as rabeprazole, pantoprazole, lansoprazole, or dexlansoprazole. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Omeprazole is an inhibitor of CYP2C19. In clinical studies, use of omeprazole significantly reduced the antiplatelet activity of clopidogrel when administered concomitantly or 12 hours apart.
    Oritavancin: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of oritavancin. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; oritavancin is a weak CYP2C19 inhibitor.
    Oxcarbazepine: (Major) Oxcarbazepine may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use oxcarbazepine and clopidogrel together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Oxcarbazepine is an inhibitor of CYP2C19.
    Oxycodone: (Moderate) Coadministration of opioid agonists, such as oxycodone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Oxymorphone: (Moderate) Coadministration of opioid agonists, such as oxymorphone, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Ozanimod: (Major) Coadministration of ozanimod with clopidogrel is not recommended. Coadministration may increase the exposure of the active metabolites of ozanimod, which may increase the risk of adverse reactions. Ozanimod is a CYP2C8 substrate and clopidogrel is a strong CYP2C8 inhibitor. Coadministration with another strong CYP2C8 inhibitor increased the exposure of active metabolites CC112273 and CC1084037 by approximately 47% and 69%, respectively. No clinically significant differences in the exposure of ozanimod were observed when coadministered with a strong CYP2C8 inhibitor.
    Paroxetine: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of paroxetine and clopidogrel. Selective serotonin reuptake inhibitors (SSRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Pentosan: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants.
    Pentostatin: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Pentoxifylline: (Moderate) A potential additive risk for bleeding exists if platelet inhibitors are given in combination with other agents that affect hemostasis such as pentoxifylline.
    Perindopril; Amlodipine: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Photosensitizing agents (topical): (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Pioglitazone: (Major) Do not exceed 15 mg/day of pioglitazone when coadministered with clopidogrel. Coadministration may increase the exposure of pioglitazone, increasing the risk for hypoglycemia. Pioglitazone is a CYP2C8 substrate and clopidogrel is a strong CYP2C8 inhibitor. Coadministration with another strong CYP2C8 inhibitor increased the exposure of pioglitazone by approximately 3.2-fold.
    Pioglitazone; Glimepiride: (Major) Do not exceed 15 mg/day of pioglitazone when coadministered with clopidogrel. Coadministration may increase the exposure of pioglitazone, increasing the risk for hypoglycemia. Pioglitazone is a CYP2C8 substrate and clopidogrel is a strong CYP2C8 inhibitor. Coadministration with another strong CYP2C8 inhibitor increased the exposure of pioglitazone by approximately 3.2-fold.
    Pioglitazone; Metformin: (Major) Do not exceed 15 mg/day of pioglitazone when coadministered with clopidogrel. Coadministration may increase the exposure of pioglitazone, increasing the risk for hypoglycemia. Pioglitazone is a CYP2C8 substrate and clopidogrel is a strong CYP2C8 inhibitor. Coadministration with another strong CYP2C8 inhibitor increased the exposure of pioglitazone by approximately 3.2-fold.
    Platelet Glycoprotein IIb/IIIa Inhibitors: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasugrel: (Moderate) Because clopidogrel and prasugrel inhibit platelet aggregation, a potential additive risk for bleeding exists if the drugs are given in combination. Patients should be instructed to monitor for signs and symptoms of bleeding and to promptly report any bleeding events.
    Propoxyphene: (Moderate) Coadministration of opioid agonists delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Purine analogs: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Remifentanil: (Moderate) Coadministration of opioid agonists, such as remifentanil, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Repaglinide: (Major) Avoid concomitant use of clopidogrel and repaglinide. If coadministration cannot be avoided, initiate repaglinide at 0.5 mg PO before each meal, and do not exceed a total daily dose of 4 mg. Increased glucose monitoring may be required. Concomitant administration of clopidogrel and repaglinide increased the systemic exposure of repaglinide 5.1-fold after a clopidogrel 300 mg loading dose and 3.9-fold on day 3 of clopidogrel 75 mg/day. The acyl-beta-gluconuride metabolite of clopidogrel is a strong CYP2C8 inhibitor, and repaglinide is primarily metabolized by CYP2C8.
    Rifampin: (Major) Avoid concomitant use of clopidogrel and rifampin due to the risk of bleeding. Concomitant use results in increased plasma concentrations of clopidogrel's active metabolite and an increase in platelet inhibition. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; rifampin is a strong CYP2C19 inducer.
    Ritonavir: (Major) Avoid coadministration of clopidogrel with ritonavir due to the potential for decreased clopidogrel efficacy. Prasugrel is preferred to clopidogrel if coadministration with ritonavir is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Ritonavir is a strong CYP3A4 inhibitor.
    Rivaroxaban: (Major) Avoid concurrent administration of platelet inhibitors such as clopidogrel with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
    Rosiglitazone: (Moderate) Coadministration of clopidogrel and rosiglitazone may result in increased serum concentrations of rosiglitazone and therefore increased risk for hypoglycemia. The dose of rosiglitazone may require adjustment during concurrent use based on clinical response. Rosiglitazone is metabolized by CYP2C8 and clopidogrel is a strong CYP2C8 inhibitor.
    Rucaparib: (Moderate) Monitor for decreased efficacy of clopidogrel if coadministration with rucaparib is necessary. Clopidogrel is a prodrug that is metabolized to its active metabolite by CYP2C19. Rucaparib is a weak CYP2C19 inhibitor. Concomitant use may reduce concentrations of the active metabolite, therefore decreasing the antiplatelet activity of clopidogrel.
    Selexipag: (Major) Reduce selexipag dose to once daily when coadministered with clopidogrel due to increased exposure to the active metabolite of selexipag, which may cause side effects. Selexipag is a CYP2C8 substrate, and clopidogrel is a CYP2C8 inhibitor.
    Selumetinib: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
    Sertraline: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of sertraline and clopidogrel. Selective serotonin reuptake inhibitors (SSRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Sufentanil: (Moderate) Coadministration of opioid agonists, such as sufentanil, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Sulfinpyrazone: (Major) Sulfinpyrazone, when used as a uricosuric agent should be avoided when possible with concurrent platelet inhibitors due to potential for additive antiplatelet effects and increased bleeding risk.
    Tapentadol: (Moderate) Coadministration of opioid agonists, such as tapentadol, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Telmisartan: (Major) Telmisartan may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and telmisartan together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Telmisartan is an inhibitor of CYP2C19.
    Telmisartan; Amlodipine: (Major) Telmisartan may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and telmisartan together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Telmisartan is an inhibitor of CYP2C19. (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Major) Telmisartan may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and telmisartan together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Telmisartan is an inhibitor of CYP2C19.
    Thioguanine, 6-TG: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Thrombolytic Agents: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Ticagrelor: (Moderate) Because clopidogrel and ticagrelor inhibit platelet aggregation, a potential additive risk for bleeding exists if the drugs are given in combination. Patients should be instructed to monitor for signs and symptoms of bleeding and to promptly report any bleeding events.
    Ticlopidine: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other drugs that affect hemostasis such as platelet inhibitors. Also, coadministration of clopidogrel and ticlopidine should be avoided. Ticlopidine and clopidogrel inhibit platelets via the same mechanism; combination therapy would therefore be duplicative and not recommended. Furthermore, ticlopidine is a CYP2C19 inhibitor, and clopidogrel requires hepatic biotransformation via CYP2C19 to its active metabolite. When clopidogrel is coadministered with other potent CYP2C19 inhibitors, the plasma concentration and platelet inhibition activity of clopidogrel are reduced. Coadministration of clopidogrel and ticlopidine would be expected to have a similar effect and should be avoided.
    Tirofiban: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
    Tramadol: (Moderate) Coadministration of opioid agonists, such as tramadol, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Tramadol; Acetaminophen: (Moderate) Coadministration of opioid agonists, such as tramadol, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Trazodone: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Treprostinil: (Moderate) Reduce the starting dose of oral treprostinil to 0.125 mg twice daily when coadministered with clopidogrel; dose adjustments should be made in 0.125 mg twice daily increments every 3 to 4 days. Human pharmacokinetic studies of oral treprostinil indicate that coadministration of another potent CYP2C8 enzyme inhibitor results in a 2-fold increase in exposure to treprostinil, a CYP2C8 substrate. The clinical significance of this interaction with orally inhaled or parenteral treprostinil or with other CYP2C8 inhibitors is unknown; treprostinil dose adjustments may be necessary. Additionally, monitor patients for signs and symptoms of bleeding if treprostinil is administered with clopidogrel. Treprostinil inhibits platelet aggregation; clopidogrel is a platelet inhibitor. Coadministration increases the risk of bleeding.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin.
    Tucatinib: (Major) Avoid coadministration of tucatinib and clopidogrel due to the risk of increased tucatinib exposure which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of tucatinib to 100 mg PO twice daily. If clopidogrel is discontinued, resume the original tucatinib dose after 3 elimination half-lives of clopidogrel. Tucatinib is a CYP2C8 substrate and clopidogrel is a strong CYP2C8 inhibitor. Coadministration with another strong CYP2C8 inhibitor increased tucatinib exposure by 3-fold.
    Venlafaxine: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of venlafaxine and clopidogrel. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with platelet inhibitors is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease platelet aggregation could decrease the efficacy of verteporfin therapy.
    Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with salicylates or other platelet inhibitors and to promptly report any bleeding events to the practitioner. Platelet aggregation may be impaired by vilazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., aspirin, cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors).
    Vorapaxar: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Voriconazole: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of voriconazole. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; voriconazole is a weak CYP2C19 inhibitor.
    Vorinostat: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of clopidogrel and vorinostat. Due to the thrombocytopenic effects of vorinostat, an additive risk of bleeding may occur in patients taking platelet inhibitors.
    Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Warfarin: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of warfarin and clopidogrel. Both agents independently affect hemostasis.

    PREGNANCY AND LACTATION

    Pregnancy

    Available data from published cases and postmarketing reports with clopidogrel use during human pregnancy have not identified any drug-associated risks for major birth defects, miscarriage, or adverse fetal outcomes. No evidence of fetotoxicity was observed when clopidogrel was administered to rats and rabbits during organogenesis at doses corresponding to 65 and 78 times the recommended daily human dose. There are risks to the pregnant woman and fetus associated with myocardial infarction and stroke. Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of clopidogrel on the fetus. Clopidogrel use during labor or obstetric delivery will increase the risk of maternal bleeding and hemorrhage. Avoid neuraxial blockade (i.e., epidural anesthesia, spinal anesthesia) during clopidogrel use due to the risk of spinal hematoma. When possible, discontinue clopidogrel 5 to 7 days prior to labor, delivery, or neuraxial blockade.[28435]

    MECHANISM OF ACTION

    Clopidogrel is a thienopyridine compound which acts to antagonize adenosine diphosphate (ADP). Clopidogrel is inactive in vitro and requires hepatic activation to exert its antiplatelet effect. The active metabolite selectively and irreversibly inhibits ADP-induced platelet aggregation. It prevents binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor. Thus, ADP-mediated activation of the glycoprotein GPIIb/IIIa complex is impaired. Because the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, impaired activation of the GPIIb/IIIa complex prevents fibrinogen binding to platelets which ultimately inhibits platelet aggregation. Because the active metabolite of clopidogrel irreversibly modifies the platelet ADP receptor, platelets exposed to the drug are affected for the remainder of their lifespan (7 to 10 days). In platelet aggregation studies, clopidogrel 75 mg once daily produced inhibition of ADP-induced platelet aggregation equivalent to that of ticlopidine 250 mg twice daily. The active metabolite of clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP; the active metabolite does not inhibit phosphodiesterase.

    PHARMACOKINETICS

    Clopidogrel is administered orally; it is inactive in vitro and requires hepatic biotransformation to an active metabolite. Clopidogrel undergoes extensive metabolism by 2 main metabolic pathways. One pathway is mediated by esterases and results in an inactive carboxylic acid derivative, accounting for 85% of circulating metabolites. The other pathway is mediated by multiple cytochrome (CYP) P450 isoenzymes. The cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the intermediate metabolite results in the formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed primarily by CYP2C19; CYP3A, CYP2B6, and CYP1A2 contribute to a lesser extent. The active metabolite rapidly and irreversibly binds to platelet receptors, inhibiting platelet aggregation for the lifespan of the platelet. Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). Approximately 50% of radiolabeled clopidogrel is eliminated in the urine and about 46% via the feces over a period of 5 days. The half-life of clopidogrel is approximately 6 hours in adults; the half-life of the active metabolite is approximately 30 minutes.
     
    Dose dependent inhibition of platelet aggregation can be seen 2 hours after a single oral dose. With repeated doses of 75 mg/day in adults, maximum inhibition of platelet aggregation is achieved within 3 to 7 days. At steady state, platelet aggregation is inhibited by 40% to 60%. Platelet aggregation and bleeding time gradually return to baseline about 5 days after discontinuation of clopidogrel.
     
    Affected cytochrome P450 isoenzymes: CYP2C9, CYP2C19, CYP2C8, CYP3A, CYP2B6,  CYP1A2
    Clopidogrel is a substrate and inhibitor of CYP2C19 and a strong inhibitor of CYP2C8. Clopidogrel requires hepatic biotransformation to an active metabolite; this activation is mediated primarily by CYP2C19 and to a lesser extent by CYP3A, CYP2B6, and CYP1A2. At high concentrations in vitro, clopidogrel is a potent inhibitor of CYP2B6 and a mild inhibitor of CYP2C9.

    Oral Route

    Clopidogrel is rapidly absorbed with a bioavailability of at least 50%. Food does not significantly affect absorption. In adults, peak concentrations occur 30 to 60 minutes after administration.