Clopidogrel

Clopidogrel may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• excessive tiredness
• headache
• dizziness
• nausea
• vomiting
• stomach pain
• diarrhea
• nosebleed

Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately:

• hives
• rash
• itching
• difficulty breathing or swallowing
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• hoarseness
• black and tarry stools
• red blood in stools
• bloody vomit
• vomit that looks like coffee grounds
• unusual bleeding or bruising
• pink or brown urine
• slow or difficult speech
• weakness or numbness of an arm or a leg
• changes in vision
• fever
• shortness of breath
• fast heartbeat
• pale skin
• purple patches or bleeding under the skin
• confusion
• yellowing of the skin or eyes
• seizures

Clopidogrel may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Plavix

There are no adequate studies of clopidogrel in pregnant women.

Studies in rats have shown that clopidogrel appears in breast milk; however, it is not known whether it also appears in human breast milk. Because of a potential for side effects in the nursing infant, the physician must weigh the potential benefits and possible risks before prescribing clopidogrel to nursing mothers.

Clopidogrel gets converted to its active form by an enzyme in the body known as CYP2C19. Drugs such as clopidogrel that require activation by the body are known as prodrugs. Some patients have a deficiency in CYP2C19. Patients with a deficiency in CYP2C19 are known as "poor metabolizers" or "intermediate metabolizers."

CYP2C19 testing is done to determine whether clopidogrel is likely to be an effective treatment. Many factors can affect levels of clopidogrel in the blood, such as drug interactions. Without testing, clopidogrel may not be an effective treatment. If you are a poor or intermediate metabolizer, your doctor may adjust your dose of clopidogrel.

Without being activated, clopidogrel is not able to stop blood clots from forming. In poor or intermediate metabolizers, clopidogrel may not get converted to its active form, and may not be effective at preventing blood clots. Being a poor or intermediate metabolizer is associated with a higher risk of heart attack or stroke in patients being treated with clopidogrel.

Clopidogrel is part of the drug class:

• Platelet aggregation inhibitors excl. heparin

Clopidogrel can cause serious side effects including:

• See "Drug Precautions" section
• A blood clotting problem called Thrombotic Thrombocytopenic Purpura (TTP). TTP can happen with clopidogrel, sometimes after a short time (less than 2 weeks). TTP is a blood clotting problem where blood clots form in blood vessels; and can happen anywhere in the body. TTP needs to be treated in a hospital right away, because it may cause death. Get medical help right away if you have any of these symptoms and they can not be explained by another medical condition:
  • purplish spots (called purpura) on the skin or in the mouth (mucous membranes) due to bleeding under the skin
  • your skin or the whites of your eyes are yellow (jaundice)
  • you feel tired or weak
  • your skin looks very pale
  • fever
  • fast heart rate or feeling short of breath
  • headache
  • speech changes
  • confusion
  • coma
  • stroke
  • seizure
  • low amount of urine, or urine that is pink or has blood in it
  • stomach area (abdominal) pain
  • nausea, vomiting, or diarrhea
  • vision changes

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of clopidogrel. For more information, ask your doctor or pharmacist.

The recommended daily dose of clopidogrel is 75 mg once daily orally, with or without food.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Clopidogrel may cause you to bleed more easily, which can be severe or life-threatening. Seek emergency medical attention if you have any unusual bleeding, or bleeding that will not stop. You may also have bleeding on the inside of your body, such as in your stomach or intestines. Call your doctor at once if you have blood in your urine, black or bloody stools, or if you cough up blood or vomit that looks like coffee grounds.

Call your doctor at once if you have any other serious side effects:

• nosebleeds;

• easy bruising, purple or red pinpoint spots under your skin;

• pale skin, weakness, fever, or jaundice (yellowing of the skin or eyes);

• little or no urination;

• fast heart rate, feeling short of breath;

• a seizure;

• nausea, vomiting, diarrhea, stomach pain;

• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating; or

• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Certain other medicines may increase your risk of bleeding. Tell your doctor if you take aspirin, especially if you have had a stroke. Talk to your doctor about whether you should take aspirin with clopidogrel.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• a blood thinner--warfarin, Coumadin, Jantoven;

• NSAIDs (nonsteroidal anti-inflammatory drugs)--aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others; or

• an antidepressant--citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine (Prozac), fluvoxamine, milnacipran, paroxetine, sertraline (Zoloft), trazodone, venlafaxine, vilazodone, and others.

This list is not complete. Other drugs may interact with clopidogrel, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

• It is used to prevent heart attacks.
• It is used to prevent strokes.
• It is used after a heart treatment to protect the arteries.
• It is used to lower the number of heart attacks in patients who have unstable angina or mild heart attacks.
• It may be given to you for other reasons. Talk with the doctor.

• If you have an allergy to clopidogrel or any other part of clopidogrel.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are taking any of these drugs: Esomeprazole, omeprazole, or repaglinide.
• If you have active bleeding.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take clopidogrel with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Chest pain or pressure.
• Very bad headache.
• Shortness of breath.
• Feeling confused.
• Change in skin color to black or purple.
• Sore throat.
• A heartbeat that does not feel normal.
• Seizures.
• Back pain.
• Not able to pass urine or change in how much urine is passed.
• Weight loss.
• Very bad and sometimes deadly blood problems like thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) have happened with this medicine in some people. Call your doctor right away if you feel very tired or weak or have any bruising or bleeding; dark urine or yellow skin or eyes; pale skin; change in the amount of urine passed; change in eyesight; change in strength on 1 side is greater than the other, trouble speaking or thinking, or change in balance; or fever.

1.1 Acute Coronary Syndrome (ACS)

• Clopidogrel is indicated to reduce the rate of myocardial infarction (MI) and stroke in patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], including patients who are to be managed medically and those who are to be managed with coronary revascularization. Clopidogrel should be administered in conjunction with aspirin.
• Clopidogrel is indicated to reduce the rate of myocardial infarction and stroke in patients with acute ST-elevation myocardial infarction (STEMI) who are to be managed medically. Clopdiogrel should be administered in conjunction with aspirin.

1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke clopdigorel is indicated to reduce the rate of MI and stroke.

Acute coronary syndrome:

Acute ST-segment elevation myocardial infarction: To reduce the rate of myocardial infarction and stroke in conjunction with aspirin in patients with acute ST-elevation MI (STEMI) who are to be managed medically.

Unstable angina/non-ST-segment elevation myocardial infarction: To decrease the rate of MI and stroke in conjunction with aspirin in patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-ST-elevation myocardial infarction [UA/NSTEMI]), including patients who are to be managed medically and those who are to be managed with coronary revascularization.

Recent myocardial infarction, recent stroke, or established peripheral arterial disease: To reduce the rate of MI and stroke in patients with a history of recent MI, recent stroke, or established peripheral arterial disease.

Adjunctive therapy to support reperfusion with primary percutaneous coronary intervention

Data from a prospective, randomized, double-blind, placebo-controlled trial supports the use of clopidogrel as an adjunctive therapy in this setting [Sabatine 2005b]. Additionally, a smaller study conducted in patients undergoing primary percutaneous coronary intervention (PCI) for STEMI demonstrated a reduction in infarct size (primary endpoint) with a 600 mg loading dose versus a 300 mg loading dose [Patti 2011].

Based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for the management of ST-elevation myocardial infarction, clopidogrel is an effective and recommended adjunctive antithrombotic agent to support reperfusion with primary PCI.

Atrial fibrillation (primary prevention of thromboembolism)

Two large randomized controlled trials evaluated the use of dual antiplatelet therapy (ie, clopidogrel and aspirin) in patients with atrial fibrillation. While the use of warfarin was found to be clearly superior to the use of dual antiplatelet therapy in the ACTIVE W trial, data from the ACTIVE A trial supports the use of clopidogrel (in combination with aspirin) for the prevention of major vascular events, especially stroke, in patients with atrial fibrillation with at least 1 risk factor for stroke who in the uncommon scenario cannot take oral anticoagulants for reasons other than elevated risk of bleeding (ACTIVE Investigators 2006; ACTIVE Investigators 2009). In a subsequent analysis of the ACTIVE trials, the addition of clopidogrel to aspirin in patients with AF for whom warfarin was unsuitable resulted in only modest net benefit. The patient with an elevated bleeding risk who is not a candidate for oral anticoagulation would not be a candidate for dual antiplatelet therapy given the comparable risk of bleeding events (Connolly 2011).

Based on the 2012 American College of Chest Physicians antithrombotic guidelines, the combination of clopidogrel and aspirin is an alternative antithrombotic strategy in patients with AF who are at intermediate to high risk of stroke; however, the use of oral anticoagulation is preferred in patients especially if the patient has multiple risk factors for stroke. For those patients who are unsuitable for or choose not to take an oral anticoagulant (for reasons other than concerns for bleeding), clopidogrel in combination with aspirin is recommended. Based on the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines on the management of patients with atrial fibrillation, the selection of an antithrombotic agent should be based on the shared decision making with the patient taking into consideration multiple factors (eg, cost, tolerability). No specific recommendation regarding the use of clopidogrel and aspirin as an alternative was made.

Coronary artery bypass graft (CABG) surgery (secondary prevention)

Based on the American Heart Association (AHA) scientific statement for the secondary prevention after coronary artery bypass graft surgery, clopidogrel is a reasonable alternative to aspirin for patients who are intolerant or allergic to aspirin. Additionally, in patients following off-pump CABG, clopidogrel in combination with aspirin should be administered for 1 year to reduce graft occlusion. In patients following on-pump CABG (without recent acute coronary syndrome), clopidogrel in combination with aspirin may be considered but benefits are not well established.

Non-ST-elevation acute coronary syndromes in patients with allergy or major gastrointestinal intolerance to aspirin

Based on the American Heart Association/American College of Cardiology (AHA/ACC) guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS), clopidogrel (given initially and continued indefinitely) may be used as an alternative for patients with allergy or major gastrointestinal intolerance to aspirin.

Percutaneous coronary intervention (PCI), non-acute coronary syndrome (ie, stable ischemic heart disease)

Based on the 2011 American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) percutaneous coronary intervention guidelines, clopidogrel is an effective and recommended adjunctive oral antithrombotic agent for patients with non-ACS (ie, stable ischemic heart disease [SIHD]) undergoing PCI.

Peripheral artery percutaneous transluminal angioplasty

Based on the American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy and prevention of thrombosis, clopidogrel is an effective and recommended treatment option for patients undergoing peripheral artery percutaneous transluminal angioplasty with or without stenting.

Secondary prevention of cardiovascular disease (patients with diabetes and an aspirin allergy)

Based on the American Diabetes Association (ADA) Standards of Medical Care in Diabetes, clopidogrel is effective and recommended for the secondary prevention of cardiovascular disease in patients with diabetes and atherosclerotic disease who have a documented aspirin allergy.

Symptomatic carotid artery stenosis (including recent carotid endarterectomy)

Based on the American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy and prevention of thrombosis, clopidogrel is effective and recommended for patients with symptomatic carotid stenosis (including recent carotid endarterectomy).

Avoid or minimize the consumption of grapefruit juice (Holmberg, 2013).

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Amiodarone: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

BuPROPion: CYP2B6 Inhibitors (Weak) may increase the serum concentration of BuPROPion. Monitor therapy

Calcium Channel Blockers: May diminish the therapeutic effect of Clopidogrel. Exceptions: Clevidipine. Monitor therapy

Cangrelor: May diminish the antiplatelet effect of Clopidogrel. More specifically, while the use of Cangrelor is expected to increase total platelet inhibition in patients who have previously received Clopidogrel, Cangrelor is expected to decrease binding of Clopidogrel metabolites to P2Y12 receptors and thus reduce the extent of irreversible platelet inhibition. Management: Avoid administration of clopidogrel until cangrelor infusion is discontinued. Consider therapy modification

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

CYP2C19 Inhibitors (Moderate): May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

CYP2C19 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a strong CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

Dabigatran Etexilate: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Antiplatelet Agents (P2Y12 Inhibitors) may increase the serum concentration of Dabigatran Etexilate. Specifically, clopidogrel may increase dabigatran serum concentrations. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Dexlansoprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Consider therapy modification

Edoxaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider the anticipated risks and benefits of this combination. If combined, increased monitoring for bleeding is recommended. Consider therapy modification

Erythromycin (Systemic): May diminish the antiplatelet effect of Clopidogrel. Monitor therapy

Esomeprazole: May diminish the antiplatelet effect of Clopidogrel. Esomeprazole may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Clopidogrel prescribing information recommends avoiding concurrent use with esomeprazole. Rabeprazole or pantoprazole may be lower-risk alternatives to esomeprazole. Consider therapy modification

FluvoxaMINE: May enhance the adverse/toxic effect of Clopidogrel. Specifically, the risk for bleeding may be increased. FluvoxaMINE may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Grapefruit Juice: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Advise patients receiving clopidogrel to minimize consumption of grapefruit and grapefruit juice. Consumption of three 200 mL glasses of grapefruit juice a day may substantially reduce clopidogrel antiplatelet effects. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Lansoprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Consider therapy modification

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Morphine (Liposomal): May diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Liposomal) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Consider therapy modification

Morphine (Systemic): May diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Systemic) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Omeprazole: May diminish the antiplatelet effect of Clopidogrel. Omeprazole may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Clopidogrel labeling recommends avoiding concurrent omeprazole due to a possible decrease in clopidogrel effectiveness. Rabeprazole or pantoprazole may be lower-risk alternatives to omeprazole. Consider therapy modification

PACLitaxel (Conventional): Clopidogrel may increase the serum concentration of PACLitaxel (Conventional). Monitor therapy

PACLitaxel (Protein Bound): Clopidogrel may increase the serum concentration of PACLitaxel (Protein Bound). Monitor therapy

Pantoprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Consider therapy modification

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Pioglitazone: Clopidogrel may increase the serum concentration of Pioglitazone. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

RABEprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Consider therapy modification

Repaglinide: Clopidogrel may increase the serum concentration of Repaglinide. Management: Avoid use of clopidogrel and repaglinide if possible; if the combination must be used, limit total repaglinide daily dose to no more than 4 mg. This is contraindicated in some non-US labeling. Consider therapy modification

Rifamycin Derivatives: May enhance the adverse/toxic effect of Clopidogrel. Specifically,clopidogrel antiplatelet effects may be enhanced. Monitor therapy

Rivaroxaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Rosuvastatin: Clopidogrel may increase the serum concentration of Rosuvastatin. Monitor therapy

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Selexipag: CYP2C8 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Selexipag. CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Selexipag. Management: If initiating selexipag in a patient on a moderate CYP2C8 inhibitor, consider a less frequent dosing regimen (ie, once daily). If initiating a moderate CYP2C8 inhibitor in a patient on selexipag, consider a selexipag dose reduction. Consider therapy modification

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Warfarin: Clopidogrel may enhance the anticoagulant effect of Warfarin. Consider therapy modification

The effectiveness of clopidogrel results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP-450) system, principally CYP2C19. Clopidogrel at recommended doses forms less of the active metabolite and has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 genes (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.

Adverse events have not been observed in animal reproduction studies. Information related to use during pregnancy is limited (Bauer 2012; DeSantis 2011; Myers 2011).

75 mg orally once a day

Uses: Prevention of atherothrombotic events in patients with a history of recent myocardial infarction, recent stroke, or established peripheral arterial disease.

Administration advice:
-This drug may be taken with or without food.
-Avoid concomitant use with omeprazole or esomeprazole. When a proton pump inhibitor is required, consider use of another acid reducing agent with minimal to no CYP450 2C19 inhibitory effect on the formation of this drug's active metabolite.
-Missed dose: A dose missed within 12 hours of its regularly scheduled time should be taken immediately; if more than 12 hours, the missed dose should be skipped and only the next regularly scheduled dose should be taken. Two doses of this drug should not be taken at the same time.

General:
-Platelets exposed to the active metabolite of this drug are affected for the remainder of their lifespan (approximately 7 to 10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover.

Monitoring:
-Hematologic: Signs and symptoms of bleeding

Patient advice:
-Inform patients of the increased risk of bleeding and bruising, and to report unanticipated, prolonged, or excessive bleeding, or blood in their stool/urine.
-Instruct patients to inform all healthcare providers, including dentists, that they are taking this drug, due to the increased risk of bleeding during surgery and dental procedures.
-Instruct patients to speak with their physician if they are taking any prescription or over the counter medications.
-Warn the patients of the symptoms of thrombotic thrombocytopenic purpura, and to seek medical attention immediately if they occur.

• Clopidogrel inhibits the way platelets clump together (aggregate) to form clots.
• Its activity is thought to be due to its active metabolite, which inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor which indirectly inhibits platelet aggregation. This action is irreversible.
• By inhibiting platelet aggregation, blood flows more freely around the body.
• Clopidogrel belongs to the class of medicines known as P2Y12 inhibitors. It is also a type of antiplatelet medicine.

• Clopidogrel may be used for the treatment of unstable angina and for certain types of heart attack (myocardial infarction) to reduce the risk of stroke or heart attack. Clopidogrel should be administered in conjunction with aspirin.
• May also be given to people with established peripheral arterial disease or with a recent history of heart attacks or stroke to reduce the risk of further heart attacks or stroke.
• Can be administered as a loading dose (a bigger than normal, one-off dose) if an antiplatelet effect is needed within hours. Otherwise, it takes several days for the full antiplatelet effect of clopidogrel to develop with usual dosages.
• The dosage of clopidogrel does not need adjusting in people with liver disease.
• Generic clopidogrel is available.

• Clopidogrel is rapidly absorbed but has to undergo metabolism via CYP2C19 enzymes in the liver to its active form. People who are poor metabolizers at CYP2C19 will have a poor response to clopidogrel.
• Even though the active form of clopidogrel doesn't last for very long in the body, its effect on platelets lasts for the lifetime of the platelet. (7 to 10 days). Some inhibition of platelet clotting is seen within two hours of taking the drug; however, it takes between three to seven days of regular clopidogrel dosing to reach its maximal effect. Bleeding time and platelet aggregation return to baseline values within 5 days of treatment discontinuation.
• In the event that the antiplatelet effect of clopidogrel needs to be reversed, platelet transfusions may be administered; However, these are less effective if given within 4 hours of a loading dose or within 2 hours of a maintenance dose of clopidogrel.

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