clopidogrel

General

Genetic Implications:

Pronunciation:
kloh-pid-oh-grel

Trade Name(s)

• Plavix

Ther. Class.

antiplatelet agents

Pharm. Class.

platelet aggregation inhibitors

Indications

• Acute coronary syndrome (ST-segment elevation MI, non-ST-segment elevation MI, or unstable angina).
• Patients with established peripheral arterial disease, recent MI, or recent stroke.

Action

Inhibits platelet aggregation by irreversibly inhibiting the binding of ATP to platelet receptors.

Therapeutic Effect(s):

Reduction in risk of MI and stroke.

Pharmacokinetics

Absorption: Well absorbed following oral administration; rapidly metabolized to an active antiplatelet compound. Parent drug has no antiplatelet activity.

Distribution: Unknown.

Protein Binding: Clopidogrel:  98%;  active metabolite:  94%.

Metabolism and Excretion: Rapidly and extensively converted by the liver via the CYP2C19 isoenzyme to its active metabolite, which is then eliminated 50% in urine and 45% in feces;  2% of White people, 4% of Black people, and 14% of Asian people have CYP2C19 genotype, which results in reduced metabolism of clopidogrel (poor metabolizers) into its active metabolite (may result in ↓ antiplatelet effects).

Half-life: 6 hr (active metabolite 30 min).

TIME/ACTION PROFILE (effects on platelet function)

Contraindication/Precautions

Contraindicated in:

• Hypersensitivity to clopidogrel or prasugrel;
• Pathologic bleeding (peptic ulcer, intracranial hemorrhage);
• Concurrent use of omeprazole or esomeprazole;
•   CYP2C19 poor metabolizers.

Use Cautiously in:

• Patients at risk for bleeding (trauma, surgery, or other pathologic conditions);
• History of GI bleeding/ulcer disease;
• Severe hepatic impairment;
• Hypersensitivity to another thienopyridine (prasugrel);
• OB:  Use should not be withheld if needed for emergent treatment of stroke or MI during pregnancy. Discontinue use 5–7 days prior to labor, delivery, or neuraxial blockade, if possible, due to ↑ risk of maternal bleeding and hemorrhage;
• Lactation:  Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
• Pedi:  Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: chest pain, edema, hypertension

Derm: ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS, DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS, pruritus, purpura, rash, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

EENT: epistaxis

GI: abdominal pain, diarrhea, dyspepsia, gastritis, GI BLEEDING

Hemat: BLEEDING, NEUTROPENIA, THROMBOTIC THROMBOCYTOPENIC PURPURA

Metabolic: hypercholesterolemia

MS: arthralgia, back pain

Neuro: depression, dizziness, fatigue, headache

Resp: cough, dyspnea, eosinophilic pneumonia

Misc: fever, HYPERSENSITIVITY REACTIONS (including anaphylaxis)

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  Eptifibatide,  tirofiban,  aspirin,  dipyridamole,  NSAIDs,  heparin,  LMWHs,  thrombolytic agents,  SSRIs,  SNRIs, or  warfarin  may ↑ risk of bleeding.
•  Strong CYP2C19 inducers, including  rifampin, may ↑ risk of bleeding; avoid concurrent use.
• May ↑ levels and risk of toxicity of  phenytoin,  repaglinide,  tamoxifen,  torsemide,  fluvastatin, and many  NSAIDs ; avoid concurrent use with  repaglinide.
•  CYP2C19 inhibitors, including  omeprazole, or  esomeprazole, may ↓ antiplatelet effects; avoid concurrent use; may consider using  H₂  antagonist  or  pantoprazole.
•  Opioids  may ↓ absorption of clopidogrel and its active metabolite and ↓ its antiplatelet effects; consider using parenteral antiplatelet in patients with acute coronary syndrome if concurrent use of opioids needed.

Drug-Natural Products:

↑ bleeding risk with  anise,  arnica,  chamomile,  clove,  fenugreek,  feverfew,  garlic,  ginger,  ginkgo,  Panax ginseng , and others.

Route/Dosage

Acute Coronary Syndrome

PO (Adults): 300 mg initially; then 75 mg once daily; aspirin 75–325 mg once daily should be given concurrently.

Recent MI, Stroke, or Peripheral Arterial Disease

PO (Adults): 75 mg once daily.

Availability (generic available)

Tablets: 75 mg, 300 mg

Assessment

• Assess for signs and symptoms of emerging cardiovascular disease such as MI (chest pain, dyspnea, diaphoresis, dizziness, nausea), stroke (weakness, slurred speech, confusion, dizziness), and peripheral vascular disease periodically during therapy.
• Monitor for signs and symptoms of bleeding (pallor of skin and conjunctiva, fatigue, weakness, easy bruising, nosebleeds, bleeding gums, hematuria), including GI bleeding (hematochezia, melena, coffee ground emesis).
• Monitor for signs and symptoms of thrombotic thrombocytopenic purpura (thrombocytopenia, microangiopathic hemolytic anemia, neurologic findings, renal impairment, fever). May rarely occur, even after short exposure (<2 wk). Requires prompt treatment.
• Monitor for development of severe cutaneous adverse reactions, including SJS and TEN. If a severe cutaneous adverse reaction is suspected, interrupt therapy.
• Monitor for signs and symptoms of exanthematous pustulosis (itching; burning; fever; nonfollicular pustular rash on a red base in the armpits or groin, behind the knees, on the inner elbows, or on the face, which then spreads to other areas), which can occur within 1–2 days of taking the medication but can take up to 2 wk; if suspected, discontinue clopidogrel.

Lab Test Considerations:

Monitor CBC with differential periodically during therapy. Neutropenia and thrombocytopenia may rarely occur.

• May ↑ serum bilirubin, hepatic enzymes, total cholesterol, nonprotein nitrogen, and uric acid concentrations.

Implementation

• Do not confuse Plavix with Paxil or Pradaxa.
•  Antiplatelet effectiveness depends on activation by the CYP450 system, primarily CYP2C19. Patients homozygous for nonfunctional CYP2C19 alleles produce less active metabolite, reducing efficacy of clopidogrel; prevalence is higher in Asian patients. Testing can identify poor metabolizers, and alternative P2Y12 inhibitors should be considered for these patients.
• Discontinue clopidogrel 5–7 days before planned surgical procedures. If clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation of therapy may increase risk of cardiovascular events.
• PO Administer once daily without regard to food.
• Nasogastric administration in critically ill patients after CPR ↑ risk of ↓ bioavailability.

Patient/Family Teaching

• Explain the purpose and side effects of clopidogrel to patient. Instruct patient to take medication exactly as directed. Take missed doses as soon as possible unless almost time for next dose; do not double doses. Do not discontinue clopidogrel without consulting health care professional; may ↑ risk of cardiovascular events. Advise patient to read the  Medication Guide  before starting clopidogrel and with each Rx refill in case of changes.
• Advise patient to notify health care professional promptly if signs and symptoms of bleeding (unexpected bleeding or bleeding that lasts a long time; blood in urine [pink, red, or brown urine], red or black tarry stools, bruises without known cause or that get larger; coughing up blood or blood clots; vomiting blood or vomit looks like coffee grounds); fever, weakness, chills, sore throat, rash, unusual bleeding or bruising, extreme skin paleness, purple skin patches, yellowing of skin or eyes, or neurological changes occur.
• Advise patients of signs and symptoms of skin reactions (fever, flu-like symptoms, mucosal lesions, progressive skin rash, swollen lymph nodes).
• Advise patient to notify health care professional of medication regimen prior to treatment or surgery.
• Caution patient to avoid taking omeprazole or esomeprazole during therapy. Consult health care professional for other options.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking any other Rx, OTC, or herbal products, especially those containing aspirin or NSAIDs or proton pump inhibitors.
• Rep:  Advise women of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Therapy should not be withheld because of potential concerns regarding effects of clopidogrel on the fetus. Use during labor or delivery ↑ risk of maternal bleeding and hemorrhage. Avoid neuraxial blockade during clopidogrel use due to risk of spinal hematoma. When possible, discontinue clopidogrel 5–7 days prior to labor, delivery, or neuraxial blockade.

Evaluation/Desired Outcomes

Prevention of stroke, MI, and vascular death in patients at risk.