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Eptifibatide

Pronunciation

(ep TIF i ba tide)

Index Terms

  • Intrifiban

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Integrilin: 75 mg/100 mL (100 mL); 20 mg/10 mL (10 mL); 200 mg/100 mL (100 mL)

Generic: 75 mg/100 mL (100 mL); 20 mg/10 mL (10 mL)

Solution, Intravenous [preservative free]:

Generic: 75 mg/100 mL (100 mL); 20 mg/10 mL (10 mL); 200 mg/100 mL (100 mL)

Brand Names: U.S.

  • Integrilin

Pharmacologic Category

  • Antiplatelet Agent, Glycoprotein IIb/IIIa Inhibitor

Pharmacology

Eptifibatide is a cyclic heptapeptide which blocks the platelet glycoprotein IIb/IIIa receptor, the binding site for fibrinogen, von Willebrand factor, and other ligands. Inhibition of binding at this final common receptor reversibly blocks platelet aggregation and prevents thrombosis.

Excretion

Primarily urine (as eptifibatide and metabolites)

Clearance: Total body: ~55 mL/kg/hour; Renal: ~50% of total body clearance in healthy subjects

Onset of Action

Immediate after initial bolus (>80% inhibition of ADP-induced aggregation achieved 5 minutes after bolus dose); maximal effect achieved within 1 hour (Gilchrist, 2001; Tardiff, 2001)

Duration of Action

Platelet function restored ~4 to 8 hours following discontinuation (Tardiff, 2001)

Half-Life Elimination

~2.5 hours

Protein Binding

~25%

Special Populations: Renal Function Impairment

Clearance reduced approximately 50% and steady-state plasma levels are approximately doubled in patients with moderate to severe renal function impairment (CrCl less than 50 mL/minute).

Special Populations: Elderly

Higher plasma levels and lower total body clearance.

Use: Labeled Indications

Acute coronary syndrome: Treatment of patients with acute coronary syndrome (unstable angina/non-ST-segment elevation myocardial infarction [UA/NSTEMI]), including patients who are to be managed medically and those undergoing percutaneous coronary intervention (PCI)

Percutaneous coronary intervention: Treatment of patients undergoing PCI, including those undergoing intracoronary stenting.

Use: Unlabeled

To support primary PCI during ST-elevation myocardial infarction; elective PCI for stable ischemic heart disease

Contraindications

Hypersensitivity to eptifibatide or any component of the formulation; active abnormal bleeding within the previous 30 days or a history of bleeding diathesis; history of stroke within 30 days or a history of hemorrhagic stroke; severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) not adequately controlled on antihypertensive therapy; major surgery within the preceding 6 weeks; current or planned administration of another parenteral GP IIb/IIIa inhibitor; dependency on hemodialysis

Canadian labeling: Additional contraindications (not in U.S. labeling): PT >1.2 times control or INR ≥2.0; known history of intracranial disease (eg, neoplasm, arteriovenous malformation, aneurysm); severe renal impairment ( CrCl <30 mL/minute); thrombocytopenia (<100,000 cells/mm3); clinically significant liver disease

Dosing: Adult

Acute coronary syndrome: IV: 180 mcg/kg bolus (maximum: 22.6 mg) administered as soon as possible following diagnosis, followed by a continuous infusion of 2 mcg/kg/minute (maximum: 15 mg/hour) until hospital discharge or initiation of CABG surgery (discontinue ≥2 to 4 hours before surgery (ACCF/AHA [Hillis, 2011]), up to 72 hours. If PCI performed during initial 72 hours, maintain continuous infusion at the time of PCI and continue until hospital discharge or for up to 18 to 24 hours, whichever comes first (total infusion time ≤96 hours). Concurrent aspirin and heparin therapy (target aPTT 50 to 70 seconds) are recommended. Note: If UA/NSTEMI, administration ≥12 hours before angiography was shown not to be superior to provisional use at the time of PCI and has a higher incidence of bleeding (Giugliano, 2009).

Percutaneous coronary intervention (PCI) with or without stenting: IV: 180 mcg/kg bolus (maximum: 22.6 mg) administered immediately before the initiation of PCI, followed by a continuous infusion of 2 mcg/kg/minute (maximum: 15 mg/hour). A second 180 mcg/kg bolus (maximum: 22.6 mg) should be administered 10 minutes after the first bolus. Infusion should be continued until hospital discharge or for up to 18 to 24 hours, whichever comes first; shorter infusion durations (ie, <2 hours) may be considered for nonemergent uncomplicated PCI in patients adequately pretreated with clopidogrel (Fung, 2007). Preprocedural aspirin and heparin therapy (ACT 200 to 250 seconds during PCI) and daily aspirin are recommended. Heparin infusion after PCI is discouraged. In patients who undergo CABG surgery, discontinue infusion ≥2 to 4 hours prior to surgery (ACCF/AHA [Hillis, 2011]).

Primary percutaneous coronary intervention (PCI) during ST-elevation myocardial infarction with or without stenting or pretreatment with clopidogrel (off-label use): IV: Bolus of 180 mcg/kg (maximum: 22.6 mg) administered at the time of PCI, followed by a continuous infusion of 2 mcg/kg/minute (maximum: 15 mg/hour) in combination with heparin or bivalirudin. A second 180 mcg/kg bolus (maximum: 22.6 mg) should be administered 10 minutes after the first bolus (ACCF/AHA [O'Gara, 2013]). Infusion was continued for 24 hours in one study (Zeymer, 2010).

Dosing: Geriatric

Refer to adult dosing. No dosing adjustment for the elderly appears to be necessary; adjust carefully to renal function.

Dosing: Renal Impairment

Note: The Cockcroft-Gault equation using actual body weight should be used to estimate renal function.

Acute coronary syndrome:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl <50 mL/minute: 180 mcg/kg bolus (maximum: 22.6 mg) administered as soon as possible following diagnosis, followed by a continuous infusion of 1 mcg/kg/minute (maximum: 7.5 mg/hour)

End-stage renal disease (ie, dialysis dependent): Use is contraindicated.

Percutaneous coronary intervention (PCI) with or without stenting:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl <50 mL/minute: 180 mcg/kg bolus (maximum: 22.6 mg) administered immediately before the initiation of PCI and followed by a continuous infusion of 1 mcg/kg/minute (maximum: 7.5 mg/hour). Administer a second 180 mcg/kg (maximum: 22.6 mg) bolus 10 minutes after the first bolus.

End-stage renal disease (ie, dialysis dependent): Use is contraindicated.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Administration

Bolus dose should be withdrawn from the 10 mL vial into a syringe and administered by IV push. Begin continuous infusion (using an IV infusion pump) immediately following bolus administration, administered undiluted directly from the 100 mL vial. The 100 mL vial should be spiked with a vented infusion set.

Compatibility

Stable in NS (infusion may contain up to 60 mEq/L KCl), D5NS (infusion may contain up to 60 mEq/L KCl).

Y-site administration: Incompatible with acyclovir, furosemide, phenytoin

Storage

Vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F). Vials can be kept at room temperature for 2 months, after which they must be discarded. Protect from light until administration. Do not use beyond the expiration date. Discard any unused portion left in the vial.

Drug Interactions

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

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

Apixaban: Agents with Antiplatelet Properties 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. Monitor therapy

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

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

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

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

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

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

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

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

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

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

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

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

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

Adverse Reactions

Frequency not always defined. Bleeding is the major drug-related adverse effect. Access site is often primary source of bleeding complications. Incidence of bleeding is also related to heparin intensity. Patients weighing <70 kg may have an increased risk of major bleeding.

>10%: Hematologic: & oncologic: Hemorrhage (major: 1% to 11%; minor: 3% to 14%; transfusion required: 2% to 13%)

1% to 10%:

Cardiovascular: Hypotension (≤7%)

Hematologic & oncologic: Thrombocytopenia (1% to 3%; includes acute profound thrombocytopenia, immune-mediated thrombocytopenia)

Local: Injection site reaction

<1% (Limited to important or life-threatening): Anaphylaxis, cerebrovascular accident, gastrointestinal hemorrhage, intracranial hemorrhage, pulmonary hemorrhage

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: The most common complication is bleeding, including retroperitoneal, pulmonary, and spontaneous GI and/or GU bleeding; monitor closely for bleeding, especially the arterial access site for the cardiac catheterization. Risk factors for bleeding include older age, a history of bleeding disorders, and concomitant use of drugs that increase the risk of bleeding (thrombolytics, oral anticoagulants, NSAIDs, and/or P2Y12 inhibitors). Patients <70 kg may be at greater risk for major and minor bleeding. Minimize invasive procedures, including arterial and venous punctures, IM injections, and the use of urinary catheters, nasotracheal intubation and nasogastric tubes.

• Hypersensitivity: Hypersensitivity reactions have occurred, including anaphylaxis and urticaria.

• Thrombocytopenia: Acute, profound thrombocytopenia (immune-mediated and nonimmune mediated) has occurred and may occur within 24 hours of initiation (Cheema, 2006; Coons, 2005; Nagge, 2003; Rezkalla, 2003; Salengro, 2003). Platelet counts should recover rapidly (within 1-5 days) after discontinuation. Use with extreme caution in patients with platelet counts <100,000/mm3 (contraindicated in the Canadian labeling). If platelet count decreases to <100,000/mm3 during therapy, discontinue eptifibatide and heparin if administered concurrently. Specific management guidelines for GP IIb/IIIa induced thrombocytopenia have been published (Huxtable, 2006; Llevadot, 2000).

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal dysfunction (estimated CrCl <50 mL/minute, using Cockcroft-Gault equation); dosage adjustment required. Use is contraindicated in patients dependent upon hemodialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Sheath removal: Prior to pulling the sheath, heparin should be discontinued for 3 to 4 hours and ACT should be <180 seconds or aPTT <50 seconds. Of note, full dose anticoagulation is no longer used after successful PCI procedures (ACCF/AHA/SCAI [Levine, 2011]). Use standard compression techniques after sheath removal. Monitor the site closely afterwards for further bleeding.

• Surgery: Discontinue ≥2 to 4 hours prior to coronary artery bypass graft surgery (Hillis, 2011).

Monitoring Parameters

Coagulation parameters, signs/symptoms of excessive bleeding. Laboratory tests at baseline and monitoring during therapy: hematocrit and hemoglobin, serum creatinine, PT/aPTT (maintain aPTT between 50-70 seconds unless PCI is to be performed), and ACT with PCI (maintain ACT between 200-300 seconds during PCI). Platelet count recommended at 2-4 hours after initiation, and at 24 hours or prior to discharge, whichever is first.

Assess sheath insertion site and distal pulses of affected leg every 15 minutes for the first hour and then every 1 hour for the next 6 hours. Arterial access site care is important to prevent bleeding. Care should be taken when attempting vascular access that only the anterior wall of the femoral artery is punctured, avoiding a Seldinger (through and through) technique for obtaining sheath access. Femoral vein sheath placement should be avoided unless needed. While the vascular sheath is in place, patients should be maintained on complete bedrest with the head of the bed at a 30° angle and the affected limb restrained in a straight position.

Observe patient for mental status changes, hemorrhage, assess nose and mouth mucous membranes, puncture sites for oozing, ecchymosis and hematoma formation, and examine urine, stool and emesis for presence of occult or frank blood; gentle care should be provided when removing dressings.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that will not stop) or injection site irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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