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Integrilin

Pronunciation

Generic Name: Eptifibatide
Class: Platelet-Aggregation Inhibitors
Chemical Name: Cyclic(1 - 6) - disulfide - N6amidino - N2 - (3 - mercaptopropionyl) - l - lysylglycyl - l - α - aspartyl - l - tryptophyl - l - prolyl - l - cysteinamide
Molecular Formula: C35H49N11O9S2
CAS Number: 148031-34-9

Introduction

Platelet-aggregation inhibitor;1 2 3 10 11 71 a platelet glycoprotein (GP IIb/IIIa)-receptor inhibitor.2 6 7 11 14 26 37 44 48 50

Uses for Integrilin

Unstable Angina and Non-ST-Segment-Elevation MI (NSTEMI)

Adjunct to anticoagulant therapy (e.g., heparin [referring throughout this monograph to unfractionated heparin], low molecular weight heparin [LMWH]), aspirin, and/or clopidogrel to reduce risk of acute cardiac ischemic events (death and/or MI) in patients with non-ST-segment-elevation acute coronary syndrome (i.e., unstable angina or NSTEMI) who are managed medically or with PCI.1 4 8 40 72 113

Adjunctive therapy with a GP IIb/IIIa-receptor inhibitor can reduce the incidence of cardiac ischemic events, including subsequent MI and death, in patients with non-ST-segment-elevation acute coronary syndromes.16 40 43 49 52 56

The American College of Cardiology Foundation (ACCF) and AHA recommend either clopidogrel or IV administration of a GP IIb/IIIa-receptor inhibitor in addition to aspirin therapy prior to diagnostic angiography (“upstream”) in patients in whom an initial invasive management strategy is planned; eptifibatide or tirofiban is the preferred GP IIb/IIIa inhibitor for this use.991 Abciximab is recommended only if there is no appreciable delay before angiography and PCI is likely to be performed.991

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The American College of Chest Physicians (ACCP) states that a clear risk-benefit profile has not been established for use of GP IIb/IIIa-receptor inhibitors in patients with acute coronary syndromes who are not routinely scheduled for early revascularization.1016

Eptifibatide and tirofiban not recommended by AHA in women with non-ST-segment-elevation acute coronary syndromes who are at lower risk for adverse cardiac events and are managed with a conservative strategy, because of little demonstrated benefit and possible detrimental effects.128

Acute Ischemic Complications of PCI

Adjunct to anticoagulant therapy (heparin, LMWH), aspirin and/or clopidogrel to reduce risk of acute ischemic complications (death, MI, and/or need for urgent revascularization procedures) in patients undergoing PCI, including coronary artery stenting.1 4 8 10 11 16 43

ACCF, AHA, the Society for Cardiovascular Angiography and Interventions (SCAI), and other experts currently do not recommend routine use of GP IIb/IIIa-receptor inhibitors in patients with STEMI undergoing PCI; however, selective use of these drugs as an adjunct to heparin may be reasonable in certain high-risk patients (e.g., those with large anterior MI and/or large thrombus).994 1016

ACCF/AHA/SCAI state that administration of a GP IIb/IIIa-receptor inhibitor at the time of PCI as an adjunct to heparin may be particularly useful in patients with unstable angina/NSTEMI who have high-risk features (e.g., elevated troponin) and are not receiving bivalirudin, and are not adequately pretreated with clopidogrel.994

Regarding choice of GP IIb/IIIa-receptor inhibitor in patients undergoing PCI, IV abciximab, “double-bolus” IV eptifibatide, and high-dose tirofiban by direct IV injection all produce a high degree of platelet inhibition and reduce ischemic complications.994

Adjunctive Therapy During Thrombolysis to Prevent Reocclusion

Has been used as an adjunct to thrombolytic therapy (e.g., alteplase, tenecteplase) in a limited number of patients to prevent coronary artery reocclusion following acute MI.6 8 13 14 34 43

Integrilin Dosage and Administration

General

  • In patients with unstable angina and NSTEMI, administer as soon as possible following diagnosis.1 8 72

  • Discontinue prior to CABG.1

Adjunctive Antithrombotic Therapy: General Considerations

  • Used in conjunction with aspirin and heparin in clinical studies.1 4 8 10 12 13 14 19 40

  • Dosage of heparin required to maintain an appropriate activated clotting time (ACT) during concomitant therapy with eptifibatide may be lower than with heparin monotherapy.19 72 113 994 (See Specific Drugs under Interactions.)

  • Caution when used in patients requiring thrombolytic therapy.1 (See Specific Drugs under Interactions.)

Adjunctive Antithrombotic Therapy When Used in Management of Unstable Angina and NSTEMI

  • Aspirin: Manufacturer recommends 160–325 mg initially and daily thereafter.1

  • Heparin sodium during medical management: In patients weighing ≥70 kg, 5000 units (IV loading dose) followed by continuous IV infusion of 1000 units/hour.1 In patients weighing <70 kg, 60 units/kg followed by continuous IV infusion of 12 units/kg per hour.1 Adjust dose to maintain a target aPTT of 50–70 seconds.1 (See Laboratory Monitoring under Cautions.)

  • Heparin sodium in patients undergoing PCI: Administer multiple IV injections of unfractionated heparin based on ACT determinations during PCI to achieve and maintain an ACT of ≥200 seconds.1 117 118

Adjunctive Antithrombotic Therapy When Used to Reduce Risk of Acute Ischemic Complications of PCI

  • Aspirin: Manufacturer recommends 160–325 mg 1–24 hours prior to PCI and daily thereafter.1 ACCF/AHA/SCAI recommends that aspirin 325 mg be given prior to PCI in patients not already receiving maintenance aspirin therapy.994 Patients already receiving maintenance aspirin therapy should receive a dose of 81–325 mg before the procedure.994

  • P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist: A loading dose of clopidogrel, prasugrel, or ticagrelor also is recommended prior to PCI in patients undergoing stent placement.994

  • Heparin: 50–70 units/kg 6 hours prior to PCI (target ACT of ≥200 seconds).1 Administer additional injections during PCI to maintain an ACT of 200–300 seconds.1 (See Laboratory Monitoring under Cautions.) Consider a lower dosage of heparin in women and geriatric patients receiving a GP IIb/IIIa-receptor inhibitor to decrease the increased risk of minor bleeding.128 Postprocedural use of heparin not recommended.1 10 26

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV injection followed by IV infusion using a controlled-infusion device (e.g., pump).1

For IV injection, withdraw appropriate dose from the 10-mL vial and administer undiluted.1 71

For continuous IV infusion, spike the 100-mL vial with a vented infusion set; center spike within the circle on stopper top.1 Administer solution directly from vial.1 8 71

Discard unused portion.1

Dilution

Administer undiluted.1

Rate of Administration

For IV injection, administer over 1–2 minutes.1 71

Dosage

Adults

Unstable Angina and NSTEMI
IV

180 mcg/kg by IV injection as soon as possible following diagnosis, followed by IV infusion of 2 mcg/kg per minute until hospital discharge or initiation of CABG, or for ≤72 hours.1 8 72

If patient undergoes PCI while receiving eptifibatide, continue infusion (at 2 mcg/kg per minute) until hospital discharge or for ≤18–24 hours after procedure, whichever comes first, up to a maximum of 96 hours.1

Acute Ischemic Complications of PCI
IV

180 mcg/kg by IV injection immediately before initiation of PCI, immediately followed by IV infusion of 2 mcg/kg per minute and a second IV injection of 180 mcg/kg 10 minutes after the first IV injection.1 117 118

Continue infusion (at 2 mcg/kg per minute) until hospital discharge or for ≤18–24 hours, whichever comes first.1 A minimum infusion period of 12 hours is recommended.1

Prescribing Limits

Adults

Unstable Angina and NSTEMI
IV

Maximum IV infusion of 72 hours.1 8 72

In patients undergoing PCI, maximum IV infusion of 96 hours.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.8

Renal Impairment

Unstable Angina and NSTEMI

No dosage adjustment required in patients with mild to moderate renal impairment (Clcr ≥50 mL/minute).1

In patients with Clcr <50 mL/minute, 180 mcg/kg by IV injection as soon as possible following diagnosis, followed by IV infusion of 1 mcg/kg per minute.1

Acute Ischemic Complications of PCI

In patients with Clcr <50 mL/minute, 180 mcg/kg by IV injection immediately before initiation of PCI, followed by IV infusion of 1 mcg/kg per minute and a second IV injection of 180 mcg/kg 10 minutes after the first IV injection.1

Geriatric Patients

No dosage adjustment was made for geriatric patients in clinical trials.1 (See Geriatric Use under Cautions.)

Cautions for Integrilin

Contraindications

  • History of bleeding diathesis1 10 13 or active abnormal bleeding within previous 30 days.1 10 12 13

  • Severe uncontrolled hypertension (SBP >200 mm Hg or DBP >110 mm Hg with antihypertensive therapy).1 10 13

  • Recent (within 6 weeks) major surgery.1 10 12 13

  • History of stroke within 30 days or any history of hemorrhagic stroke.1 10 12 13

  • Current or planned therapy with another GP IIb/IIIa-receptor inhibitor.1

  • Patients undergoing renal dialysis.1

  • Known hypersensitivity to eptifibatide or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Bleeding

Risk of major bleeding (e.g., intracranial hemorrhage, GU or GI bleeding, bleeding at femoral vascular access site)1 8 17 71 85 117 and minor bleeding (e.g., spontaneous gross hematuria, spontaneous hematemesis);1 8 17 72 85 may require blood or platelet transfusions.1 10 117 (See Bleeding Precautions and see Laboratory Monitoring under Cautions.) Patients weighing <70 kg at increased risk of major bleeding.1

If bleeding cannot be controlled by pressure, discontinue eptifibatide and concomitant heparin immediately.1

Use not recommended in patients with hematocrit <30%.8 72

Thrombocytopenia

Thrombocytopenia reported.110 111 Severe thrombocytopenia (platelet count <20,000/mm3) reported less frequently than with abciximab.8 26 40 55 72 93 99 111

Determine platelet counts prior to treatment and periodically (e.g., daily)72 during concomitant eptifibatide and heparin therapy.8 72 88 Consider possibility of heparin-induced thrombocytopenia in patients receiving concomitant heparin therapy.29 55 93 107 111

If platelet count decreases to <100,000/mm3, discontinue eptifibatide and heparin and initiate appropriate treatment and monitoring.1 Consider platelet transfusions for management of severe thrombocytopenia.55 93 106 111 112

No clinical experience with eptifibatide in patients with platelet counts <100,000/mm3.1

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis reported.1

Major Toxicities

General Precautions

Bleeding Precautions

To reduce risk of bleeding, adhere to strict anticoagulation guidelines; use a short course of low-dose, weight-adjusted heparin; avoid vascular and other trauma; carefully manage vascular (e.g., femoral artery) access site; and monitor all potential bleeding sites during and following treatment.1 26 29 43 52 97 107 109 Manufacturer recommends that concomitant thrombolytic therapy be used with caution.1

In patients undergoing PCI, use caution in the placement, maintenance, and removal of vascular access sheath.1 26 44 52 When inserting sheath, puncture only anterior wall of femoral artery; avoid Seldinger (through and through) technique.8 26 72 Observe appropriate precautions while sheath is in place (e.g., complete bed rest, elevation of head ≤30°, restrain limb in which sheath is inserted, frequent monitoring of vascular access site and distal pulse in the involved limb).26 27 72 Following PCI, consider early sheath removal (during eptifibatide IV infusion).1 Prior to removal of sheath, discontinue heparin for 3–4 hours and allow aPTT to return to <45 seconds or ACT to <150–180 seconds.1 26 27 35 44 Discontinue eptifibatide and heparin and achieve hemostasis (by applying pressure to femoral artery for at least 20–30 minutes after sheath removal26 27 ) at least 2–4 hours before hospital discharge.1 Measure and monitor hematomas for enlargement.8 26 72

To avoid vascular and other trauma, minimize needle punctures (e.g., arterial, IM, IV, lumbar, sub-Q, intradermal), cutdown sites, and use of nasotracheal intubation, nasogastric tubes, urinary catheters, and automatic BP cuffs26 during and following treatment;1 8 72 avoid establishment of IV access at noncompressible sites (e.g., subclavian or jugular veins);1 consider using an indwelling venipuncture device (e.g., heparin lock) for drawing blood; document and monitor vascular puncture sites; and remove dressings gently and carefully.8 26 72

Laboratory Monitoring

Prior to administration, obtain hematocrit or hemoglobin, platelet count, Scr, and PT or aPTT.1 In patients undergoing PCI, also obtain ACT prior to administration.1

In patients with unstable angina or non-ST-segment-elevation MI undergoing medical management, target aPTT between 50–70 seconds.1

In patients undergoing PCI the manufacturer recommends targeting ACT between 200–300 seconds during PCI.1

Monitor aPTT or ACT prior to arterial sheath removal; do not remove sheath unless aPTT ≤45 seconds or ACT <150–180 seconds.1 26 27 35 44

Specific Populations

Pregnancy

Category B.1

Lactation

Not known whether eptifibatide is distributed into milk.1 Use with caution.1

Pediatric Use

Safety and efficacy not established.1 8

Geriatric Use

No substantial differences in efficacy relative to younger adults.1 However, increased incidence of bleeding complications.1

Hepatic Impairment

Use contraindicated in patients with hepatic disease severe enough to alter synthesis of coagulation factors.8

Renal Impairment

Decreased clearance and increased plasma concentrations in patients with moderate to severe renal impairment (estimated Clcr <50 mL/minute);1 reduced dosage recommended in such patients.1 (See Renal Impairment under Dosage and Administration.) Use contraindicated in patients undergoing renal dialysis.1

Common Adverse Effects

Bleeding,1 hypotension.1 8 43

Interactions for Integrilin

Specific Drugs

Drug

Interaction

Comments

Anticoagulants, oral

Potential increased risk of bleeding1

Use with caution1

Dipyridamole

Potential increased risk of bleeding1

Use with caution1

Enoxaparin

Pharmacokinetic or pharmacodynamic (e.g., effect on platelet aggregation) interaction unlikely1

GP IIb/IIIa-receptor inhibitors (abciximab, tirofiban)

Possible additive pharmacologic effects1 4

Avoid concomitant use1 4

Heparin

Possible additive effects on ACT19

Reduce dosage of heparin to maintain appropriate ACT19

NSAIAs

Potential increased risk of bleeding1

Use with caution1

Thrombolytics (e.g., alteplase, streptokinase)

Increased risk of bleeding, including that requiring blood transfusions1 5 34

Use with caution1 4 34 43 72

Integrilin Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved within 5 minutes and steady-state concentrations attained within 4–6 hours following IV administration.1 4 9 41 43

Onset

Maximal inhibition of platelet aggregation occurs within 15 minutes following IV administration and is rapidly reversible.1 8 12

Duration

Platelet aggregation usually returns to normal within 4–8 hours after discontinuing therapy.8 13 31 41 43

Special Populations

Steady-state plasma concentrations double in patients with moderate to severe renal impairment (estimated Clcr <50 mL/minute).1

Increased plasma concentrations in geriatric patients.1

Distribution

Extent

Not known whether eptifibatide is distributed into breast milk.1

Plasma Protein Binding

Approximately 25% (mainly albumin).1 8 41 43

Elimination

Metabolism

Principally metabolized to a less active metabolite;1 9 41 71 27% of dose is converted in plasma into naturally occurring amino acids.4 41

Elimination Route

Eliminated by renal (40–50% of total body clearance)1 8 9 71 and nonrenal mechanisms,9 41 43 71 mainly as parent drug and metabolites.1 In healthy men, approximately 98, 1.5, and 0.8% of a single dose was recovered in urine, feces, and breath carbon dioxide, respectively.9

May be removed by hemodialysis.1

Half-life

2.5–2.8 hours in patients with CAD;1 8 19 0.83–2.4 hours in healthy individuals.2 8 42 71

Special Populations

Clearance reduced by 50% in patients with moderate to severe renal impairment (estimated Clcr <50 mL/minute).1

Reduced total body clearance in geriatric patients.1

Stability

Storage

Parenteral

Injection

2–8°C.1 8 Protect from light.1 8

May store at room temperature (15–30°C) for ≤2 months.1 8

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

No incompatibilities observed with IV administration sets; no compatibility studies performed with polyvinyl chloride (PVC) bags.1

Solution Compatibility1

*Infusion may contain up to 60 mEq/L of potassium chloride.1

Compatible

Dextrose 5% and sodium chloride 0.9%*

Sodium chloride 0.9%*

Drug Compatibility1
Admixture CompatibilityHID

Compatible

Alteplase

Amiodarone HCl

Atropine

Bivalirudin

Dobutamine HCI

Heparin sodium

Lidocaine HCI

Meperidine HCI

Metoprolol tartrate

Midazolam HCI

Morphine sulfate

Nitroglycerin

Verapamil HCI

Incompatible

Furosemide

Actions

  • Binds selectively to platelet GP IIb/IIIa receptors and reversibly inhibits platelet aggregation (by preventing binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa receptors).1 2 3 4 7 8 16 37 71

  • Modest effect on hemostatic indices (e.g., bleeding times) and platelet function; normal hemostasis restored more rapidly than with abciximab.1 2 6 10 17 72

  • Usually does not affect PT or aPTT when administered as monotherapy.1

Advice to Patients

  • Risk of serious bleeding or hemorrhage.1

  • Importance of close laboratory monitoring.1

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Eptifibatide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV Use

2 mg/mL (20 mg)

Integrilin

Schering

0.75 mg/mL (75 mg)

Integrilin

Schering

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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