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Tirofiban

Class: Platelet-Aggregation Inhibitors
ATC Class: B01AC17
Chemical Name: N-(butylsulfonyl)-4-[4-(4-piperidyl)butoxy]-l-phenylalanine monohydrochloride monohydrate
Molecular Formula: C22H36N2O5S
CAS Number: 144494-65-5
Brands: Aggrastat

Introduction

Platelet-aggregation inhibitor;1 15 22 a platelet glycoprotein (GP IIb/IIIa)-receptor inhibitor.b

Uses for Tirofiban

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), 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), including those who are to receive medical management or to undergo PCI.1 5 6 21 91

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.5 6 11 35 36 42 46 51 71 72 73 80 83 84 85 91

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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-receptor inhibitor for this use.991

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

In patients undergoing PCI, ACCF, AHA, and the Society for Cardiovascular Angiography and Intervention (SCAI) state that administration of a GP IIb/IIIa-receptor inhibitor at the time of PCI may be used as an adjunct to heparin in those with high-risk features (e.g., elevated troponin) who 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

Tirofiban and eptifibatide not recommended by AHA in women with non-ST-segment elevation acute coronary syndromes who are at lower risk for adverse events and are managed with a conservative strategy, because of little demonstrated benefit and possible detrimental effects.109

ACCF, AHA, SCAI, and other experts currently do not recommend routine use of GP IIb/IIIa-receptor inhibitors in patients with ST-segment elevation MI (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

Tirofiban Dosage and Administration

General

  • Administer as soon as possible following diagnosis.21 91

  • Discontinue at least 4–6 hours prior to CABG.21 91

Adjunctive Antithrombotic Therapy

  • In clinical trials, almost all patients receiving tirofiban also received concomitant aspirin and/or heparin.1 5 6 11 14 Tirofiban and heparin may be administered through the same IV line.1

  • Aspirin: In clinical studies, patients received 300–325 mg daily for at least 48 hours after randomization or within 12 hours prior to PCI, unless the drug was contraindicated; some patients received aspirin indefinitely.1 5 6 11 14 ACCF/AHA/SCAI recommends aspirin 325 mg prior to PCI in patients not already receiving maintenance aspirin therapy.994 Patients already receiving maintenance aspirin therapy should receive 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 in patients undergoing PCI with stent placement.994

  • Heparin during medical management: In clinical studies, patients received an IV loading dose of 5000 units followed by continuous IV infusion of 1000 units/hour.1 5 6 (See Laboratory Monitoring under Cautions.)

  • Heparin prior to PCI: In clinical studies, patients undergoing PCI after at least 48 hours of medical management received an IV loading dose of 5000–7500 units followed by continuous IV infusion of 1000 units/hour titrated to an aPTT approximately 2 times the control value with additional IV injections of heparin as needed. (See Laboratory Monitoring under Cautions.)1 6

  • Heparin prior to urgent PCI: In a clinical study, patients at high risk for abrupt closure of the affected coronary artery who underwent urgent or emergency PCI received an IV loading dose of 10,000 units (body weight ≥70 kg) or 150 units/kg (body weight <70 kg).1 11 37 44 Additional injections during PCI were administered to maintain target activated clotting time (ACT) between 300–400 seconds.1 11 37 44

  • The manufacturer and other experts suggest use of lower dosages of concomitant IV heparin (50–70 units/kg) prior to PCI and targeted to an ACT of ≥200 seconds.1 18 35 44 53 71 74 77 80 81 95 96 (See Laboratory Monitoring under Cautions.)

  • Postprocedural use of heparin not recommended.6 11 42 52 53

Administration

IV Administration

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

Administer by IV infusion using either diluted injection concentrate or premixed injection in plastic (IntraVia™) containers.1 1

Discard unused portion.1

The plastic container of the premixed injection may be somewhat opaque because of moisture absorption during sterilization; this opacity will diminish gradually.1

Do not introduce additives into the injection container.1

Do not use the plastic IV container in series connections with other plastic containers; such use may result in air embolism.1

Dilution

Tirofiban hydrochloride injection concentrate for IV infusion must be diluted to 50 mcg/mL (the same concentration as the premixed injection) before administration.1

Prepare injection concentrate for infusion by withdrawing and discarding 50 or 100 mL of solution from a 250- or 500-mL bag, respectively, of 0.9% sodium chloride or 5% dextrose injection and replacing this volume with an equivalent volume (i.e., 50 or 100 mL, respectively) of tirofiban hydrochloride injection to achieve a final concentration of 50 mcg/mL.1 21

Alternatively, a vial labeled as containing 5 mg of tirofiban may be added to a 100 mL bag of 0.9% sodium chloride injection or 5% dextrose injection.1

Mix solutions well prior to infusion.1

Rate of Administration

Administer as a continuous infusion.1 20 21 91

Dosage

Available as tirofiban hydrochloride; dosage expressed in terms of tirofiban.1

Adults

Unstable Angina and NSTEMI
IV

Patients receiving medical therapy: IV loading dose of 0.4 mcg/kg per minute for 30 minutes given as soon as possible after diagnosis, followed by continuous IV infusion of 0.1 mcg/kg per minute for at least 24–48 hours.21 91

Patients who undergo PCI: IV loading dose of 0.4 mcg/kg per minute for 30 minutes followed by continuous IV infusion of 0.1 mcg/kg per minute given during angiography and for 12–24 hours after angioplasty or atherectomy.1 20 21 91

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 20

Renal Impairment

In patients with severe renal impairment (i.e., Clcr ≤30 mL/minute), decrease the usual loading and maintenance rate of infusion by 50%.1

Geriatric Patients

Dosage adjustment not required.1

Cautions for Tirofiban

Contraindications

  • Active internal bleeding or history of bleeding diathesis 1 5 6 14 20 21 91 within previous 30 days.1 20 21 91

  • History of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm.1 52

  • History of thrombocytopenia following prior exposure to tirofiban.1 5 6 11 20 52

  • History of stroke within 30 days or any history of hemorrhagic stroke.1 5 6 11 14 20 52

  • Recent (within 30 days) major surgery or severe physical trauma.1 5 20 52

  • History, symptoms, or findings suggestive of aortic dissection.1 20

  • Severe uncontrolled hypertension (SBP >180 or DBP >110 mm Hg).1 5 20

  • Concomitant therapy with another parenteral GP IIb/IIIa-receptor inhibitor.1 20

  • Acute pericarditis.1 20

  • Known hypersensitivity to tirofiban or any ingredient in the formulation.1 20

Warnings/Precautions

Warnings

Hematologic Effects

Risk of major bleeding (e.g., intracranial hemorrhage, GU or GI bleeding, bleeding at arterial access site) and minor bleeding (e.g., spontaneous gross hematuria, spontaneous hematemesis); may require blood or platelet transfusions.1 5 6 11 20 21 91 (See Bleeding Precautions and also see Laboratory Monitoring under Cautions.)

Pulmonary alveolar hemorrhage, spinal-epidural hematoma, retroperitoneal bleeding, and hemopericardium reported rarely.1

Fatal hemorrhage reported rarely.1

Use with caution in patients with platelet count <150,000/mm3, anemia (hemoglobin <10–12 g/dL), hemorrhagic retinopathy, and those requiring chronic hemodialysis.1 20 91

Use with caution in patients receiving other drugs that affect hemostasis (e.g., thrombolytic agents, oral anticoagulants, NSAIAs, dipyridamole, ticlopidine, and clopidogrel).1 20 21 91 (See Specific Drugs under Interactions.)

If bleeding cannot be controlled by pressure, discontinue tirofiban and concomitant heparin.1 20

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis and other severe allergic reactions reported on the first day of infusion, during initial treatment, and during readministration of the drug.1 21

Severe allergic reactions sometimes associated with severe thrombocytopenia (platelet counts <10,000/mm3).1

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 5 6 11 21 91

In patients undergoing PCI, use caution in the placement, maintenance, and removal of vascular access sheath; avoid femoral vein sheath placement.1 18 35 37 42 46 52 When inserting sheath, puncture only anterior wall of femoral artery; avoid Seldinger (through and through) technique.1 18 20 52 77 81 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).1 18 19 20 52 Following PCI, consider early sheath removal (during tirofiban 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 <180 seconds.1 11 14 20 30 41 52 53 70 Discontinue tirofiban and heparin and achieve hemostasis (by applying pressure to femoral artery for at least 20–30 minutes after sheath removal18 19 ) at least 4 hours before hospital discharge.1 20 Measure and monitor hematomas for enlargement.18

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,1 18 20 and automatic BP cuffs18 during and following treatment;1 18 avoid establishment of IV access at noncompressible sites (e.g., subclavian or jugular veins);1 18 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.18

Thrombocytopenia

Thrombocytopenia reported.1 5 32 37 43 44 45 50 52 Severe thrombocytopenia (platelet count <20,000/mm3) reported less frequently than with abciximab.18 30 32 35 37 44 50 53

Determine platelet counts prior to treatment and periodically (e.g., within the first 6 hours of the loading infusion, and daily thereafter) during concomitant tirofiban and heparin therapy.1 11 20 43 44 Consider possibility of pseudothrombocytopenia or heparin-induced thrombocytopenia in patients receiving concomitant heparin therapy.1 20 35 37 52 (See Thrombocytopenia under Cautions.)

If true thrombocytopenia is verified, discontinue tirofiban and initiate appropriate treatment and monitoring.1 Thrombocytopenia usually reversible following discontinuance of GP IIb/IIIa-receptor inhibitors and anticoagulant (heparin) therapy; consider platelet transfusions for the management of severe thrombocytopenia.35 37 43 52

Use with caution in patients with platelet count <150,000/mm3;1 20 contraindicated in patients with a history of thrombocytopenia following prior exposure to tirofiban.1 5 6 11 20 52

Laboratory Monitoring

Prior to administration, within the first 6 hours of the loading infusion and at least daily thereafter, obtain hematocrit and hemoglobin,1 11 20 35 43 44 and platelet counts.1 11 20 35 43 44

Closely monitor ACT or aPTT.1 30 52 70 Monitor aPTT 6 hours after the start of the heparin infusion and maintain at 50–70 seconds or approximately 2 times the control value unless PCI is to be performed.1 6 30 In patients undergoing PCI, measure the ACT.21 52 70 In patients undergoing PCI in clinical studies, ACT was maintained between 300–400 seconds during PCI;1 11 37 44 ACCP suggests targeting ACT between 200–250 seconds to reduce risk of major bleeding.1 18 35 44 53 71 74 77 80 81 95 96 Monitor aPTT or ACT prior to arterial sheath removal; do not remove sheath unless aPTT <45 seconds or ACT <180 seconds.1 30 41 53 70

Determine platelet counts prior to administration, within the first 6 hours of the loading infusion and at least daily thereafter.1 11 20 43 44 Perform additional platelet counts if a patient experiences a reduction in platelet count to <90,000/mm3 to exclude the possibility of pseudothrombocytopenia.1 18 90

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in rats;1 not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1 20

Geriatric Use

No substantial differences in efficacy relative to younger adults.1 However, increased incidence of bleeding complications and non-bleeding adverse events in some studies.1 20

Women

Increased incidence of minor bleeding complications and non-bleeding adverse events in some studies.1 109

Hepatic Impairment

Clearance not affected in patients with mild to moderate hepatic impairment;1 20 information on plasma clearance limited in patients with severe hepatic impairment since these patients were excluded from participation in clinical studies.21

Renal Impairment

Substantially decreased clearance (>50%) in patients with severe renal impairment (i.e., Clcr ≤30 mL/minute), including patients requiring hemodialysis;1 reduced dosage recommended in such patients.1 20 (See Renal Impairment under Dosage and Administration.)

Use with caution in patients requiring chronic hemodialysis.1 20 91

Common Adverse Effects

Bleeding,1 pelvic pain,1 coronary artery dissection,1 bradycardia,1 leg pain,1 dizziness,1 edema/swelling, 1 vasovagal reaction,1 sweating.1

Interactions for Tirofiban

Specific Drugs

Drug

Interaction

Comments

Anticoagulants, oral

Potential increased risk of bleeding1

Use with caution1 20 21 91

Clopidogrel

Potential increased risk of bleeding1 4 22

Use with caution1 20 21 91

Dextran

Increased risk of bleeding1

Some clinicians recommend against concomitant use91

Dipyridamole

Potential increased risk of bleeding1

Use with caution1 20 21 91

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

Possible additive pharmacologic effects1 4

Concomitant use contraindicated1

Heparin

Increased risk of bleeding; 1 5 6 11 14 possible additive effects on ACT56

Monitor aPTT or ACT during therapy;1 5 6 11 37 44 consider dosage adjustment of heparin56

Levothyroxine

Possible increased tirofiban clearance 1

Clinical importance not known1

NSAIAs

Potential increased risk of bleeding1

Use with caution1 20 21 91

Omeprazole

Possible increased tirofiban clearance 1

Clinical importance not known1

Thrombolytics

Increased risk of bleeding1

Use concomitantly with caution; no concomitant use studies to date20 21 91

Ticlopidine

Potential increased risk of bleeding1 4 22

Use with caution1 20 21 91

Tirofiban Pharmacokinetics

Absorption

Onset

Rapid onset;11 14 20 90% inhibition of platelet aggregation occurs by the end of the IV loading infusion administration.1 20 21

Duration

Short duration of action;11 14 20 platelet aggregation persists during maintenance infusion.1 20 21 Platelet function generally recovers within 4–8 hours following discontinuance of infusion.1 20

Distribution

Extent

Distributed into milk in rats and crosses the placenta in pregnant rats and rabbits.1 20 Not known whether tirofiban crosses the placenta or is distributed into milk in humans.1 20

Plasma Protein Binding

Approximately 65%.1 4 20

Elimination

Metabolism

Metabolism appears limited.1 20

Elimination Route

Excreted in urine (65%) and in feces (25%) mainly as unchanged drug.1 20

Half-life

Approximately 1.2–2 hours.1 3 4 15 20 22 91

Special Populations

Plasma clearance may decrease substantially (>50%) in patients with severe renal impairment (i.e., Clcr ≤30 mL/minute and those requiring hemodialysis) 1 (See Renal Impairment under Dosage and Administration.)

Removed by hemodialysis.1 20

Plasma clearance decreased approximately 19–26% in geriatric patients.20

Stability

Storage

Parenteral

For Injection, Concentrate, for IV Infusion

25°C (may be exposed to 15–30°C).1 20 Do not freeze; protect from light.1 20

Contains no preservative; discard unused solution.1

Injection, for IV Infusion

25°C (may be exposed to 15–30°C).1 Do not freeze; protect from light.1

Contains no preservative; discard unused solution.1

Compatibility

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

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in sodium chloride 0.45%

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Y-Site Compatibility1HID

Compatible

Amiodarone HCl

Atropine sulfate

Bivalirudin

Dobutamine HCl

Dopamine HCl

Epinephrine HCl

Famotidine HCl

Furosemide

Heparin sodium

Lidocaine HCl

Midazolam HCl

Morphine sulfate

Nitroglycerin

Potassium chloride

Propranolol HCl

Incompatible1 HID

Diazepam

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 11 16 17 22 24 43 45

  • Modest effect on hemostatic indices (e.g., bleeding times);1 2 normal hemostasis restored more rapidly than with abciximab.8 31 32 35 74 91

  • Usually does not affect aPTT when administered as monotherapy.5 6

Advice to Patients

  • Risk of serious bleeding or hemorrhage.1

  • Importance of close laboratory monitoring.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).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.

Tirofiban Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, concentrate, for IV infusion

250 mcg (of tirofiban) per mL (5 and 12.5 mg)

Aggrastat

Medicure

Tirofiban Hydrochloride in Sodium Chloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV infusion

50 mcg (of tirofiban) per mL (5 and 12.5 mg) in 0.9% Sodium Chloride

Aggrastat Premixed in Iso-osmotic Sodium Chloride Injection (in IntraVia flexible container)

Medicure

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

References

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