Tirofiban

B01A - Antithrombotic agents ATC B01AC17 Small molecule approved 1998 Parenteral Natural product

JFDA label: Ribofan

Mechanism of Action

A reversible antagonist of fibrinogen binding to the glycoprotein (GP) IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. When administered intravenously, it inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. When given according to the recommended regimen, >90% inhibition is attained within 10 minutes after initiation. Platelet aggregation inhibition is reversible following cessation of the infusion.

Indications

Approved

Unstable angina/non-ST-elevation myocardial infarction

Off-label

To support PCI (administered at the time of PCI) for ST-elevation myocardial infarction (STEMI)
To support PCI (administered at the time of elective PCI) for stable ischemic heart disease (high risk features)

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): History of thrombocytopenia following prior exposure to any other GPIIb/IIIa inhibitor Absolute
Severe hypersensitivity reaction (ie, anaphylactic reaction) to tirofiban or any component of the formulation Absolute
active internal bleeding or a history of bleeding diathesis, major surgical procedure, or severe physical trauma within the previous month Absolute
acute pericarditis Absolute
angina precipitated by obvious provoking factors (eg, arrhythmia, severe anemia, hyperthyroidism, hypotension) Absolute
cirrhosis or clinically significant liver disease Absolute
current use with other GP IIb/IIIa inhibitors Absolute
history of intracranial hemorrhage or neoplasm, arteriovenous malformation, or aneurysm Absolute
history of thrombocytopenia following prior exposure to tirofiban Absolute
history, symptom or findings suggestive of aortic dissection Absolute
known coagulopathy, platelet disorder or history of thrombocytopenia Absolute
major surgical procedure or relevant trauma within the previous 6 weeks Absolute
malignant or severe uncontrolled hypertension (>180 mmHg/110 mmHg) Absolute
recent (within the previous 30 days) internal bleeding Absolute
recent epidural procedure Absolute
stroke within 30 days prior to hospitalization or any history of hemorrhagic stroke Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Common bradycardia · Coronary artery dissection · edema · vasodepressor syncope

Nervous system disorders (2)

Common Dizziness · headache

Renal and urinary disorders (1)

Common Pelvic pain

Blood and lymphatic system disorders (2)

Common Major hemorrhage · thrombocytopenia: 3

Gastrointestinal disorders (1)

Common Nausea

Skin and subcutaneous tissue disorders (1)

Common Diaphoresis

Musculoskeletal and connective tissue disorders (1)

Common Leg pain

General disorders and administration site conditions (1)

Common Fever

Other (1)

Very Common Hematologic & oncologic: Minor hemorrhage

Dosing

Source: Lexicomp

Unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI): IV: Loading dose: 25 mcg/kg administered over 5 minutes or less; Maintenance infusion: 0.15 mcg/kg/minute continued for up to 18 hours Percutaneous coronary intervention (PCI): IV: Loading dose: 25 mcg/kg administered over 5 minutes or less at the time of PCI; Maintenance infusion: 0.15 mcg/kg/minute continued for up to 18 hours (ACCF/AHA/SCAI [Levine 2011]; Valgimigli 2004) Stable ischemic heart disease (high-risk features) undergoing elective PCI (off-label use): Loading dose: 25 mcg/kg administered over 5 minutes or less at the time of PCI; Maintenance infusion: 0.15 mcg/kg/minute; was continued for up to 48 hours in the clinical trial (ACCF/AHA/SCAI [Levine 2011]; Valgimigli 2004). Note: Reserve for patients who were not pretreated with clopidogrel or who are undergoing elective PCI with stent implantation with adequate clopidogrel pretreatment (ACCF/AHA/SCAI [Levine 2011]). ST-elevation myocardial infarction (STEMI) undergoing primary PCI (off-label use): IV Loading dose: 25 mcg/kg administered over 5 minutes or less at the time of PCI; Maintenance infusion: 0.15 mcg/kg/minute in combination with heparin or bivalirudin in selected patients; was continued for 18-24 hours in clinical trials (ACCF/AHA [O’Gara 2013]; ACCF/AHA/SCAI [Levine 2011]; Valgimigli 2008; Van’t Hof 2008)

Refer to adult dosing.

CrCl >60 mL/minute: No dosage reduction necessary. CrCl ≤60 mL/minute: IV Loading dose: 25 mcg/kg administered over 5 minutes or less; Maintenance infusion: 0.075 mcg/kg/minute continued for up to 18 hours. Hemodialysis: Dialyzable: Yes (NCS/SCCM [Frontera 2016])

Warnings & Precautions

Source: Lexicomp

Bleeding

The most common complication is bleeding, including retroperitoneal, pulmonary, and spontaneous GI and/or GU bleeding; watch closely for bleeding, especially the arterial access site for the cardiac catheterization. Fatal bleeding has been reported. Use with extreme caution in patients with platelet counts 3, patients with hemorrhagic retinopathy, previous history of GI disease, recent thrombolytic therapy and in chronic dialysis patients. Use caution with administration of other drugs affecting hemostasis. Minimize other procedures including arterial and venous punctures, IM injections, nasogastric tubes, etc.

Thrombocytopenia

Profound thrombocytopenia has been reported with use of tirofiban. If during therapy platelet count decreases to 3, monitor platelet counts to exclude pseudothrombocytopenia. If thrombocytopenia is confirmed, discontinue tirofiban and heparin if administered concurrently. Platelet counts should recover rapidly (within 1 to 5 days) after discontinuation. Previous exposure to a glycoprotein IIb/IIIa inhibitor may increase the risk of thrombocytopenia. Use is contraindicated in patients with a history of thrombocytopenia following exposure to tirofiban. Specific management guidelines for GP IIb/IIIa induced thrombocytopenia have been published (Huxtable 2006; Llevadot 2000). Disease-related concerns:

Renal impairment

Dosage reduction of the maintenance infusion rate is necessary in patients with CrCl ≤60 mL/minute. Other warnings/precautions:

Percutaneous coronary intervention

Sheath removal: Prior to pulling the sheath, ACT should be • Surgery: Discontinue at least 2 to 4 hours prior to coronary artery bypass graft surgery (ACC/AHA [Amsterdam 2014]; ACCF/AHA [Hillis, 2011]).

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events have not been observed in animal reproduction studies. Information related to use in pregnancy is limited; successful use during pregnancy has been described in a case report (Boztosun, 2008).

Lactation

It is not known if tirofiban is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

LactMed: monitor the infant.

Monitoring

Clinical pearl	Platelet count (baseline; 6 hours after initiation and daily thereafter during therapy). Monitor platelet counts more closely in patients who have had previous exposure to glycoprotein IIb/IIa antagonists. Persistent reductions of platelet counts 3 may require interruption or discontinuation of infusion; hemoglobin and hematocrit; signs of bleeding. Standard post-PCI assessment if patient undergoes PCI (eg, monitoring vascular access site, monitoring for chest pain and signs of bleeding)

Clinical pearl

Platelet count (baseline; 6 hours after initiation and daily thereafter during therapy). Monitor platelet counts more closely in patients who have had previous exposure to glycoprotein IIb/IIa antagonists. Persistent reductions of platelet counts 3 may require interruption or discontinuation of infusion; hemoglobin and hematocrit; signs of bleeding. Standard post-PCI assessment if patient undergoes PCI (eg, monitoring vascular access site, monitoring for chest pain and signs of bleeding)

Chemistry & Properties

Formula	C22H36N2O5S
Molecular weight	440.61 g/mol
IUPAC name	(2S)-2-(butylsulfonylamino)-3-[4-(4-piperidin-4-ylbutoxy)phenyl]propanoic acid
CAS	144494-65-5
PubChem CID	60947
InChIKey	`COKMIXFXJJXBQG-NRFANRHFSA-N`
logP	2.95 (XLogP 1.4)
Polar surface area	104.73 Å²
H-bond acceptors / donors	5 / 3
Drug-likeness (QED)	0.38
Lipinski violations	0

SMILES

CCCCS(=O)(=O)N[C@@H](Cc1ccc(OCCCCC2CCNCC2)cc1)C(=O)O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	0.761 h
Volume of distribution	1.055 L/kg
Protein binding	63.3%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
integrin αIIbβ3 (ITGA2B\|ITGB3)	Inhibitor	pIC50 9.4

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Abciximab	major
Acalabrutinib	major
Alteplase	major
Anagrelide	major
Anisindione	major
Anistreplase	major
Apixaban	major
Ardeparin	major
Argatroban	major
Avapritinib	major
Betrixaban	major
Cabozantinib	major
Cangrelor	major
Caplacizumab	major
Clopidogrel	major
Dalteparin	major
Danaparoid	major
Dasatinib	major
Deferasirox	major
Defibrotide	major
Desirudin	major
Dicoumarol	major
Dipyridamole	major
Drotrecogin alfa	major
Edoxaban	major
Enoxaparin	major
Eptifibatide	major
Fondaparinux	major
Heparin	major
Ibritumomab tiuxetan	major
Ibrutinib	major
Inotersen	major
Lepirudin	major
Omacetaxine mepesuccinate	major
Panobinostat	major
Ponatinib	major
Prasugrel	major
Ramucirumab	major
Regorafenib	major
Reteplase	major

Showing 40 of 100+.

Registered Products (4)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Aggrastat Concentrate For Infusion	Infusion 0.25 mg/ml	1 vial	Adatco Drug Store	—
Fibrostat	Vial 281.0 mcg/1 ml	1 vial	/ HIKMA PHARMACEUTICALS.IND/JORDAN / General / / HIKMA PHARMACEUTICALS.IND/JORDAN / General / General / / HIKMA PHARMACE	—
Ribofan	Vial 0.25 mg/ml	1 vial	MS PHARMA/JORDAN	—
Tirofiban Altan 0.05 mg/mL solution for infusion	Infusion 12.5 mg/250 ml	1 BAG/1 BOX	Reda Jardaneh Drug Store	—