Integrilin (eptifibatide) Injection

Available from Teva Pharmaceuticals

A generic version of

Integrilin^® (eptifibatide) Injection

Teva Pharmaceuticals is pleased to introduce Eptifibatide Injection, 2 mg/mL, 20 mg, to our line of generic products. This product is AP rated and bioequivalent to Integrilin^®* (eptifibatide) Injection, and is available in a 10 mL single-use vial.

About the medicine:


Eptifibatide  is an antiplatelet drug of theglycoprotein IIb/IIIa inhibitor class. Eptifibatide is a cyclic heptapeptide derived from a protein found in the venom of the southeastern pygmy rattlesnake (Sistrurus miliarius barbouri).
 It belongs to the class of the arginin-glycin-aspartat-mimetics and reversibly binds to platelets. Eptifibatide has a short half-life.

Integrilin is sold in two strengths, globally: vials containing 2 mg/ml (20 mg totally) and 0.75 mg/ml (75 mg totally). A third size is sold in the US: 100 ml vials containing 2 mg/ml (200 mg totally).

Indication:

Eptifibatide is used to reduce the risk of acute cardiac ischemic events (death and/or myocardial infarction) in patients with unstable angina or non-ST-segment-elevation (e.g., non-Q-wave) myocardial infarction (i.e., non-ST-segment elevation acute coronary syndromes) both in patients who are to receive non surgery (conservative) medical treatment and those undergoing percutaneous coronary intervention (PCI).

The drug is usually applied together with aspirin or clopidogrel and (low molecular weight or unfractionated) heparin. Additionally, the usual supportive treatment consisting of applications of nitrates, beta-blockers, opioid analgesics and/or benzodiazepines should be employed as indicated.

 Angiographic evaluation and other intensive diagnostic procedures may be considered a first line task before initiating therapy with eptifibatide.

The drug should exclusively be used in hospitalized patients both because of the serious degree of patients' illness and because of the possible side-effects of eptifibatide.

Descriptions:

Eptifibatide is a cyclic heptapeptide containing 6 amino acids and 1 mercaptopropionyl (desamino cysteinyl) residue. 

An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Chemically it is N6 -(aminoiminomethyl)-N2 -(3-mercapto­ 1-oxopropyl-L-lysylglycyl-L-α-aspartyl-L-tryptophyl-L-prolyl-L-cysteinamide, cyclic (1→6)­ disulfide.

 Eptifibatide binds to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets and inhibits platelet aggregation. The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophilized. The structural formula is:

CLINICAL PHARMACOLOGY

Mechanism of Action:

 Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. 

Platelet aggregation inhibition is reversible following cessation of the eptifibatide infusion; this is thought to result from dissociation of eptifibatide from the platelet. 

Pharmacodynamics:

 Infusion of eptifibatide into baboons caused a dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than 5.0 mcg/kg/min. In a baboon model that is refractory to aspirin and heparin, doses of eptifibatide that inhibit aggregation prevented acute thrombosis with only a modest prolongation (2- to 3­ fold) of the bleeding time. Platelet aggregation in dogs was also inhibited by infusions of eptifibatide, with complete inhibition at 2.0 mcg/kg/min. 

This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury (Folts model). 

Human pharmacodynamic data were obtained in healthy subjects and in patients presenting with unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI) and/or undergoing percutaneous coronary interventions. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, eptifibatide inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in a dose- and concentration-dependent manner.

 The effect of eptifibatide was observed immediately after administration of a 180-mcg/kg intravenous bolus. 

 The effects of the dosing regimen used in ESPRIT on platelet aggregation have not been studied.

Pharmacokinetics :

The pharmacokinetics of eptifibatide are linear and dose-proportional for bolus doses ranging from 90 to 250 mcg/kg and infusion rates from 0.5 to 3.0 mcg/kg/min. 

Plasma elimination halflife is approximately 2.5 hours. Administration of a single 180-mcg/kg bolus combined with an infusion produces an early peak level, followed by a small decline prior to attaining steady state (within 4-6 hours). 

This decline can be prevented by administering a second 180-mcg/kg bolus 10 minutes after the first. The extent of eptifibatide binding to human plasma protein is about 25%.

 Clearance in patients with coronary artery disease is about 55 mL/kg/h. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatide, deaminated eptifibatide, and other, more polar metabolites.

 No major metabolites have been detected in human plasma. In patients with moderate to severe renal insufficiency (creatinine clearance <50 mL/min using the Cockcroft-Gault equation), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels approximately doubled

Side Effects:

• Abdominal or stomach pain or swelling
• back pain or backaches
• bleeding from the bladder
• bleeding gums
• blood in the urine
• bloody or black, tarry stools
• blurred vision
• confusion
• constipation
• coughing up blood
• difficulty with breathing or swallowing
• dizziness