Eptifibatide (Page 3 of 6)

6.2 Postmarketing Experience

The following adverse reactions have been reported in post-approval use of eptifibatide in combination with heparin and aspirin. Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: cerebral, GI, and pulmonary hemorrhage. Fatal bleeding reactions have been reported. Acute profound thrombocytopenia, as well as immune-mediated thrombocytopenia, have been reported [see Adverse Reactions (6.1)].

7 DRUG INTERACTIONS

7.1 Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents

Coadministration of antiplatelet agents, thrombolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. Concomitant treatment with other inhibitors of platelet receptor GP IIb/IIIa should be avoided.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
Available data on eptifibatide use in pregnant women from published literature and the pharmacovigilance database are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Untreated myocardial infarction can be fatal to the pregnant woman and fetus (see Clinical Considerations). In animal reproduction studies, there was no evidence of adverse developmental effects when eptifibatide was administered intravenously to pregnant rats and rabbits at approximately 4 times the recommended maximum daily human dose.


The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Myocardial infarction is a medical emergency in pregnancy which can be fatal to the pregnant woman and fetus if left untreated. Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of eptifibatide on the fetus


Data
Animal Data Embryo-fetal development studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats during the period of organogenesis at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis) and in pregnant rabbits during the period of organogenesis at total daily doses of up to 36 mg/kg/day (also about 4 times the recommended maximum daily human dose on a body surface area basis). These studies revealed no evidence of harm to the fetus due to eptifibatide.

8.2 Lactation

Risk Summary

There are no available data on the presence of eptifibatide in human milk, the effects on the breastfed infant, or the effects on milk production. As eptifibatide is a peptide, it is likely to be destroyed in the infant’s gastrointestinal tract and not absorbed orally by the breastfed infant.

8.4 Pediatric Use

Safety and effectiveness of eptifibatide in pediatric patients have not been studied.

8.5 Geriatric Use

The PURSUIT and IMPACT II clinical studies enrolled patients up to the age of 94 years (45% were age 65 and over; 12% were age 75 and older). There was no apparent difference in efficacy between older and younger patients treated with eptifibatide. The incidence of bleeding complications was higher in the elderly in both placebo and eptifibatide groups, and the incremental risk of eptifibatide-associated bleeding was greater in the older patients. No dose adjustment was made for elderly patients, but patients over 75 years of age had to weigh at least 50 kg to be enrolled in the PURSUIT study; no such limitation was stipulated in the ESPRIT study [see Adverse Reactions (6.1)].

8.6 Renal Impairment

Approximately 50% of eptifibatide is cleared by the kidney in patients with normal renal function. Total drug clearance is decreased by approximately 50% and steady-state plasma eptifibatide concentrations are doubled in patients with an estimated CrCl <50 mL/min (using the Cockcroft-Gault equation). Therefore, the infusion dose should be reduced to 1 mcg/kg/min in such patients [see Dosage and Administration (2)]. The safety and efficacy of eptifibatide in patients dependent on dialysis has not been established.

10 OVERDOSAGE

There has been only limited experience with overdosage of eptifibatide. There were 8 patients in the IMPACT II study, 9 patients in the PURSUIT study, and no patients in the ESPRIT study who received bolus doses and/or infusion doses more than double those called for in the protocols. None of these patients experienced an intracranial bleed or other major bleeding.
Eptifibatide was not lethal to rats, rabbits, or monkeys when administered by continuous intravenous infusion for 90 minutes at a total dose of 45 mg/kg (about 2 to 5 times the recommended maximum daily human dose on a body surface area basis). Symptoms of acute toxicity were loss of righting reflex, dyspnea, ptosis, and decreased muscle tone in rabbits and petechial hemorrhages in the femoral and abdominal areas of monkeys.
From in vitro studies, eptifibatide is not extensively bound to plasma proteins and thus may be cleared from plasma by dialysis.

11 DESCRIPTION

Eptifibatide is a cyclic heptapeptide containing 6 amino acids and 1 mercaptopropionyl (des-amino 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. Eptifibatide is a white to off-white powder. The structural formula is:

Eptifibatide Chemical Structure
(click image for full-size original)

Eptifibatide injection is a clear, colorless, sterile, non-pyrogenic solution free from visible particles for intravenous (I.V.) use with a molecular formula of C35 H49 N11 O9 S2 and a molecular weight of 831.96. Each 10 mL vial contains 2 mg/mL of eptifibatide and each 100 mL vial contains either 0.75 mg/mL of eptifibatide or 2 mg/mL of eptifibatide. Each vial of either size also contains 5.25 mg/mL citric acid and sodium hydroxide to adjust the pH to 5.35.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 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 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 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 UA or NSTEMI and/or undergoing percutaneous coronary intervention. 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. Table 4 shows the effects of dosing regimens of eptifibatide used in the IMPACT II and PURSUIT studies on ex vivo platelet aggregation induced by 20 µM ADP in PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of the dosing regimen used in ESPRIT on platelet aggregation have not been studied.

Table 4: Platelet Inhibition and Bleeding Time
* 180 mcg/kg bolus followed by a continuous infusion of 2 mcg/kg/min.
PURSUIT 180/2*
Inhibition of platelet aggregation 15 min after bolus 84%
Inhibition of platelet aggregation at steady state >90%
Bleeding-time prolongation at steady state <5x
Inhibition of platelet aggregation 4h after infusion discontinuation <50%
Bleeding-time prolongation 6h after infusion discontinuation 1.4x

The eptifibatide dosing regimen used in the ESPRIT study included two 180 mcg/kg bolus doses given 10 minutes apart combined with a continuous 2 mcg/kg/min infusion.
When administered alone, eptifibatide has no measurable effect on PT or aPTT.
There were no important differences between men and women or between age groups in the pharmacodynamic properties of eptifibatide. Differences among ethnic groups have not been assessed.

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