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GLYCOPROTEIN IIB-IIIA RECEPTOR ANTAGONISTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Glycoprotein IIb/IIIa receptor antagonists prevent the binding of fibrinogen to platelets, via the glycoprotein IIb/IIIa receptor, and inhibit platelet aggregation.

Specific Substances

    A) ABCIXIMAB
    1) Immunoglobulin G (human-mouse monoclonal c7E3
    2) clone p7E3V(H)hC(gamma)4 Fab fragment
    3) anti-human platelet glycoprotein IIb/IIIa
    4) complex), disulphide with human-mouse
    5) monoclonal c7E3 clone p7E3V(kappa)hC(kappa)
    6) light chain c7E3
    7) ReoPro(R)
    8) Molecular Formula: C2101-H3229-N551-O673-S15
    9) CAS 143653-53-6
    EPTIFIBATIDE
    1) N(6)-Amidino-N(2)-(3-mercaptopropionyl)-L-
    2) lysylglycyl-L-alpha-aspartyl-L-tryptophyl-L-
    3) prolyl-L- cysteinamide, cyclic (1->6)-
    4) disulfide; S(1),S(6)-Cyclo[N(6)-carbamimidoyl-
    5) N(2)-(3-sulfanylpropanoyl)-L-lysylglycyl-L-
    6) alpha-aspartyl-L-tryptophyl-L-prolyl-L-
    7) cysteinamide]
    8) Integrelin(R)
    9) Molecular Formula: C35-H49-N11-O9-S2
    10) CAS 148031-34-9
    11) CAS 157630-07-4
    TIROFIBAN
    1) N-(butylsulfonyl)-4-[4-(4-piperidyl)butoxy]-
    2) L-phenylalanine hydrochloride monohydrate
    3) L-700462
    4) MK-383
    5) MK-0383
    6) Molecular Formula: C22-H36-N2-O5-S,HCl,H2O
    7) CAS 144494-65-5 (tirofiban)
    8) CAS 142373-60-2 (anhydrous tirofiban
    9) hydrochloride)
    10) CAS 150915-40-5 (tirofiban hydrochloride
    11) monohydrate)
    GENERAL TERMS
    1) ANTAGONISTS, GLYCOPROTEIN IIB-IIIA RECEPTORS
    2) INHIBITORS, GLYCOPROTEIN IIB-IIIA RECEPTORS
    3) RECEPTOR ANTAGONISTS, GLYCOPROTEIN IIB-IIIA

    1.2.1) MOLECULAR FORMULA
    1) EPTIFIBATIDE: C35H49N11O9S2
    2) TIROFIBAN: C22H36N2O5S.HCl.H2O

Available Forms Sources

    A) FORMS
    1) Abciximab is available as single use vials containing 10 mg/5 mL of abciximab for IV administration (Prod Info ReoPro(R) IV injection, 2011).
    2) Eptifibatide is available in 10 mL vials as 20 mg eptifibatide and in 100 mL vials as 75 mg eptifibatide or 200 mg eptifibatide (Prod Info INTEGRILIN(R) intravenous injection, 2013).
    3) Tirofiban is available in premixed solutions of 5 mg tirofiban per 100 mL (50 mcg/mL) and 12.5 mg tirofiban per 250 mL (50 mcg/mL) in a sterile iso-osmotic solution (Prod Info AGGRASTAT(R) intravenous injection solution, 2012).
    B) USES
    1) Abciximab, eptifibatide, and tirofiban, as glycoprotein IIb/IIIa receptor antagonists administered intravenously, are indicated, in conjunction with heparin and aspirin, for the treatment of acute coronary syndrome, particularly in those patients who are being medically managed and in those patients who are undergoing percutaneous coronary intervention (Prod Info ReoPro(R) IV injection, 2011; Prod Info INTEGRILIN(R) intravenous injection, 2013; Prod Info AGGRASTAT(R) intravenous injection solution, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Abciximab, eptifibatide and tirofiban are indicated in conjunction with hepatin and aspirin, for the treatment of acute coronary syndrome, particularly in those patients who are undergoing percutaneous coronary intervention. Orbofiban has been investigated as an oral glycoprotein llb/IIIa receptor antagonist in unstable angina and myocardial infarction but has been associated with an increase in mortality.
    B) PHARMACOLOGY: Glycoprotein llb/llla receptor antagonists prevent the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to glycoprotein llb/llla receptors, resulting in inhibition of platelet aggregation. Inhibition of platelet aggregation is reversible following discontinuation of glycoprotein llb/llla receptor antagonist therapy, and is thought to be due to dissociation of the receptor antagonist from platelets.
    C) TOXICOLOGY: Inhibition of platelet aggregation can result in bleeding.
    D) EPIDEMIOLOGY: Clinically significant toxicity from overdose is rare since these drugs are used in an inpatient setting. Approximately, 5% of patients treated with therapeutic doses of glycoprotein llb/llla inhibitors will develop major bleeding.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Bleeding, particularly at the site of catheterization, and thrombocytopenia are the most common complications following therapeutic administration of glycoprotein llb/llla receptor antagonists. The risk of bleeding is increased with concomitant administration of heparin or aspirin. Alveolar and intracranial hemorrhage are rare occurrences following therapy. Hypotension may occur during infusion of the glycoprotein llb/llla receptor antagonists.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: In clinical trials, eptifibatide overdose occurred in 17 cases and no one experienced intracranial bleeding or significant bleeding. In case reports, prolonged infusions of glycoprotein llb/llla receptor antagonists were associated with gastrointestinal bleeding and thrombocytopenia. Alveolar hemorrhage should be suspected in patients with hemoptysis, dyspnea or new infiltrates on chest x-ray.
    0.2.6) RESPIRATORY
    A) Alveolar hemorrhage, sometimes fatal, has been infrequently reported with abciximab and tirofiban therapy.
    0.2.13) HEMATOLOGIC
    A) Thrombocytopenia and bleeding at the site of catheterization are the most common complications associated with glycoprotein IIb/IIIa receptor antagonist therapy and following overdose.
    0.2.20) REPRODUCTIVE
    A) Abciximab is classified by the manufacturer as FDA pregnancy category C, eptifibatide and tirofiban are classified as FDA pregnancy category B. Animal studies conducted with tirofiban and eptifibatide have not shown any evidence of teratogenicity. At the time of this review, animal reproduction studies have not been conducted with abciximab to determine its teratogenicity. It is not known whether glycoprotein IIb/IIIa receptor antagonists are excreted in human breast milk.

Laboratory Monitoring

    A) Monitor the aPTT, INR, platelet counts and hematocrit. Severe thrombocytopenia has occurred with therapeutic use.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) See parenteral overview for further treatment.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) PARENTERAL EXPOSURE: Monitor CBC, including platelets, aPTT, and PT/INR. Administer platelet transfusion in cases of severe thrombocytopenia (platelet count less than 20 x 10(9)/L). If the patient develops hypotension infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, evaluate for bleeding and transfuse as needed, administer dopamine or norepinephrine; titrate to desired response. If the patient develops major bleeding treatment may include packed red blood cells, as well as fresh frozen plasma and platelet transfusion to increase coagulation.
    B) ANTIDOTE
    1) None.
    C) PATIENT DISPOSITION
    1) ADMISSION CRITERIA: Any patient who develops hypotension, thrombocytopenia, or clinically significant bleeding should remain admitted in a monitored setting until symptoms resolve, bleeding is stopped, and thrombocytopenia has resolved.
    D) ENHANCED ELIMINATION
    1) Tirofiban is removed by hemodialysis. Hemodialysis has been successfully used to normalize hemostasis in renal failure patients receiving eptifibatide. The potential benefit must be weighed against the risk of placing dialysis catheters in a patient with abnormal hemostasis.
    E) PITFALLS
    1) Patients receiving these agents generally have concomitant conditions such as acute coronary syndrome that place them at greater risk of complications, if hemorrhage develops.
    F) PHARMACOKINETICS
    1) These drugs generally have small volumes of distribution and limited protein binding. Elimination half lives: abciximab 10 to 30 min, lamifiban and tirofiban 2 hours and eptifibatide 2.5 hours.

Range Of Toxicity

    A) TOXIC DOSE: A specific minimum toxic dose has not been established. Minor bleeding occurred following inadvertent overdosage or tirofiban in doses up to 9.8 time the 0.15 mcg/kg/min maintenance infusion rate. An adult who received an infusion of eptifibatide at 5 times the intended infusion rate for 90 minutes had no complications, normal bleeding times and platelet counts.
    B) THERAPEUTIC DOSE: ADULT: ABCIXIMAB: RECOMMENDED DOSE: 0.25 mg/kg IV bolus administered 10 to 60 minutes before beginning percutaneous coronary intervention (PCI), followed by a continuous IV infusion of 0.125 mcg/kg/min (up to a maximum dose of 10 mcg/minute) for 12 hours. EPTIFIBATIDE 180 mcg/kg IV bolus administered immediately after diagnosis, followed by a continuous infusion of 2 mcg/kg/min continued until the patient is discharged or until initiation of coronary artery bypass graft (CABG) surgery, up to a maximum of 72 hours. TIROFIBAN: RECOMMENDED DOSE: Infuse a 50 mcg/mL solution administered at an initial rate of 0.4 mcg/kg/min for 30 minutes followed by a continuous infusion of 0.1 mcg/kg/min. Continue the infusion through angiography and for 12 to 24 hours after angioplasty or atherectomy. PEDIATRIC: The safety and efficacy of glycoprotein IIb/IIIa receptor antagonists in the pediatric population has not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Abciximab, eptifibatide and tirofiban are indicated in conjunction with hepatin and aspirin, for the treatment of acute coronary syndrome, particularly in those patients who are undergoing percutaneous coronary intervention. Orbofiban has been investigated as an oral glycoprotein llb/IIIa receptor antagonist in unstable angina and myocardial infarction but has been associated with an increase in mortality.
    B) PHARMACOLOGY: Glycoprotein llb/llla receptor antagonists prevent the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to glycoprotein llb/llla receptors, resulting in inhibition of platelet aggregation. Inhibition of platelet aggregation is reversible following discontinuation of glycoprotein llb/llla receptor antagonist therapy, and is thought to be due to dissociation of the receptor antagonist from platelets.
    C) TOXICOLOGY: Inhibition of platelet aggregation can result in bleeding.
    D) EPIDEMIOLOGY: Clinically significant toxicity from overdose is rare since these drugs are used in an inpatient setting. Approximately, 5% of patients treated with therapeutic doses of glycoprotein llb/llla inhibitors will develop major bleeding.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Bleeding, particularly at the site of catheterization, and thrombocytopenia are the most common complications following therapeutic administration of glycoprotein llb/llla receptor antagonists. The risk of bleeding is increased with concomitant administration of heparin or aspirin. Alveolar and intracranial hemorrhage are rare occurrences following therapy. Hypotension may occur during infusion of the glycoprotein llb/llla receptor antagonists.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: In clinical trials, eptifibatide overdose occurred in 17 cases and no one experienced intracranial bleeding or significant bleeding. In case reports, prolonged infusions of glycoprotein llb/llla receptor antagonists were associated with gastrointestinal bleeding and thrombocytopenia. Alveolar hemorrhage should be suspected in patients with hemoptysis, dyspnea or new infiltrates on chest x-ray.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension is commonly reported following therapeutic administration of glycoprotein IIb/IIIa receptor antagonists (Prod Info INTEGRILIN(R) intravenous injection, 2013; Prod Info ReoPro(R) IV injection, 2011).
    b) INCIDENCE: Hypotension was reported in 14.4% of patients (n=3111) following abciximab therapy, during clinical trials, as compared with 10.3% of patients (n=2226) who received placebo (Prod Info ReoPro(R) IV injection, 2011).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) ABCIXIMAB: Bradycardia was infrequently reported in patients following therapeutic administration of abciximab during clinical trials (Prod Info ReoPro(R) IV injection, 2011).

Respiratory

    3.6.1) SUMMARY
    A) Alveolar hemorrhage, sometimes fatal, has been infrequently reported with abciximab and tirofiban therapy.
    3.6.2) CLINICAL EFFECTS
    A) PULMONARY HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Alveolar hemorrhage, characterized by the development of hypoxia, hemoptysis, a reduction in hemoglobin levels, and the appearance of diffuse alveolar infiltrates on chest x-ray, has been infrequently reported as a complication following therapeutic administration of abciximab or tirofiban (Kalra et al, 2001; Ali et al, 2000; Khanlou et al, 1998; Stiges & Villa, 1997) and may be fatal.
    b) CASE REPORTS: Two patients, who underwent percutaneous transluminal coronary angioplasty and received abciximab during and after the procedure, began to develop severe hypoxemia within 1 hour after completion of abciximab therapy. A chest x-ray revealed diffuse bilateral alveolar infiltrates and a complete blood count showed a significant decrease in the hemoglobin level. Bronchoscopies showed profuse bloody secretions without an endobronchial lesion or other obvious source of bleeding, consistent with a diagnosis of diffuse alveolar hemorrhage. Despite aggressive supportive care, both patients died, 20 days after initial events in one patient, and within 6 hours after initial events in the other patient (Khanlou et al, 1998).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) INTRACRANIAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Intracranial hemorrhage has been infrequently reported as a complication following therapeutic administration of glycoprotein IIb/IIIa receptor antagonists (Moshiri et al, 2001; Memon et al, 2000; Cheung & Ho, 2000) and may be fatal.
    b) CASE REPORT: A 56-year-old woman developed right-sided hemiplegia, right-sided facial paralysis, and a decreased level of consciousness approximately 90 minutes after beginning an abciximab infusion, that was given during a percutaneous transluminal coronary angioplasty for treatment of an acute myocardial infarction. A complete blood count revealed thrombocytopenia and a cerebral CT scan showed a large fronto-parietal hemorrhage. Despite administration of platelets, the patient continued to deteriorate and died (Vahdat et al, 2000). It is believed that the cerebral hemorrhage was due to abciximab-induced thrombocytopenia.
    2) WITH POISONING/EXPOSURE
    a) LACK OF EFFECT
    1) In clinical trials, eptifibatide overdose occurred in 17 cases and no one experienced intracranial bleeding or significant bleeding (Prod Info INTEGRILIN(R) intravenous injection, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) HEMATEMESIS
    1) WITH THERAPEUTIC USE
    a) Hematemesis is a minor bleeding complication that may occur following glycoprotein IIb/IIIa receptor antagonist therapy (Prod Info INTEGRILIN(R) intravenous injection, 2013; Dasgupta et al, 2000; Juran, 1999).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, and abdominal pain were reported following therapeutic administration of abciximab during clinical trials (Prod Info ReoPro(R) IV injection, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) Hematuria is a minor bleeding complication following glycoprotein IIb/IIIa receptor antagonist therapy (Prod Info INTEGRILIN(R) intravenous injection, 2013; Juran, 1999).

Hematologic

    3.13.1) SUMMARY
    A) Thrombocytopenia and bleeding at the site of catheterization are the most common complications associated with glycoprotein IIb/IIIa receptor antagonist therapy and following overdose.
    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Severe thrombocytopenia (platelet count < 50,000/mm(3)) has been reported in patients from approximately 2 hours up to 6 days following therapeutic administration of glycoprotein IIb/IIIa receptor antagonists (Reddy et al, 2001; Jubelirer et al, 1999; McClure et al, 1999; Stiegler et al, 1999; Berkowitz et al, 1997) and has been associated with cerebral hemorrhaging (Vahdat et al, 2000) (Jenkins et al, 1998).
    b) INCIDENCE: Evaluation of 8 large placebo-controlled, randomized trials involving glycoprotein IIb/IIIa inhibitors showed that the incidence of thrombocytopenia significantly increased following abciximab administration as compared with placebo (4.2% vs 2.0%, p<0.001). The incidence of thrombocytopenia did not appear to increase with administration of eptifibatide or tirofiban (Dasgupta et al, 2000). The incidence of thrombocytopenia appeared to increase when abciximab was given with heparin (Prod Info ReoPro(R) IV injection, 2011; Dasgupta et al, 2000) and high doses of clopidogrel (300 mg) (Dillon et al, 2000).
    c) CASE REPORT: A 71-year-old man, with a baseline platelet count of 193,000/mm(3), received a 0.25 mg/kg bolus of abciximab followed by a 10 mcg/min abciximab infusion prior to performance of a percutaneous transluminal coronary angioplasty. Within one hour after beginning the infusion, the patient began shivering and had warm, dry skin. The infusion was discontinued and the laboratory analysis showed that the patient's platelet count was 52,000/mm(3), which continued to decrease to a low of 10,000/mm(3). The patient gradually recovered following a platelet transfusion (Bishara & Hagmeyer, 2000).
    d) PSEUDOTHROMBOCYTOPENIA: Pseudothrombocytopenia has been reported following abciximab therapy, and may be due to the presence of EDTA as an anticoagulant in the blood tube used to determine the platelet count. following abciximab therapy. Pseudothrombocytopenia appears to be a laboratory artifact due to artificial clumping of platelets in vitro. It can be diagnosed if a platelet count performed using blood anticoagulated with citrate (blue top vacutainer) is normal. It is not associated with bleeding complications and does not require discontinuation of abciximab therapy (Sane et al, 2000; Holmes et al, 2000; Moll et al, 1999).
    e) LACK OF EFFECT
    1) CASE REPORT: An 80-year-old woman, who developed acute thrombocytopenia (platelet count of 67,000/mm(3)) approximately 10 hours after beginning abciximab therapy, recovered following discontinuation of therapy. Due to recurrent ECG abnormalities, the patient was started on eptifibatide therapy. Laboratory analysis at 4 hours and 8 hours following initiation of therapy showed no evidence of thrombocytopenia, with the platelet counts of 129,000/mm(3) and 224,000/mm(3), respectively (Coto, 2000).
    2) CASE REPORT: Thrombocytopenia did not occur with tirofiban therapy in a 52-year-old man who had experienced abciximab-associated thrombocytopenia 10 months prior to beginning tirofiban therapy (Desai & Lucore, 2000).
    B) HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Excessive bleeding at the site of vascular access is a frequent occurrence with therapeutic administration of the glycoprotein IIb/IIIa receptor antagonists (Prod Info INTEGRILIN(R) intravenous injection, 2013; Jong et al, 2001; Prod Info AGGRASTAT(R) intravenous injection solution, 2012; Kranjec & Cerne, 2000; Dasgupta et al, 2000; Juran, 1999) and appears to increase with concomitant administration of heparin or thrombolytic agents (Blankenship, 1999).
    b) INCIDENCE: In the EPIC trial, conducted for the determination of abciximab efficacy versus placebo in patients undergoing coronary angioplasty or atherectomy and who were at risk for ischemic complications, bleeding at the vascular access site occurred in 56% (n=682) and 58% (n=689) of patients following abciximab bolus and abciximab bolus plus infusion, respectively, as compared with 30% of patients (n=682) who received placebo (Juran, 1999).
    c) TIROFIBAN: In clinical trials, inadvertent overdosage of tirofiban occurred in doses up to 9.8 times the 0.15 mcg/kg/min maintenance infusion rate, primarily resulting in minor mucocutaneous bleeding events and minor bleeding at cardiac catheterization sites (Prod Info AGGRASTAT(R) intravenous injection solution, 2012).
    d) EPTIFIBATIDE: There were 450 deaths of patients on a glycoprotein IIb/IIIa inhibitor reported to the FDA between November 1997 and December 2000, and 103 of these deaths involved treatment with eptifibatide; however, only 44% of the deaths were directly attributed to glycoprotein IIb/IIIa inhibitor use. All related deaths were due to excessive bleeding with the CNS being the most common bleed site (Brown, 2003).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 58-year-old woman developed severe hypotension and acute airway obstruction approximately 19 minutes after beginning abciximab therapy during a coronary artery stenting procedure. The patient recovered following administration of epinephrine, diphenhydramine, and methylprednisolone (Guzzo & Nichols, 1999).

Reproductive

    3.20.1) SUMMARY
    A) Abciximab is classified by the manufacturer as FDA pregnancy category C, eptifibatide and tirofiban are classified as FDA pregnancy category B. Animal studies conducted with tirofiban and eptifibatide have not shown any evidence of teratogenicity. At the time of this review, animal reproduction studies have not been conducted with abciximab to determine its teratogenicity. It is not known whether glycoprotein IIb/IIIa receptor antagonists are excreted in human breast milk.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of abciximab, eptifibatide, or tirofiban in humans (Prod Info ReoPro(R) intravenous injection, 2013; Prod Info AGGRASTAT(R) intravenous injection solution, 2012; Prod Info Integrilin(R) IV injection, 2011).
    B) ANIMAL STUDIES
    1) ABCIXIMAB
    a) Animal studies evaluating the teratogenicity potential of abciximab have not been preformed (Prod Info ReoPro(R) intravenous injection, 2013).
    2) EPTIFIBATIDE
    a) Reproductive studies involving continuous IV infusion of eptifibatide in pregnant animals at total daily doses of approximately 4 times the maximum recommended human dose did not result in fetal harm (Prod Info Integrilin(R) IV injection, 2011).
    b) Animal studies conducted with tirofiban and eptifibatide have not shown any evidence of teratogenicity when administered at up to 13 times and at 4 times the maximum recommended daily human dose, respectively (Prod Info Integrilin(R) IV injection, 2011; Prod Info AGGRASTAT(R) intravenous injection solution, 2012).
    3) TIROFIBAN
    a) In animal studies, tirofiban crossed the placental barrier; however, animal studies with IV tirofiban hydrochloride doses up to approximately 5 and 13 times the maximum recommended human dose, respectively, have shown no evidence of fetal harm (Prod Info AGGRASTAT(R) intravenous injection, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to abciximab, eptifibatide, or tirofiban during pregnancy in humans (Prod Info ReoPro(R) intravenous injection, 2013; Prod Info AGGRASTAT(R) intravenous injection solution, 2012; Prod Info Integrilin(R) IV injection, 2011).
    B) PREGNANCY CATEGORY
    1) Abciximab is classified by the manufacturer as FDA pregnancy category C (Prod Info ReoPro(R) intravenous injection, 2013), eptifibatide and tirofiban are classified as FDA pregnancy category B (Prod Info AGGRASTAT(R) intravenous injection, 2013; Prod Info Integrilin(R) IV injection, 2011).
    C) TIROFIBAN
    1) There are no adequate or well-controlled studies on the use of tirofiban in pregnant women. The effects, if any, on the developing fetus are unknown. In animal studies, tirofiban crossed the placental barrier; however, animal studies with IV tirofiban hydrochloride doses up to approximately 5 and 13 times the maximum recommended human dose, respectively, have shown no evidence of fetal harm (Prod Info AGGRASTAT(R) intravenous injection, 2013). Until more information is available, tirofiban should only be used during pregnancy only if the potential maternal benefit outweighs the risk to the fetus.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to abciximab, eptifibatide or tirofiban during lactation in humans (Prod Info ReoPro(R) intravenous injection, 2013; Prod Info AGGRASTAT(R) intravenous injection solution, 2012; Prod Info Integrilin(R) IV injection, 2011).
    B) TIROFIBAN
    1) No reports describing the use of tirofiban during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown. It is not known if tirofiban affects the quantity and composition of breast milk; however, significant concentrations of tirofiban have been observed in the milk of lactating animals. It is recommended to either discontinue nursing or tirofiban, because many drugs are excreted in human milk, and the potential for adverse reactions from tirofiban exists in nursing infants (Prod Info AGGRASTAT(R) intravenous injection, 2013).
    C) ANIMAL STUDIES
    1) TIROFIBAN
    a) A significant amount of tirofiban was detected in animal milk during lactation studies (Prod Info AGGRASTAT(R) intravenous injection solution, 2012).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) ANIMAL STUDIES
    a) ABCIXIMAB
    1) At the time of this review, no long term studies evaluating the effects of abciximab on fertility have been preformed (Prod Info ReoPro(R) intravenous injection, 2013).
    B) LACK OF EFFECT
    1) ANIMAL STUDIES
    a) EPTIFIBATIDE
    1) Eptifibatide had no effects on fertility in male and female animals when administered continuous IV infusions at a dose of 4 times the maximum recommended human dosage based on body surface area (Prod Info Integrilin(R) IV injection, 2011).
    b) TIROFIBAN
    1) Fertility was not effected in studies with male and female animals given IV doses of tirofiban up to approximately 5 times the maximum recommended daily human dose when compared to body surface area (Prod Info AGGRASTAT(R) intravenous injection solution, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor the aPTT, INR, platelet counts and hematocrit. Severe thrombocytopenia has occurred with therapeutic use.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Monitor CBC, including platelets, INR, and activated partial thromboplastin time (aPTT). Platelet counts should be measured within 2 to 4 hours after initiation of glycoprotein IIb/IIIa receptor antagonist therapy, twice on the first day of therapy, and periodically for the duration of therapy (Berkowitz, 2000). Severe thrombocytopenia may occur between 2 hours and 6 days after initiation of therapy.
    2) Pseudothrombocytopenia can be ruled out by careful examination of a peripheral blood smear (platelet clumping suggests pseudothrombocytopenia). If pseudothrombocytopenia occurs, a platelet count on citrate anticoagulated blood should be normal. Heparin-induced thrombocytopenia can be ruled out by the absence of heparin-dependent immunoglobulin G antibodies (Bishara & Hagmeyer, 2000).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain a chest x-ray in patients with hemoptysis, hypoxia or pulmonary symptoms.
    B) CT RADIOGRAPH
    1) Obtain a head CT scan/MRI in patients with altered mentation or an abnormal neurologic exam.

Methods

    A) CHROMATOGRAPHY
    1) Liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) was used to cross-validate an immunoassay method performed for the determination of tirofiban in human plasma. The limit of quantitation of the LC-MS/MS was 0.4 ng/mL (Ellis et al, 1997).
    2) High-performance liquid chromatography with solid phase extraction was performed for quantitative analysis of eptifibatide and its metabolite, deamidated eptifibatide (DE), in human plasma and urine. The limits of quantitation for eptifibatide and DE, in plasma, were 41.7 ng/mL and 18.0 ng/mL, respectively, and the limits of quantitation for eptifibatide and DE, in urine, were 52.2 ng/mL and 44.9 ng/mL, respectively (Alton et al, 1998).
    B) IMMUNOASSAY
    1) Radioimmunoassay was described for determination of tirofiban in human plasma and urine. Using 5 mcL of plasma and 0.5 mcL of urine, this method had a sensitivity of 1 ng/mL and 10 ng/mL, respectively (Hand et al, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Any patient who develops hypotension, thrombocytopenia, or clinically significant bleeding should remain admitted in a monitored setting until symptoms resolve, bleeding is stopped, and thrombocytopenia has resolved.

Monitoring

    A) Monitor the aPTT, INR, platelet counts and hematocrit. Severe thrombocytopenia has occurred with therapeutic use.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL

Range Of Toxicity

Summary

    A) TOXIC DOSE: A specific minimum toxic dose has not been established. Minor bleeding occurred following inadvertent overdosage or tirofiban in doses up to 9.8 time the 0.15 mcg/kg/min maintenance infusion rate. An adult who received an infusion of eptifibatide at 5 times the intended infusion rate for 90 minutes had no complications, normal bleeding times and platelet counts.
    B) THERAPEUTIC DOSE: ADULT: ABCIXIMAB: RECOMMENDED DOSE: 0.25 mg/kg IV bolus administered 10 to 60 minutes before beginning percutaneous coronary intervention (PCI), followed by a continuous IV infusion of 0.125 mcg/kg/min (up to a maximum dose of 10 mcg/minute) for 12 hours. EPTIFIBATIDE 180 mcg/kg IV bolus administered immediately after diagnosis, followed by a continuous infusion of 2 mcg/kg/min continued until the patient is discharged or until initiation of coronary artery bypass graft (CABG) surgery, up to a maximum of 72 hours. TIROFIBAN: RECOMMENDED DOSE: Infuse a 50 mcg/mL solution administered at an initial rate of 0.4 mcg/kg/min for 30 minutes followed by a continuous infusion of 0.1 mcg/kg/min. Continue the infusion through angiography and for 12 to 24 hours after angioplasty or atherectomy. PEDIATRIC: The safety and efficacy of glycoprotein IIb/IIIa receptor antagonists in the pediatric population has not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) ABCIXIMAB
    a) The recommended dosage is 0.25 mg/kg IV bolus administered 10 to 60 minutes before beginning percutaneous coronary intervention (PCI), followed by a continuous IV infusion of 0.125 mcg/kg/min (up to a maximum dose of 10 mcg/minute) for 12 hours (Prod Info ReoPro(R) IV injection, 2011).
    b) Patients with unstable angina not responding to conventional medical therapy and who are planned to undergo percutaneous coronary intervention within 24 hours may be treated with an abciximab 0.25 mg/kg IV bolus followed by an 18 to 24 hour IV infusion of 10 mcg/min, concluding one hour after the percutaneous coronary intervention (Prod Info ReoPro(R) IV injection, 2011).
    2) EPTIFIBATIDE
    a) ACUTE CORONARY SYNDROME
    1) NORMAL RENAL FUNCTION: 180 mcg/kg IV bolus administered immediately after diagnosis, followed by a continuous infusion of 2 mcg/kg/min continued until the patient is discharged or until initiation of coronary artery bypass graft (CABG) surgery, up to a maximum of 72 hours (Prod Info INTEGRILIN(R) intravenous injection, 2013).
    2) CREATININE CLEARANCE LESS THAN 50 mL/min: 180 mcg/kg IV bolus administered immediately after diagnosis, followed by a continuous infusion of 1 mcg/kg/min continued until the patient is discharged or until initiation of coronary artery bypass graft (CABG) surgery, up to a maximum of 72 hours (Prod Info INTEGRILIN(R) intravenous injection, 2013).
    b) PERCUTANEOUS CORONARY INTERVENTION
    1) NORMAL RENAL FUNCTION: 180 mcg/kg IV bolus administered immediately before beginning the procedure followed by a continuous infusion of 2 mcg/kg/min and a second 180 mcg/kg bolus 10 minutes after the first bolus. Infusion should be continued for up to 18 to 24 hours or upon discharge, whichever comes first (minimum of 12 hours of infusion is recommended) (Prod Info INTEGRILIN(R) intravenous injection, 2013).
    2) CREATININE CLEARANCE LESS THAN 50 mL/min: 180 mcg/kg IV bolus administered immediately before beginning the procedure followed by a continuous infusion of 1 mcg/kg/min and a second 180 mcg/kg bolus 10 min after the first bolus. Infusion should be continued for up to 18 to 24 hours or upon discharge, whichever comes first (minimum of 12 hours of infusion is recommended) (Prod Info INTEGRILIN(R) intravenous injection, 2013).
    3) TIROFIBAN
    a) INTRAVENOUS: The recommended dosage is 25 mcg/kg infused within 5 minutes followed by a continuous infusion of 0.15 mcg/kg/min for up to 18 hours (Prod Info AGGRASTAT(R) intravenous injection, 2015).
    7.2.2) PEDIATRIC
    A) SUMMARY
    1) The safety and efficacy of glycoprotein IIb/IIIa receptor antagonists in the pediatric population has not been established (Prod Info ReoPro(R) IV injection, 2011; Prod Info INTEGRILIN(R) intravenous injection, 2013; Prod Info AGGRASTAT(R) intravenous injection, 2015).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) TIROFIBAN: In clinical trials, inadvertent overdosage of tirofiban occurred in doses up to 9.8 times the 0.15 mcg/kg/min maintenance infusion rate, primarily resulting in minor mucocutaneous bleeding events and minor bleeding at cardiac catheterization sites (Prod Info Aggrastat(R), tirofiban hydrochloride, 2000).
    2) EPTIFIBATIDE: A 66-year-old woman received eptifibatide during and proceeding percutaneous coronary intervention (PCI) at a rate of 14 mL/hr. During transfer to the ICU, the eptifibatide infusion was stopped; when restarted, the infusion was resumed at a rate of 75 mL/hr (5 times the intended infusion rate). Estimated time lapse was 90 min before the infusion was stopped. The patient showed no clinical or laboratory abnormalities, and bleeding times as well as platelet counts remained normal for the remainder of the hospital stay (Parakh et al, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The glycoprotein IIb/IIIa receptor is the most abundant of the integrins found on the surface membrane of platelets. The alpha (a) subunit of the receptor consists of a heavy chain and a light chain, and the beta (b) subunit consists of a single polypeptide of 762 amino acids (Lefkovits et al, 1995). In platelet aggregation, platelet activation, by platelet agonists, triggers conformational changes in the unactivated glycoprotein receptor transforming it into an activated, ligand-competent state. The activated receptor will then bind to fibrinogen, as well as other adhesive glycoproteins (ie, fibronectin, von Willebrand factor, and vitronectin), forming in cross-bridges between adjacent platelets and linking them together to aggregate into a hemostatic plug (Lefkovits & Topol, 1996; Lefkovits et al, 1995).
    B) Glycoprotein IIb/IIIa receptor antagonists prevent the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to glycoprotein IIb/IIIa receptors, resulting in inhibition of platelet aggregation (Prod Info INTEGRILIN(R) intravenous injection, 2013; Prod Info AGGRASTAT(R) intravenous injection solution, 2012). Inhibition of platelet aggregation is reversible following discontinuation of glycoprotein IIb/IIIa receptor antagonist therapy, and is thought to be due to dissociation of the receptor antagonist from the platelet.

Toxicologic Mechanism

    A) The exact mechanism of glycoprotein IIb/IIIa receptor antagonist-induced thrombocytopenia is not well understood. With abciximab, it is speculated that the binding of abciximab to the IIb/IIIa receptor produces a conformational change, which produces epitopes, called ligand-induced binding sites (LIBS). If patients who are on abciximab therapy have antibodies that would cross-react with the LIBS, platelets would be coated with immunoglobulin and then removed from the circulation (Desai & Lucore, 2000; Jubelirer et al, 1999).

Physicochemical

Physical Characteristics

    A) ABCIXIMAB is a clear and colorless solution (Prod Info ReoPro(R) IV injection, 2011)
    B) EPTIFIBATIDE is a clear and colorless solution (Prod Info Integrilin(R) IV injection, 2011).
    C) TIROFIBAN is a white to off-white, free-flowing powder, which is very slightly soluble in water (Prod Info AGGRASTAT(R) intravenous injection, 2008).

Ph

    A) ABCIXIMAB: 7.2 (Prod Info ReoPro(R) IV injection, 2011)
    B) EPTIFIBATIDE: 5.35 (Prod Info Integrilin(R) IV injection, 2011)
    C) TIROFIBAN: 5.5 to 6.5 (premixed solution) (Prod Info AGGRASTAT(R) intravenous injection, 2008)

Molecular Weight

    A) ABCIXIMAB: 47,615 daltons (Prod Info ReoPro(R) IV injection, 2011)
    B) EPTIFIBATIDE: 831.96 (Prod Info Integrilin(R) IV injection, 2011)
    C) TIROFIBAN: 495.08 (Prod Info AGGRASTAT(R) intravenous injection, 2008)

References

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