Integrilin Side Effects

Generic Name: eptifibatide

Please note - some side effects for Integrilin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Integrilin - for the Consumer

Integrilin

All medicines may cause side effects, but many people have no, or minor, side effects. When used in small doses, no COMMON side effects have been reported with Integrilin. Seek medical attention right away if any of these SEVERE side effects occur when using Integrilin:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; bleeding from gums when brushing or flossing teeth; coughing up blood; excessive bleeding from cuts; increased menstrual bleeding; major bleeding episodes; nosebleeds; one-sided weakness; red urine; redness or pain after an injection; severe headache; stomach pain or swelling; unexplained vaginal bleeding; unusual bruising; vision or speech changes; vomiting blood or material that looks like coffee grounds.

Integrilin Side Effects - for the Professional

Integrilin

A total of 16,782 patients were treated in the Phase III clinical trials (PURSUIT, ESPRIT, and IMPACT II). These 16,782 patients had a mean age of 62 years (range 20–94 years). Eighty-nine percent of the patients were Caucasian, with the remainder being predominantly Black (5%) and Hispanic (5%). Sixty-eight percent were men. Because of the different regimens used in PURSUIT, IMPACT II, and ESPRIT, data from the three studies were not pooled.

Bleeding

The incidences of bleeding events and transfusions in the PURSUIT, IMPACT II, and ESPRIT studies are shown in Table 8. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding events consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria, spontaneous hematemesis, other observed blood loss with a hemoglobin decrease of more than 3 g/dL, and other hemoglobin decreases that were greater than 4 g/dL but less than 5 g/dL. In patients who received transfusions, the corresponding loss in hemoglobin was estimated through an adaptation of the method of Landefeld et al.

The majority of major bleeding events in the ESPRIT study occurred at the vascular access site (1 and 8 patients, or 0.1% and 0.8% in the placebo and eptifibatide groups, respectively). Bleeding at "other" locations occurred in 0.2% and 0.4% of patients, respectively.

In the PURSUIT study, the greatest increase in major bleeding in eptifibatide-treated patients compared to placebo-treated patients was also associated with bleeding at the femoral artery access site (2.8% vs 1.3%). Oropharyngeal (primarily gingival), genitourinary, gastrointestinal, and retroperitoneal bleeding were also seen more commonly in eptifibatide-treated patients compared to placebo-treated patients.

Among patients experiencing a major bleed in the IMPACT II study, an increase in bleeding on eptifibatide versus placebo was observed only for the femoral artery access site (3.2% vs 2.8%).

Table 9 displays the incidence of TIMI major bleeding according to the cardiac procedures carried out in the PURSUIT study. The most common bleeding complications were related to cardiac revascularization (CABG-related or femoral artery access site bleeding). A corresponding table for ESPRIT is not presented as every patient underwent PCI in the ESPRIT study and only 11 patients underwent CABG.

In the PURSUIT and ESPRIT studies, the risk of major bleeding with eptifibatide increased as patient weight decreased. This relationship was most apparent for patients weighing less than 70 kg.

Bleeding adverse events resulting in discontinuation of the study drug were more frequent among patients receiving eptifibatide than placebo (4.6% vs 0.9% in ESPRIT, 8% vs 1% in PURSUIT, 3.5% vs 1.9% in IMPACT II).

Intracranial Hemorrhage and Stroke

Intracranial hemorrhage was rare in the PURSUIT, IMPACT II, and ESPRIT clinical studies. In the PURSUIT study, 3 patients in the placebo group, 1 patient in the group treated with eptifibatide 180/1.3 and 5 patients in the group treated with eptifibatide 180/2.0 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving eptifibatide 180/1.3, 0.7% in patients receiving eptifibatide 180/2.0, and 0.8% in placebo patients.

In the IMPACT II study, intracranial hemorrhage was experienced by 1 patient treated with eptifibatide 135/0.5, 2 patients treated with eptifibatide 135/0.75 and 2 patients in the placebo group. The overall incidence of stroke was 0.5% in patients receiving 135/0.5 eptifibatide, 0.7% in patients receiving eptifibatide 135/0.75 and 0.7% in the placebo group.

In the ESPRIT study, there were 3 hemorrhagic strokes, 1 in the placebo group, and 2 in the eptifibatide group. In addition there was 1 case of cerebral infarction in the eptifibatide group.

Thrombocytopenia

In the PURSUIT and IMPACT II studies, the incidence of thrombocytopenia (<100,000/mm3 or ≥50% reduction from baseline) and the incidence of platelet transfusions were similar between patients treated with eptifibatide and placebo. In the ESPRIT study, the incidence was 0.6% in the placebo group and 1.2% in the eptifibatide group.

Allergic Reactions

In the PURSUIT study, anaphylaxis was reported in 7 patients receiving placebo (0.15%) and 7 patients receiving eptifibatide 180/2.0 (0.16%). In the IMPACT II study, anaphylaxis was reported in 1 patient (0.08%) on placebo and in no patients on eptifibatide. In the IMPACT II study, 2 patients (1 patient [0.04%] receiving eptifibatide and 1 patient [0.08%] receiving placebo) discontinued study drug because of allergic reactions. In the ESPRIT study, there were no cases of anaphylaxis reported. There were 3 patients who suffered an allergic reaction, 1 on placebo and 2 on eptifibatide. In addition, 1 patient in the placebo group was diagnosed with urticaria.

The potential for development of antibodies to eptifibatide has been studied in 433 subjects. Eptifibatide was nonantigenic in 412 patients receiving a single administration of eptifibatide (135-µg/kg bolus followed by a continuous infusion of either 0.5 µg/kg/min or 0.75 µg/kg/min), and in 21 subjects to whom eptifibatide (135-µg/kg bolus followed by a continuous infusion of 0.75 µg/kg/min) was administered twice, 28 days apart. In both cases, plasma for antibody detection was collected approximately 30 days after each dose. The development of antibodies to eptifibatide at higher doses has not been evaluated.

Other Adverse Reactions

In the PURSUIT and ESPRIT studies, the incidence of serious nonbleeding adverse events was similar in patients receiving placebo or eptifibatide (19% and 19%, respectively, in PURSUIT; 6% and 7%, respectively, in ESPRIT). In PURSUIT, the only serious nonbleeding adverse event that occurred at a rate of at least 1% and was more common with eptifibatide than placebo (7% vs 6%) was hypotension. Most of the serious nonbleeding events consisted of cardiovascular events typical of an unstable angina population. In the IMPACT II study, serious nonbleeding events that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo- and eptifibatide-treated patients.

Discontinuation of study drug due to adverse events other than bleeding was uncommon in the PURSUIT, IMPACT II, and ESPRIT studies, with no single event occurring in >0.5% of the study population (except for "other" in the ESPRIT study). In the PURSUIT study, nonbleeding adverse events leading to discontinuation occurred in the eptifibatide and placebo groups in the following body systems with an incidence of ≥0.1%: cardiovascular system (0.3% and 0.3%), digestive system (0.1% and 0.1%), hemic/lymphatic system (0.1% and 0.1%), nervous system (0.3% and 0.4%), urogenital system (0.1% and 0.1%), and whole body system (0.2% and 0.2%). In the ESPRIT study, the following nonbleeding adverse events leading to discontinuation occurred in the eptifibatide and placebo groups with an incidence of ≥0.1%: "other" (1.2% and 1.1%). In the IMPACT II study, nonbleeding adverse events leading to discontinuation occurred in the 135/0.5 eptifibatide and placebo groups in the following body systems with an incidence of ≥0.1%: whole body (0.3% and 0.1%), cardiovascular system (1.4% and 1.4%), digestive system (0.2% and 0%), hemic/lymphatic system (0.2% and 0%), nervous system (0.3% and 0.2%), and respiratory system (0.1% and 0.1%).

Post-Marketing Experience

The following adverse events have been reported in post-marketing experience, primarily with eptifibatide in combination with heparin and aspirin: cerebral, GI, and pulmonary hemorrhage. Fatal bleeding events have been reported. Acute profound thrombocytopenia has been reported.

Side Effects by Body System

General

Prior to approval by the FDA, the efficacy and safety of eptifibatide was evaluated in 8,737 patients. The average age of these patients was 62 years (range 20 to 94). Eighty-nine percent were Caucasian, 5% were Black, and 5% were Hispanic. Sixty-seven percent were male. The most common side effect was bleeding. Discontinuation of eptifibatide due to adverse events other than bleeding has been uncommon; no single event occurred in greater than 0.5% of the study population.

Hematologic

The overall incidence of intracranial hemorrhage or stroke in large clinical trials has ranged from 0.5% to 0.7% of patients, depending on dose. The incidences of thrombocytopenia and the need for platelet transfusions were similar between patients who received eptifibatide and those who received placebo, suggesting a stronger relationship between these problems and the use of heparin than with the use of the study drug. However, bleeding times and activated clotting times have been significantly higher among treated patients compared with placebo, in some cases despite receiving less heparin.

The incidence of thrombocytopenia (less than 100,000 cells/mcL) associated with eptifibatide is 1.2% to 6.8%, while severe thrombocytopenia (less than 50,000 cells/mcL) has been reported in 0.2% of patients. Platelet transfusions have been reported in 1.3% to 1.5% of patients.

The results of one study (PROTECT-TIMI-30 trial) indicate that in high-risk non-ST-segment elevation acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) and treated with eptifibatide, increased age significantly correlated with bleeding events. Patients with reduced CrCl (less than or equal to 50 mL/min), given a full-dose eptifibatide infusion, were associated with a greater incidence of bleeding events. No bleeding events occurred in patients with reduced CrCl who received a reduced-dose infusion. In addition, the majority of bleeding events occurred more than 6 hours after initiation of the eptifibatide infusion.

Risk factors for bleeding events in patients treated with glycoprotein (GP) IIb/IIIa inhibitors undergoing percutaneous coronary intervention have been identified and include advanced age, renal dysfunction, female gender, peripheral vascular disease, lower body weight, duration of GP IIb/IIIa inhibitor infusion, baseline platelet count, lower baseline hemoglobin, diabetes, and elevated peak activated clotting time. According to one study (CRUSADE trial) involving patients with non-ST-segment elevation acute coronary syndrome treated with a GPIIb/IIIa inhibitor, women are at a greater risk of bleeding than men, primarily because of excessive dosing.

Hematologic side effects have been the most common and potentially serious. The incidences of major (intracranial hemorrhage or decreases in hemoglobin of 5 mg/dL or more) and minor bleeding (spontaneous gross hematuria or hematemesis, decreases in hemoglobin of less than 5 mg/dL) were 10.8% and 13.1% (PURSUIT study) and 4.7% and 14.2% (IMPACT II study), respectively. The incidences of the transfusion requirements in these two studies were 12.8% and 5.8%, respectively. The overall incidence of major bleeding was strongly associated with the incidence of coronary artery bypass graft surgery, and occurred mainly at arterial puncture sites. The next most common sites of bleeding--occurring in 0% to 6% of patients--were oropharyngeal (primarily gingival), gastrointestinal (incidences of upper and lower GI bleeding similar), genitourinary, then retroperitoneal. In the PURSUIT study, the risk of major bleeding was inversely related to body weight; patients less than 70 kg showed the highest correlation. Bleeding was cited as the reason to discontinue therapy in 3.5% to 8.0% of patients.

Fatal bleeding, thrombocytopenia, as well as cerebral, gastrointestinal and pulmonary hemorrhage (when used in combination with aspirin and heparin) have been reported during postmarketing experience.

Hypersensitivity

Hypersensitivity reactions have been rare, and have included anaphylaxis in approximately 0.05% of patients.

Cardiovascular

Cardiovascular side effects have included hypotension (7% versus 6% among placebo patients). Other cardiovascular side effects may have been related to underlying disease as they were typical of side effects among patients with unstable angina.

Nervous system

Nervous system side effects have been limited to non-hemorrhagic stroke in approximately 0.5% of treated and placebo patients in controlled trials.

Musculoskeletal

Musculoskeletal discomfort--basically back pain--was reported in significantly more patients who received eptifibatide compared with placebo patients in the IMPACT II trial (50% versus 47%).

Local

Local intravenous site reactions have been reported in significantly more treated patients compared with placebo patients in controlled trials. Arterial access sites are the most common sites of bleeding.

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