Adverse reactions : תופעות לוואי

6      ADVERSE REACTIONS
The following serious adverse reaction is also discussed elsewhere in the labeling: 
•    Bleeding [see Contraindications (4) and Warnings and Precautions (5.1)] 
6.1    Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
A total of 16,782 patients were treated in the Phase III clinical trials (PURSUIT, ESPRIT, and IMPACT II) [see Clinical Studies (14)]. 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 3 studies were not pooled.
Bleeding and hypotension were the most commonly reported adverse reactions (incidence ≥5% and greater than placebo) in the INTEGRILIN controlled clinical trial database.
Bleeding
The incidence of bleeding and transfusions in the PURSUIT and ESPRIT studies are shown in Table 2. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding 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.
Table 2: Bleeding and Transfusions in the PURSUIT and ESPRIT Studies

PURSUIT (ACS)
Placebo                INTEGRILIN
180/2 n (%)                n (%)
Patients                                                     4696                 4679 Major bleeding*                                          425 (9.3%)            498 (10.8%) 347 (7.6%)            604 (13.1%)
Minor bleeding*                                          490 (10.4%)           601 (12.8%) Requiring transfusions†

ESPRIT (PCI)
Placebo                INTEGRILIN
180/2/180 n (%)                n (%)
Patients                                                      1024                 1040 Major bleeding*                                             4 (0.4%)             13 (1.3%) 18 (2%)              29 (3%)
Minor bleeding*                                             11 (1.1%)            16 (1.5%) Requiring transfusions†
Note: Denominator is based on patients for whom data are available.
* For major and minor bleeding, patients are counted only once according to the most severe classification.
†
Includes transfusions of whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion during the initial hospitalization.

The majority of major bleeding reactions in the ESPRIT study occurred at the vascular access site (1 and 8 patients, or 0.1% and 0.8% in the placebo and INTEGRILIN 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 INTEGRILIN-treated patients compared to placebo-treated patients was also associated with bleeding at the femoral artery access site (2.8% versus 1.3%).
Oropharyngeal (primarily gingival), genitourinary, gastrointestinal, and retroperitoneal bleeding were also seen more commonly in INTEGRILIN-treated patients compared to placebo-treated patients.
Among patients experiencing a major bleed in the IMPACT II study, an increase in bleeding on INTEGRILIN versus placebo was observed only for the femoral artery access site (3.2% versus 2.8%).
Table 3 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.
Table 3: Major Bleeding by Procedures in the PURSUIT Study
Placebo         INTEGRILIN
180/2 n (%)            n (%)

Patients                                                        4577                4604 
Overall incidence of major bleeding                          425 (9.3%)        498 (10.8%) 
Breakdown by procedure:

CABG                                                       375 (8.2%)        377 (8.2%) 
Angioplasty without CABG                                    27 (0.6%)         64 (1.4%) 
Angiography without angioplasty or CABG                     11 (0.2%)         29 (0.6%) 
Medical therapy only                                        12 (0.3%)         28 (0.6%) Note: Denominators are based on the total number of patients whose TIMI classification was resolved.

In the PURSUIT and ESPRIT studies, the risk of major bleeding with INTEGRILIN increased as patient weight decreased. This relationship was most apparent for patients weighing less than 70 kg.
Bleeding resulting in discontinuation of the study drug was more frequent among patients receiving INTEGRILIN than placebo (4.6% versus 0.9% in ESPRIT, 8% versus 1% in PURSUIT, 3.5% versus 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 INTEGRILIN 180/1.3, and 5 patients in the group treated with INTEGRILIN 180/2 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving INTEGRILIN 180/1.3, 0.7% in patients receiving INTEGRILIN 180/2, and 0.8% in placebo patients.
In the IMPACT II study, intracranial hemorrhage was experienced by 1 patient treated with INTEGRILIN 135/0.5, 2 patients treated with INTEGRILIN 135/0.75, and 2 patients in the placebo group. The overall incidence of stroke was
0.5% in patients receiving 135/0.5 INTEGRILIN, 0.7% in patients receiving INTEGRILIN 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 INTEGRILIN group.
In addition there was 1 case of cerebral infarction in the INTEGRILIN group.
Immunogenicity/Thrombocytopenia
The potential for development of antibodies to eptifibatide has been studied in 433 subjects. INTEGRILIN was nonantigenic in 412 patients receiving a single administration of INTEGRILIN (135-mcg/kg bolus followed by a continuous infusion of either 0.5 mcg/kg/min or 0.75 mcg/kg/min), and in 21 subjects to whom INTEGRILIN (135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/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.
In patients with suspected INTEGRILIN-related immune-mediated thrombocytopenia, IgG antibodies that react with the GP IIb/IIIa complex were identified in the presence of eptifibatide and in INTEGRILIN-naïve patients. These findings suggest acute thrombocytopenia after the administration of INTEGRILIN can develop as a result of naturally occurring drug-dependent antibodies or those induced by prior exposure to INTEGRILIN. Similar antibodies were identified with other GP IIb/IIIa ligand-mimetic agents. Immune-mediated thrombocytopenia with INTEGRILIN may be associated with hypotension and/or other signs of hypersensitivity.


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 INTEGRILIN and placebo. In the ESPRIT study, the incidence was 0.6% in the placebo group and 1.2% in the INTEGRILIN 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.
Other Adverse Reactions
In the PURSUIT and ESPRIT studies, the incidence of serious nonbleeding adverse reactions was similar in patients receiving placebo or INTEGRILIN (19% and 19%, respectively, in PURSUIT; 6% and 7%, respectively, in ESPRIT). In PURSUIT, the only serious nonbleeding adverse reaction that occurred at a rate of at least 1% and was more common with INTEGRILIN than placebo (7% versus 6%) was hypotension. Most of the serious nonbleeding adverse reactions consisted of cardiovascular reactions typical of a UA population. In the IMPACT II study, serious nonbleeding adverse reactions that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo- and INTEGRILIN-treated patients.
Discontinuation of study drug due to adverse reactions other than bleeding was uncommon in the PURSUIT, IMPACT II, and ESPRIT studies, with no single reaction 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 INTEGRILIN 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 INTEGRILIN 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 INTEGRILIN 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%).

6.2   Postmarketing Experience
The following adverse reactions have been reported in post-approval use of INTEGRILIN 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; anaphylaxis, rash and application site disorders such as urticaria. Cases of pulmonary hemorrhage have also been reported very rarely. Fatal bleeding reactions have been reported. Acute profound thrombocytopenia, as well as immune-mediated thrombocytopenia, have been reported [see Adverse Reactions (6.1)].

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il