ANNEX I. SUMMARY OF PRODUCT CHARACTERISTICS. 1 INTEGRILIN is indicated for the prevention of early myocardial infarction in adults presenting. Package leaflet: Information for the patient. Integrilin mg/ml solution for infusion eptifibatide. Read all of this leaflet carefully before you start using this. 1. Package leaflet: Information for the patient. Eptifibatide Accord 2 mg/ml solution for injection eptifibatide. Read all of this leaflet carefully before you start using.
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Medically reviewed on Jan 1, Integrilin is indicated to decrease the rate of a combined endpoint of death, new MI, or need for urgent intervention in patients undergoing PCI, including those undergoing intracoronary stenting [see Clinical Studies Before infusion of Integrilin, the following laboratory lntegrilin should be performed to identify pre-existing hemostatic abnormalities: The activated partial thromboplastin time aPTT should be maintained between 50 and 70 seconds unless PCI is to be performed.
Integrilin should be given concomitantly with heparin dosed to achieve the following parameters:. Administer Integrilin by volume according to patient weight see Table 1. Bleeding is the most common complication encountered during Integrilin therapy. Administration of Integrilin is associated with an increase in major and minor bleeding, as classified by the criteria of the Thrombolysis in Myocardial Infarction Study group TIMI [see Adverse Reactions 6.
Most major bleeding associated with Integrilin has been at the arterial access site for cardiac catheterization or from integrilkn gastrointestinal or genitourinary tract. Minimize the use of arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation, and nasogastric tubes. When obtaining intravenous access, avoid non-compressible sites e.
Risk factors for bleeding include older age, a history of bleeding disorders, and paciage use of drugs pacoage increase the risk of packabe thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs, and P2Y 12 inhibitors. In patients undergoing PCI, treatment with Inyegrilin is associated with an increase in major and minor bleeding at the site of arterial sheath placement. After PCI, Integrilin infusion should be continued until hospital discharge or up to 18 to 24 hours, whichever comes first.
Heparin use is discouraged after the PCI procedure. Early sheath removal is encouraged while Integrilin is being infused. In any case, both heparin and Integrilin should be discontinued and sheath hemostasis should be achieved at least 2 to 4 packagw before hospital discharge.
If bleeding at access site cannot be controlled with pressure, infusion of Integrilin and heparin should be discontinued immediately. There have been reports of acute, profound thrombocytopenia immune-mediated and non-immune mediated with Integrilin.
Monitor serial platelet counts, assess the presence of drug-dependent antibodies, and treat as appropriate [see Adverse Reactions 6. If a patient with low platelet counts is receiving Integrilin, their platelet count should be monitored closely. The following serious adverse reaction is also discussed elsewhere in the labeling:.
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. These 16, patients had a mean age of 62 years range: Sixty-eight percent were men. Bleeding was classified integrilib major or minor by the criteria of the TIMI study group. 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 reactions pacckage the ESPRIT study occurred at the vascular access site 1 and 8 patients, or 0.
Bleeding at “other” locations occurred packagee 0. 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. Oropharyngeal primarily gingivalgenitourinary, 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.
The most common bleeding complications were related to cardiac revascularization CABG-related or femoral artery access site bleeding. 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. Intracranial Hemorrhage and Stroke. The overall incidence of stroke was 0. In addition there was 1 case of cerebral infarction in the Integrilin group. The potential for development of antibodies to eptifibatide has been studied in subjects.
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. 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.
Most of the serious nonbleeding adverse reactions consisted of cardiovascular reactions typical of a UA population. 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.
The following adverse reactions have been reported in postmarketing experience, primarily with Integrilin in combination with heparin and aspirin: Fatal bleeding reactions have been reported. Acute profound thrombocytopenia, as well as immune-mediated thrombocytopenia, has been reported [see Adverse Reactions 6. Coadministration of antiplatelet agents, thrombolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. These studies revealed no evidence of harm to the fetus due to eptifibatide.
There are, however, no adequate and well-controlled studies in pregnant women with Integrilin. Because animal reproduction studies are not always predictive of human response, Integrilin should be used during pregnancy only if clearly needed.
It is not known whether eptifibatide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Integrilin is administered to a nursing mother. Safety and effectiveness of Integrilin in pediatric patients have not been studied.
There was no apparent difference in efficacy between older and younger patients treated with Integrilin. The incidence of intrgrilin complications was higher in the elderly in both placebo and Integrilin groups, and the incremental risk of Integrilin-associated bleeding was greater in the older patients. The safety and efficacy of Integrilin in patients dependent on dialysis has not been established. There has been only limited experience with overdosage of Integrilin.
None of these patients experienced an intracranial bleed or other major bleeding.
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.
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. 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:. Integrilin Injection is a clear, colorless, sterile, non-pyrogenic solution for intravenous IV use with an empirical formula of C 35 H 49 N 11 O 9 S 2 and a molecular weight of Each vial of either size also contains 5.
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. 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. This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury Folts model.
Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, Integrilin inhibited ex vivo platelet aggregation induced by adenosine diphosphate ADP and other agonists in a dose- and concentration-dependent manner.
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. Plasma elimination half-life is approximately 2. No major metabolites have been detected in human plasma. Patients in clinical studies were older range: Elderly patients with coronary artery disease demonstrated higher plasma levels and lower total body clearance of eptifibatide when given the same dose as younger patients.
Males and females have not demonstrated any clinically significant differences in the pharmacokinetics of eptifibatide. No long-term studies in animals have been performed to evaluate the carcinogenic potential of eptifibatide.
Integrilin was studied in 3 placebo-controlled, randomized studies. Receptor Suppression Using Integrilin Therapy. The infusion was continued for 72 hours, until hospital discharge, or until the time of CABG, whichever occurred first, except that if PCI was performed, the Integrilin infusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to 96 hours.
The lower-infusion-rate arm was stopped after the first interim analysis when the 2 active-treatment arms appeared to have the same incidence of bleeding. This was a “real world” study; each patient was managed according to the usual standards of the investigational site; frequencies of angiography, PCI, and CABG therefore differed widely from site to site and from country to country.
The majority of patients received aspirin mg once daily. A target aPTT of 50 to 70 seconds was recommended. A total of patients underwent PCI within 72 hours after randomization, in which case they received intravenous heparin to maintain an ACT of to seconds.
The primary endpoint of the study was the occurrence of death from any cause or new MI evaluated by a blinded Clinical Endpoints Committee within 30 days of randomization.
The reduction in the incidence of endpoint events in patients receiving Integrilin was evident early during treatment, and this reduction was maintained through at least 30 days see Figure 1.
Table 5 also shows the incidence of the components of the primary endpoint, death whether or not preceded by an MI and new MI in surviving patients at 30 days.
Dilution Eptifibatide – Integrilin ® – GlobalRPH
Treatment with Integrilin prior to determination of patient management strategy reduced clinical events regardless of whether patients ultimately underwent diagnostic catheterization, revascularization i. Table 6 shows the incidence of death or MI within 72 hours. All of the effect inetgrilin Integrilin was established within 72 hours during the period of drug infusionregardless of management strategy.
Moreover, for patients undergoing early PCI, a reduction in events was evident prior to the procedure. This difference may be a true treatment difference, the effect of other differences in these subgroups, or a statistical anomaly.
As reported by the investigators, the occurrence of death from any cause or new MI for patients followed for at least days was reduced from Patients were randomly assigned to ibsert of 3 treatment regimens, each incorporating a bolus dose initiated immediately prior to PCI followed by a continuous infusion lasting 20 to 24 hours:.