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warnings and cautions
5 WARNINGS AND PRECAUTIONS Increases the risk of bleeding. Avoid intramuscular injections. ( 5.1 ) Hypersensitivity ( 5.2 ) Cholesterol embolism ( 5.3 ) 5.1 Bleeding RETAVASE can cause significant and sometimes fatal bleeding. Avoid intramuscular injections and other trauma to a patient administered RETAVASE. Minimize venipunctures. Avoid puncturing noncompressible veins, such as the internal jugular and subclavian. If an arterial puncture is necessary, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. As fibrin is lysed during RETAVASE therapy, bleeding from recent puncture sites or other recent trauma may occur. Should serious bleeding (not controllable by local pressure) occur, terminate concomitant anticoagulant therapy. Withhold the second RETAVASE dose if serious bleeding occurs before it is administered. 5.2 Hypersensitivity Reactions Hypersensitivity reactions have been reported with RETAVASE administration. Signs and symptoms observed included rash, pruritis, erythema, glossal (tongue) edema, hypotension and respiratory distress. If an anaphylactoid reaction occurs, withhold the second dose of RETAVASE and initiate appropriate therapy. 5.3 Cholesterol Embolization Cholesterol embolism has been reported in patients treated with thrombolytic agents. Cholesterol embolism may present with livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis and can be fatal. It is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. 5.4 Drug/Laboratory Test Interactions Coagulation tests and measures of fibrinolytic activity are unreliable during RETAVASE therapy unless specific precautions are taken to prevent in vitro artifacts. When present in blood at pharmacologic concentrations, RETAVASE remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.
warnings and cautions
5.1 Bleeding RETAVASE can cause significant and sometimes fatal bleeding. Avoid intramuscular injections and other trauma to a patient administered RETAVASE. Minimize venipunctures. Avoid puncturing noncompressible veins, such as the internal jugular and subclavian. If an arterial puncture is necessary, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. As fibrin is lysed during RETAVASE therapy, bleeding from recent puncture sites or other recent trauma may occur. Should serious bleeding (not controllable by local pressure) occur, terminate concomitant anticoagulant therapy. Withhold the second RETAVASE dose if serious bleeding occurs before it is administered.
warnings and cautions
5.2 Hypersensitivity Reactions Hypersensitivity reactions have been reported with RETAVASE administration. Signs and symptoms observed included rash, pruritis, erythema, glossal (tongue) edema, hypotension and respiratory distress. If an anaphylactoid reaction occurs, withhold the second dose of RETAVASE and initiate appropriate therapy.
warnings and cautions
5.3 Cholesterol Embolization Cholesterol embolism has been reported in patients treated with thrombolytic agents. Cholesterol embolism may present with livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis and can be fatal. It is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the other sections of the label: Bleeding [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] Cholesterol Embolization [see Warnings and Precautions ( 5.3 )] The most common adverse reaction (>5%) is bleeding. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Bleeding The most frequent adverse reaction associated with RETAVASE is bleeding. Intracranial hemorrhage [see Clinical Studies ( 14 )] In the INJECT clinical trial, the overall rate of in-hospital, intracranial hemorrhage was 0.8%. The risk for intracranial hemorrhage is increased in patients with advanced age (2.2% among patients >70 years old) or with elevated blood pressure (2.4% among patients with systolic blood pressure >160 mmHg). Other types of hemorrhage The incidence of other types of bleeding events in clinical studies of RETAVASE varied depending upon the use of arterial catheterization or other invasive procedures and whether the study was performed in Europe or the USA. The overall incidence of any bleeding event in patients treated with RETAVASE in clinical studies (n = 3,805) was 21.1%. The rates for bleeding events, regardless of severity, for the 10 + 10 unit RETAVASE regimen from controlled clinical studies are summarized in Table 1. Table 1: RETAVASE Hemorrhage Rates Bleeding Site INJECT RAPID 1 and RAPID 2 Europe N = 2,965 USA N = 210 Europe N =113 Injection Site includes the arterial catheterization site (all patients in the RAPID studies underwent arterial catheterization). 4.6% 48.6% 19.5% Gastrointestinal 2.5% 9.0% 1.8% Genitourinary 1.6% 9.5% 0.9% Anemia, site unknown 2.6% 1.4% 0.9% In these studies the severity and sites of bleeding events were similar for RETAVASE and the comparison thrombolytic agents. Allergic Reactions Among the 2,965 patients receiving RETAVASE in the INJECT trial, serious allergic reactions were noted in 3 patients, with one patient experiencing dyspnea and hypotension. Among the 9,938 patients that received RETAVASE in a postmarketing clinical study, 8 patients experienced allergic and/or anaphylactoid reactions. Signs and symptoms observed included rash, pruritis, erythema, glossal (tongue) edema, hypotension, and respiratory distress.
adverse reactions
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Bleeding The most frequent adverse reaction associated with RETAVASE is bleeding. Intracranial hemorrhage [see Clinical Studies ( 14 )] In the INJECT clinical trial, the overall rate of in-hospital, intracranial hemorrhage was 0.8%. The risk for intracranial hemorrhage is increased in patients with advanced age (2.2% among patients >70 years old) or with elevated blood pressure (2.4% among patients with systolic blood pressure >160 mmHg). Other types of hemorrhage The incidence of other types of bleeding events in clinical studies of RETAVASE varied depending upon the use of arterial catheterization or other invasive procedures and whether the study was performed in Europe or the USA. The overall incidence of any bleeding event in patients treated with RETAVASE in clinical studies (n = 3,805) was 21.1%. The rates for bleeding events, regardless of severity, for the 10 + 10 unit RETAVASE regimen from controlled clinical studies are summarized in Table 1. Table 1: RETAVASE Hemorrhage Rates Bleeding Site INJECT RAPID 1 and RAPID 2 Europe N = 2,965 USA N = 210 Europe N =113 Injection Site includes the arterial catheterization site (all patients in the RAPID studies underwent arterial catheterization). 4.6% 48.6% 19.5% Gastrointestinal 2.5% 9.0% 1.8% Genitourinary 1.6% 9.5% 0.9% Anemia, site unknown 2.6% 1.4% 0.9% In these studies the severity and sites of bleeding events were similar for RETAVASE and the comparison thrombolytic agents. Allergic Reactions Among the 2,965 patients receiving RETAVASE in the INJECT trial, serious allergic reactions were noted in 3 patients, with one patient experiencing dyspnea and hypotension. Among the 9,938 patients that received RETAVASE in a postmarketing clinical study, 8 patients experienced allergic and/or anaphylactoid reactions. Signs and symptoms observed included rash, pruritis, erythema, glossal (tongue) edema, hypotension, and respiratory distress.