Retavase Side Effects

Please note - some side effects for Retavase may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Retavase - for the Consumer

Retavase Half-Kit

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Retavase Half-Kit:

Pain, redness, or swelling at the injection site.

Seek medical attention right away if any of these SEVERE side effects occur when using Retavase Half-Kit:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; bleeding at the injection site; chest pain; severe bleeding; sudden, severe headache; trouble breathing; vomiting blood or material that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Retavase

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Retavase:

Pain, redness, or swelling at the injection site.

Seek medical attention right away if any of these SEVERE side effects occur when using Retavase:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; bleeding at the injection site; chest pain; severe bleeding; sudden, severe headache; trouble breathing; vomiting blood or material that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Retavase Side Effects - for the Professional

Retavase

Bleeding: The most frequent adverse reaction associated with Retavase® is bleeding. The types of bleeding events associated with thrombolytic therapy may be broadly categorized as either intracranial hemorrhage or other types of hemorrhage.

• Intracranial hemorrhage
  In the INJECT clinical trial the rate of in-hospital, intracranial hemorrhage among all patients treated with Retavase® was 0.8% (23 of 2,965 patients). As seen with Retavase® and other thrombolytic agents, the risk for intracranial hemorrhage is increased in patients with advanced age or with elevated blood pressure.
• 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 3.

Table 3 Retavase® Hemorrhage Rates

Bleeding Site	INJECT	RAPID 1 and RAPID 2
	Europe n = 2,965	USA n = 210	Europe n =113
*includes the arterial catheterization site (all patients in the RAPID studies underwent arterial catheterization).
Injection Site*	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 comparable for Retavase® and the comparison thrombolytic agents.

Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial) occur, any concomitant heparin should be terminated immediately. In addition, the second bolus of Retavase® should not be given if the serious bleeding occurs before it is administered. Death and permanent disability are not uncommonly reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.

Fibrin which is part of the hemostatic plug formed at needle puncture sites will be lysed during Retavase® therapy. Therefore, Retavase® therapy requires careful attention to potential bleeding sites (e.g., catheter insertion sites, arterial puncture sites).

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. No anaphylactoid reactions were observed among the 3,856 patients treated with Retavase® in initial clinical trials. In an ongoing clinical trial two anaphylactoid reactions have been reported among approximately 2,500 patients receiving Retavase®.

Other Adverse Reactions: Patients administered Retavase® as treatment for myocardial infarction have experienced many events which are frequent sequelae of myocardial infarction and may or may not be attributable to Retavase® therapy. These events include cardiogenic shock, arrhythmias (e.g., sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation), AV block, pulmonary edema, heart failure, cardiac arrest, recurrent ischemia, reinfarction, myocardial rupture, mitral regurgitation, pericardial effusion, pericarditis, cardiac tamponade, venous thrombosis and embolism, and electromechanical dissociation. These events can be life-threatening and may lead to death. Other adverse events have been reported, including nausea and/or vomiting, hypotension, and fever.

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Side Effects by Body System - for Healthcare Professionals

Hematologic

Hematologic side effects have been the most frequently reported side effects. In the INJECT trial, the overall incidence of bleeds from any site was 15.0%, of which 4.6% were clinically significant. Transfusion requirements have ranged from 1.0% (INJECT trial) to 12.4% (RAPID-2 trial). The types of bleeds associated with this drug (and thrombolytic therapy, in general) may be broadly categorized as either intracranial hemorrhage or other types of hemorrhage.

The overall incidence of intracranial hemorrhage has averaged 0.8%. This risk is increased in patients with advanced age or hypertension. The incidence of transient ischemic attack (TIA) or reversible ischemic neurologic deficit (RIND) in the INJECT trial averaged 0.20%, and the incidence of frank stroke in the RAPID-2 trial averaged 1.8%. The average incidence of nonintracranial hemorrhage ranged from 1.9% to 9.0%, depending on the trial, use of arterial catheterization, and whether the study was performed in the US or Europe.

The incidence of IV site bleeding ranged from 4.6% to 48.6%. Arterial and venous punctures should be minimized. Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, or pericardial) occur, any concomitant heparin should be terminated immediately, and the second bolus of reteplase should be withheld.

The incidences of bleeding have been reported in the following sites within the following clinical trials, respectively (European INJECT study [n=2965], US RAPID-1 study [n=210], European RAPID-2 study [n=113]: injection site 4.6%, 48.6%, 19.5%; intracranial 1.2% (stroke), 0%, 1.8% (stroke); gastrointestinal 2.5%, 9.0%, 1.8%; genitourinary 1.6%, 9.5%, 0.9%; anemia 2.6%; 1.4%, 0.9%).

Since reteplase causes lysis of the fibrin plug, which is necessary to stop bleeding at puncture sites, careful attention should be paid to potential sites of bleeding during therapy (injection site, arterial puncture sites, catheter insertion sites, etc.).

Cardiovascular

The following incidences were reported from the RAPID-2 trial: myocardial reinfarction 4.7%, congestive heart failure 9.5%, and ischemia or angina in 29.0%.

Cholesterol embolization--sometimes fatal--has been reported rarely in patients treated with thrombolytic agents. The exact incidence is unknown. Its relationship with lytic therapy might be coincidental as there is such risk associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.

Reperfusion arrhythmias during thrombolytic therapy can be a sign of successful lytic therapy. These arrhythmias (e.g., sinus bradycardia, accelerated idioventricular rhythm, ventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) may also be seen during the natural course of acute myocardial infarction, and they should be treated with standard antiarrhythmic measures, as indicated. It is recommended that antiarrhythmic therapy for bradycardia and/or ventricular irritability be available during reteplase therapy.

Cardiovascular side effects are probably sequelae of myocardial infarction and not due to reteplase. These side effects have included hypotension, cardiogenic shock, arrhythmias (e.g., sinus bradycardia, accelerated idioventricular rhythm, premature ventricular depolarizations, supraventricular tachycardia, ventricular tachycardia, and ventricular fibrillation), AV block, pulmonary edema, heart failure, cardiac arrest, recurrent ischemia, reinfarction, myocardial rupture, mitral regurgitation, pericardial effusion, pericarditis, cardiac tamponade, venous thrombosis and embolism, and electromechanical dissociation.

Hypersensitivity

Serious hypersensitivity reactions to reteplase have been rare. Among the 2,965 patients in the INJECT trial, such reactions were noted in 3 patients, with 1 patient experiencing dyspnea and hypotension. No cases of anaphylaxis were reported among the 3,856 patients treated with reteplase in initial clinical trials, but 2 cases of anaphylaxis were associated with the use of reteplase among approximately 2,500 patients in ongoing clinical trials.

There are no data to demonstrate the formation of anti-reteplase antibodies among the approximately 2,400 patients who have been tested for the presence of such antibodies. Nevertheless, the use of reteplase (including the second bolus of reteplase) is not recommended if anaphylaxis has occurred with any prior use of reteplase in a given patient.

Gastrointestinal

Gastrointestinal side effects have included nausea and vomiting.

General

Fever, a general body side effect, has been reported.

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