Activase (alteplase) Side Effects, Warnings, and Drug Interactions

Activase (alteplase) is an enzyme used to treat conditions caused by arterial blood clots including:

• heart attacks (acute myocardial infarctions),
• strokes,
• chest pain at rest (unstable angina),
• blood clots in the lungs (pulmonary thrombosis or embolus),
• and other less common conditions involving blood clots.

Activase is also used for clearing blood clots from blocked venous catheters.

Common side effects of Activase include:

• bleeding,
• nausea,
• and vomiting.

Serious side effects of Activase include:

• significant bleeding such as into the brain (intracranial hemorrhage) or fatal bleeding,
• pulmonary embolism (PE),
• cholesterol embolism,
• abnormal heartbeats,
• allergic reactions,
• re-embolization of deep venous thrombi (DVT) during treatment of acute massive pulmonary embolism,
• and angioedema.

Drug interactions of Activase include drugs that also interfere with the body's ability to form blood clots (or the clot-promoting effects of platelets), which increase the risk of bleeding in patients receiving Activase.

Such drugs include:

• warfarin,
• aspirin,
• nonsteroidal anti-inflammatory drugs (NSAIDs),
• and platelet inhibitors. 

Activase has been shown to cause damage to embryos of rabbits. No damage has been reported in humans. Doctors must carefully balance potential risks and possible benefits when prescribing Activase to pregnant women. It is not known whether Activase passes into breast milk. Consult your doctor before breastfeeding.

The most common and serious side effect of alteplase is bleeding. Minor bleeding is more common, but significant bleeding such as into the brain (intracranial hemorrhage) or fatal bleeding also occurs.

Other important side effects include:

• Nausea
• Vomiting

Other possible serious side effects include:

• Pulmonary embolism
• Cholesterol embolism
• Abnormal heartbeats
• Allergic reactions
• Re-embolization of deep DVT venous thrombi during treatment of acute massive pulmonary embolism
• Angioedema

The following adverse reactions are discussed in greater detail in the other sections of the label:

• Bleeding
• Orolingual Angioedema
• Cholesterol Embolization
• Reembolization of Deep Venous Thrombi during Treatment for Acute Massive Pulmonary Embolism

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 clinical practice.

The most frequent adverse reaction associated with Activase in all approved indications is bleeding.

Bleeding

Acute Ischemic Stroke (AIS)

In clinical studies in patients with AIS (Studies 1 and 2) the incidence of intracranial hemorrhage, especially symptomatic intracranial hemorrhage, was higher in Activase-treated patients than in placebo patients. A dose-finding study of Activase suggested that doses greater than 0.9 mg/kg may be associated with an increased incidence of intracranial hemorrhage.

The incidence of all-cause 90-day mortality, intracranial hemorrhage, and new ischemic stroke following Activase treatment compared to placebo are presented in Table 3 as a combined safety analysis (n=624) for Studies 1 and 2.

These data indicate a significant increase in intracranial hemorrhage following Activase treatment, particularly symptomatic intracranial hemorrhage within 36 hours. There was no increase in the incidences of 90-day mortality or severe disability in Activasetreated patients compared to placebo.

Table 3 : Combined Safety Outcomes for Studies 1 and 2

Bleeding events other than intracranial hemorrhage were noted in the studies of AIS and were consistent with the general safety profile of Activase. In Studies 1 and 2, the frequency of bleeding requiring red blood cell transfusions was 6.4% for Activase-treated patients compared to 3.8% for placebo (p = 0.19).

Although exploratory analyses of Studies 1 and 2 suggest that severe neurological deficit (National Institutes of Health Stroke Scale [NIHSS > 22]) at presentation was associated with an increased risk of intracranial hemorrhage, efficacy results suggest a reduced but still favorable clinical outcome for these patients.

Acute Myocardial Infarction (AMI)

For the 3-hour infusion regimen in the treatment of AMI, the incidence of significant internal bleeding (estimated as > 250 mL blood loss) has been reported in studies in over 800 patients (Table 4). These data do not include patients treated with the Activase accelerated infusion.

Table 4 : Incidence of Bleeding in 3-Hour Infusion in AMI Patients

The incidence of intracranial hemorrhage in AMI patients treated with Activase is presented in Table 5.

Table 5 : Incidence of Intracranial Hemorrhage in AMI Patients

A dose of 150 mg or greater should not be used in the treatment of AMI because it has been associated with an increase in intracranial bleeding.

Pulmonary Embolism (PE)

For acute massive pulmonary embolism, bleeding events were consistent with the general safety profile observed with Activase treatment of AMI patients receiving the 3-hour infusion regimen.

Allergic Reactions

Allergic-type reactions, e.g., anaphylactoid reaction, laryngeal edema, orolingual angioedema, rash, and urticaria have been reported. When such reactions occur, they usually respond to conventional therapy.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Activase. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions are frequent sequelae of the underlying disease, and the effect of Activase on the incidence of these events is unknown.

Acute Ischemic Stroke

Cerebral edema, cerebral herniation, seizure, new ischemic stroke. These events may be life threatening and may lead to death.

Acute Myocardial Infarction

Arrhythmias, AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia, myocardial reinfarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema. These events may be life threatening and may lead to death. Nausea and/or vomiting, hypotension and fever have also been reported.

Pulmonary Embolism

Pulmonary reembolization, pulmonary edema, pleural effusion, thromboembolism, hypotension. These events may be life threatening and may lead to death. Fever has also been reported.

The interaction of Activase with other cardioactive or cerebroactive drugs has not been studied. Anticoagulants and antiplatelet drugs increase the risk of bleeding if administered prior to, during, or after Activase therapy.

In the post-marketing setting, there have been reports of orolingual angioedema in patients (primarily patients with AIS) receiving concomitant angiotensin-converting enzyme inhibitors.