July 27, 2016
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Activase

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Activase

Side Effects
Interactions

SIDE EFFECTS

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

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 Activase-treated patients compared to placebo.

Table 3: Combined Safety Outcomes for Studies 1 and 2

  Placebo
(n= 312)
Activase
(n=312)
p-Valueb
All-Cause 90-day Mortality 64 (20.5%) 54 (17.3%) 0.36
Total ICHa 20 (6.4%) 48 (15.4%) <0.01
Symptomatic 4 (1.3%) 25 (8.0%) <0.01
Asymptomatic 16 (5.1%) 23 (7.4%) 0.32
Symptomatic Intracranial Hemorrhage within 36 hours 2 (0.6%) 20 (6.4%) <0.01
New Ischemic Stroke (3-months) 17 (5.4%) 18 (5.8%) 1.00
a Within trial follow-up period. Symptomatic intracranial hemorrhage was defined as the occurrence of sudden clinical worsening followed by subsequent verification of intracranial hemorrhage on CT scan. Asymptomatic intracranial hemorrhage was defined as intracranial hemorrhage detected on a routine repeat CT scan without preceding clinical worsening.
b Fisher's Exact Test.

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

  Total Dose ≤100 mg
Gastrointestinal 5%
Genitourinary 4%
Ecchymosis 1%
Retroperitoneal <1%
Epistaxis <1%
Gingival <1%

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

Dose Number of Patients Intracranial Hemorrhage (%)
100 mg, 3-hour 3272 0.4
≤ 100 mg, accelerated 10,396 0.7
150 mg 1779 1.3
1-1.4 mg/kg 237 0.4

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.

Read the Activase (alteplase) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

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. [see WARNINGS AND PRECAUTIONS].

Read the Activase Drug Interactions Center for a complete guide to possible interactions

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 7/12/2016

Side Effects
Interactions

Additional Activase Information

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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