Activase (Alteplase) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

BLEEDING

The most frequent adverse reaction associated with Activase in all approved indications is bleeding (see WARNINGS).^15,16

Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial) occur, Activase therapy should be discontinued immediately, along with any concomitant therapy with heparin. Death and permanent disability are not uncommonly reported in patients that have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.

In the GUSTO trial for the treatment of acute myocardial infarction, using the accelerated infusion regimen the incidence of all strokes for the Activase-treated patients was 1.6%, while the incidence of nonfatal stroke was 0.9%. The incidence of hemorrhagic stroke was 0.7%, not all of which were fatal. The incidence of all strokes, as well as that for hemorrhagic stroke, increased with increasing age (see CLINICAL PHARMACOLOGY: Accelerated Infusion in AMI Patients). Data from previous trials utilizing a 3-hour infusion of </= 100 mg indicated that the incidence of total stroke in six randomized, double-blind, placebo-controlled trials^2,7-11,17 was 1.2% (37/3161) in Alteplase-treated patients compared with 0.9% (27/3092) in placebo-treated patients.

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

The incidence of intracranial hemorrhage (ICH) in acute myocardial infarction patients treated with Activase is as follows:

These data indicate that a dose of 150 mg of Activase should not be used in the treatment of AMI because it has been associated with an increase in intracranial bleeding.¹⁸

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

The incidence of ICH, especially symptomatic ICH, in patients with acute ischemic stroke was higher in Activase-treated patients than placebo patients (see CLINICAL PHARMACOLOGY).

A study of another alteplase product, Actilyse, in acute ischemic stroke, suggested that doses greater than 0.9 mg/kg may be associated with an increased incidence of ICH. ¹⁹ Doses greater than 0.9 mg/kg (maximum 90 mg) should not be used in the management of acute ischemic stroke.

Bleeding events other than ICH were noted in the studies of acute ischemic stroke and were consistent with the general safety profile of Activase. In The NINDS t-PA Stroke Trial (Parts 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, using Mantel-Haenszel Chi-Square).

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

ALLERGIC REACTIONS

Allergic-type reactions, e.g., anaphylactoid reaction, laryngeal edema, orolingual angioedema, rash, and urticaria have been reported. A cause and effect relationship to Activase therapy has not been established. When such reactions occur, they usually respond to conventional therapy.

There have been postmarketing reports of orolingual angioedema associated with the use of Activase. Most reports were of patients treated for acute ischemic stroke, some reports were of patients treated for acute myocardial infarctions (see PRECAUTIONS: General). Many of these patients received concomitant angiotensin-converting enzyme inhibitors (see PRECAUTIONS: Drug Interactions). Most cases resolved with prompt treatment; there have been rare fatalities as a result of upper airway hemorrhage from intubation trauma.

OTHER ADVERSE REACTIONS

The following adverse reactions have been reported among patients receiving Activase in clinical trials and in postmarketing experience. These reactions are frequent sequelae of the underlying disease and the effect of Activase on the incidence of these events is unknown.

Use in 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.

Use in 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.

Use in Acute Ischemic Stroke:   Cerebral edema, cerebral herniation, seizure, new ischemic stroke. These events may be life threatening and may lead to death.

REPORTS OF SIDE EFFECTS / ADVERSE REACTIONS RELATED TO ACTIVASE

Possible Activase side effects / adverse reactions in 69 year old female

Reported by a physician from United States on 2007-01-04

Patient: 69 year old female

Reactions: Haemorrhage Intracranial, Drug Interaction

Adverse event resulted in: death

Suspect drug(s):
Reopro
    Dosage: 12 hour infusion 0.125 mcg/kg/min

Reopro
    Indication: Cerebral Artery Occlusion

Activase
    Indication: Cerebral Artery Occlusion

Other drugs received by patient: Heparin

Possible Activase side effects / adverse reactions in 71 year old female

Reported by a health professional (non-physician/pharmacist) from Germany on 2007-01-18

Patient: 71 year old female

Reactions: Pneumonia, Blood Potassium Decreased, Cardiac Failure, Drug Hypersensitivity, Prothrombin Time Prolonged, Hypertensive Crisis, Infusion Related Reaction

Adverse event resulted in: hospitalization

Suspect drug(s):
Activase

Other drugs received by patient: Aspirin

Possible Activase side effects / adverse reactions in 81 year old female

Reported by a health professional (non-physician/pharmacist) from Germany on 2007-01-18

Patient: 81 year old female

Reactions: Bronchopneumonia, Paranoia, Swollen Tongue, Hemiparesis

Adverse event resulted in: hospitalization

Suspect drug(s):
Activase

Other drugs received by patient: Melperone (Melperone Hydrochloride)

Possible Activase side effects / adverse reactions in 65 year old male

Reported by a health professional (non-physician/pharmacist) from India on 2007-01-23

Patient: 65 year old male

Reactions: Drug Ineffective

Adverse event resulted in: death

Suspect drug(s):
Activase

Other drugs received by patient: Aspirin; Clopidogrel; Heparin

Possible Activase side effects / adverse reactions in 81 year old female

Reported by a health professional (non-physician/pharmacist) from Germany on 2007-02-02

Patient: 81 year old female

Reactions: Hypersensitivity, Paranoia, Bronchopneumonia, Cerebral Infarction, Tongue Haemorrhage, Hemiparesis, Swollen Tongue

Adverse event resulted in: hospitalization

Suspect drug(s):
Activase

Other drugs received by patient: Melperone (Melperone Hydrochloride)

Possible Activase side effects / adverse reactions in 70 year old female

Reported by a health professional (non-physician/pharmacist) from Germany on 2007-02-05

Patient: 70 year old female

Reactions: Sepsis

Adverse event resulted in: death

Suspect drug(s):
Activase

Possible Activase side effects / adverse reactions in 40 year old male

Reported by a health professional (non-physician/pharmacist) from Colombia on 2007-02-15

Patient: 40 year old male

Reactions: Brain Oedema

Adverse event resulted in: death

Suspect drug(s):
Activase

Possible Activase side effects / adverse reactions in 71 year old male

Reported by a physician from United States on 2007-02-21

Patient: 71 year old male

Reactions: Back Pain, Paralysis Flaccid, Reperfusion Injury, Muscle Contractions Involuntary, Hypotension, Condition Aggravated, Spinal Shock, Hyperhidrosis, Muscle Spasms

Suspect drug(s):
Activase

Possible Activase side effects / adverse reactions in 53 year old female

Reported by a physician from Canada on 2007-02-27

Patient: 53 year old female

Reactions: Partial Seizures, Cerebral Haemorrhage

Suspect drug(s):
Activase

Other drugs received by patient: .

Possible Activase side effects / adverse reactions in 58 year old male

Reported by a physician from Japan on 2007-04-11

Patient: 58 year old male

Reactions: Venous Thrombosis

Adverse event resulted in: hospitalization

Suspect drug(s):
Activase

Other drugs received by patient: Takepron; Heparin

Possible Activase side effects / adverse reactions in 65 year old male

Reported by a physician from Japan on 2007-04-12

Patient: 65 year old male

Reactions: Hydrocephalus

Suspect drug(s):
Activase

Possible Activase side effects / adverse reactions in 56 year old male

Reported by a health professional (non-physician/pharmacist) from Japan on 2007-04-16

Patient: 56 year old male

Reactions: Cystitis

Adverse event resulted in: hospitalization

Suspect drug(s):
Activase

Other drugs received by patient: Radicut; Glyceol

Possible Activase side effects / adverse reactions in 85 year old female

Reported by a health professional (non-physician/pharmacist) from Japan on 2007-04-17

Patient: 85 year old female

Reactions: Renal Failure, Renal Failure Acute

Adverse event resulted in: hospitalization

Suspect drug(s):
Activase
    Dosage: unk, single
    Indication: Cerebral Artery Embolism
    Start date: 2006-12-17

Olmetec
    Administration route: Oral
    Indication: Drug USE FOR Unknown Indication
    Start date: 2006-12-22

Other drugs received by patient: Radicut; Lipitor; Nicardipine Hydrochloride; Deslanoside; Cefozopran; Glycerin

Possible Activase side effects / adverse reactions in 58 year old male

Reported by a physician from Japan on 2007-04-17

Patient: 58 year old male

Reactions: Venous Thrombosis

Adverse event resulted in: hospitalization

Suspect drug(s):
Activase

Other drugs received by patient: Takepron; Heparin

Possible Activase side effects / adverse reactions in 65 year old male

Reported by a physician from Japan on 2007-04-23

Patient: 65 year old male

Reactions: Brain Herniation

Adverse event resulted in: hospitalization

Suspect drug(s):
Activase

Other drugs received by patient: LR; Aspirin

Possible Activase side effects / adverse reactions in 65 year old male

Reported by a physician from Japan on 2007-04-30

Patient: 65 year old male

Reactions: Brain Herniation

Adverse event resulted in: hospitalization

Suspect drug(s):
Activase

Other drugs received by patient: LR; Aspirin

Possible Activase side effects / adverse reactions in 57 year old female

Reported by a physician from Japan on 2007-05-09

Patient: 57 year old female

Reactions: Shock

Adverse event resulted in: death

Suspect drug(s):
Activase

Possible Activase side effects / adverse reactions in 85 year old female

Reported by a health professional (non-physician/pharmacist) from Japan on 2007-05-11

Patient: 85 year old female

Reactions: Renal Failure

Adverse event resulted in: hospitalization

Suspect drug(s):
Activase
    Dosage: unk, single
    Indication: Cerebral Artery Embolism
    Start date: 2006-12-17

Olmetec
    Administration route: Oral
    Indication: Drug USE FOR Unknown Indication
    Start date: 2006-12-22

Other drugs received by patient: Radicut; Lipitor; Nicardipine Hydrochloride; Deslanoside; Cefozopran; Glycerin

Possible Activase side effects / adverse reactions in 70 year old male

Reported by a consumer/non-health professional from Japan on 2007-05-21

Patient: 70 year old male

Reactions: Stevens-Johnson Syndrome

Adverse event resulted in: life threatening event

Suspect drug(s):
Activase
    Dosage: 24 miu/m2, single
    Indication: Cerebral Infarction
    Start date: 2006-07-11
    End date: 2006-07-11

Radicut
    Dosage: 60 mg, unk
    Indication: Cerebral Infarction
    Start date: 2006-07-11
    End date: 2006-07-19

Cefpirome Sulfate
    Dosage: 2 g, unk
    Indication: Pneumonia
    Start date: 2006-07-11
    End date: 2006-07-15

Omepral
    Dosage: 2 unk, unk
    Indication: Prophylaxis
    Start date: 2006-07-11
    End date: 2006-07-17

Cataclot
    Dosage: 160 mg, unk
    Indication: Cerebral Infarction
    Start date: 2006-07-12
    End date: 2006-07-19

Other drugs received by patient: Dextran 40 W Glucose; Heparin; Aspirin

Possible Activase side effects / adverse reactions in 76 year old male

Reported by a physician from Japan on 2007-05-21

Patient: 76 year old male

Reactions: Respiratory Failure

Adverse event resulted in: death

Suspect drug(s):
Activase

Other drugs received by patient: Perdipine; Gaster; Horizon; Radicut; Glyceol