Activase

Name: Activase

What is the most important information I should know about Activase (alteplase)?

If possible before you receive alteplase, tell your doctor if you have a brain tumor or aneurysm, high blood pressure, stomach bleeding, hemophilia or other bleeding disorder, or if you have recently had a head injury, brain or spinal surgery, or other major surgery or serious injury.

In an emergency situation it may not be possible to tell your caregivers about your health conditions. Make sure any doctor caring for you afterward knows you have received this medicine.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Activase (alteplase) side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Alteplase increases your risk of bleeding, which can be severe or life-threatening. Call your doctor or seek emergency medical attention if you have bleeding that will not stop. Bleeding may occur from a surgical incision, or from the skin where a needle was inserted during a blood test or while receiving injectable medication. You may also have bleeding on the inside of your body, such as in your stomach or intestines, kidneys or bladder, brain, or within the muscles.

Call your doctor at once if you have signs of bleeding inside your body, such as:

  • easy bruising or bleeding (nosebleeds, bleeding gums, bleeding from a wound, incision, catheter, or needle injection);

  • bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

  • red or pink urine; or

  • sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance.

Also call your doctor at once if you have:

  • chest pain or heavy feeling, pain spreading to the jaw or shoulder, nausea, sweating, general ill feeling;

  • swelling, rapid weight gain, little or no urinating;

  • severe stomach pain, nausea, and vomiting;

  • darkening or purple discoloration of your fingers or toes;

  • very slow heartbeats, shortness of breath, feeling light-headed;

  • sudden severe back pain, muscle weakness, numbness or loss of feeling in your arms or legs;

  • dangerously high blood pressure--severe headache, blurred vision, pounding in your neck or ears, nosebleed, anxiety, confusion, severe chest pain, shortness of breath, irregular heartbeats; or

  • pancreatitis--severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Uses For Activase

Alteplase injection is used to dissolve blood clots that have formed in the blood vessels. It is used immediately after symptoms of a heart attack occur to improve patient survival. It is also used after symptoms of a stroke and to treat blood clots in the lungs (pulmonary embolism).

Alteplase is used to dissolve blood clots in tubes (catheters) that are placed in large blood vessels (central venous access devices).

This medicine is available only with your doctor's prescription.

Proper Use of alteplase, recombinant

This section provides information on the proper use of a number of products that contain alteplase, recombinant. It may not be specific to Activase. Please read with care.

A doctor or other trained health professional will give you this medicine. This medicine is given through a needle or tube placed into one of your blood vessels.

Indications and Usage for Activase

Acute Ischemic Stroke

Activase is indicated for the treatment of acute ischemic stroke.

Exclude intracranial hemorrhage as the primary cause of stroke signs and symptoms prior to initiation of treatment [see Contraindications (4.1)]. Initiate treatment as soon as possible but within 3 hours after symptom onset.

Acute Myocardial Infarction

Activase is indicated for use in acute myocardial infarction (AMI) for the reduction of mortality and reduction of the incidence of heart failure.

Limitation of Use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose AMI puts them at low risk for death or heart failure.

Pulmonary Embolism

Activase is indicated for the lysis of acute massive pulmonary embolism, defined as:

  • Acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments.
  • Acute pulmonary emboli accompanied by unstable hemodynamics, e.g., failure to maintain blood pressure without supportive measures.

Activase Dosage and Administration

Acute Ischemic Stroke

Administer Activase as soon as possible but within 3 hours after onset of symptoms.

The recommended dose is 0.9 mg/kg (not to exceed 90 mg total dose), with 10% of the total dose administered as an initial intravenous bolus over 1 minute and the remainder infused over 60 minutes.

During and following Activase administration for the treatment of acute ischemic stroke, frequently monitor and control blood pressure.

In patients without recent use of oral anticoagulants or heparin, Activase treatment can be initiated prior to the availability of coagulation study results. Discontinue Activase if the pretreatment International Normalized Ratio (INR) is greater than 1.7 or the activated partial thromboplastin time (aPTT) is elevated [see Contraindications (4.1)].

Acute Myocardial Infarction

Administer Activase as soon as possible after the onset of symptoms.

The recommended total doses for acute myocardial infarction (AMI) is based on patient weight, not to exceed 100 mg, regardless of the selected administration regimen (accelerated or 3 hour, described below).

There are two Activase dose regimens (accelerated and 3-hour) for use in the management of AMI; there are no controlled studies to compare clinical outcomes with these regimens [see Clinical Studies (14.2)].

Accelerated Infusion

The recommended accelerated infusion dose consists of an IV bolus [see Dosage and Administration (2.5)] followed by an IV infusion as set forth in Table 1.

Table 1 Accelerated Infusion Weight-Based Doses for Patients with AMI
Patient weight Intravenous Bolus First 30 min Next 60 min
> 67 kg 15 mg 50 mg 35 mg
≤ 67 kg 15 mg 0.75 mg/kg 0.50 mg/kg

The safety and efficacy of accelerated infusion of Activase have only been investigated with concomitant administration of heparin and aspirin [see Clinical Studies (14.2)].

3-Hour Infusion

For patients weighing ≥ 65 kg, the recommended dose is 100 mg administered as 60 mg in the first hour (6-10 mg administered as a bolus), 20 mg over the second hour, and 20 mg over the third hour. For smaller patients (< 65 kg), a dose of 1.25 mg/kg administered over 3 hours may be used. Weight-based doses are shown in Table 2.

Table 2 3-hour Infusion Weight-Based Doses for Patients with AMI
Patient weight Bolus Rest of 1st hour 2nd hour 3rd hour
≥ 65 kg 6-10 mg 50-54 mg 20 mg 20 mg
< 65 kg 0.075 mg/kg 0.675 mg/kg 0.25 mg/kg 0.25 mg/kg

Pulmonary Embolism (PE)

The recommended dose is 100 mg administered by IV infusion over 2 hours.

Institute parenteral anticoagulation near the end of or immediately following the Activase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less.

Preparation for Administration

Reconstitution

Use only the accompanying Sterile Water for Injection (SWFI), USP without preservatives. Do not use Bacteriostatic Water for Injection, USP.

Reconstitute using aseptic technique. Do not add other medication to solutions containing Activase. Reconstitute Activase no more than 8 hours before use, as it contains no antibacterial preservatives [see How Supplied/Storage and Handling (16.2)].

Slight foaming is not unusual; let stand undisturbed for several minutes to allow large bubbles to dissipate. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit.

Activase may be administered as reconstituted at 1 mg/mL or further diluted immediately before administration in an equal volume of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to yield a concentration of 0.5 mg/mL, using either polyvinyl chloride bags or glass vials.

Avoid excessive agitation during dilution; mix by gently swirling and/or slow inversion.

50 mg Vials

  DO NOT USE IF VACUUM IS NOT PRESENT.   Using a large bore needle (e.g., 18 gauge) and a syringe, reconstitute by adding the contents of the accompanying 50 mL vial of SWFI to the 50 mg vial of Activase, directing the SWFI stream into the lyophilized cake.

100 mg Vials

  THE 100 mg VIALS DO NOT CONTAIN VACUUM.   Using the transfer device provided, reconstitute by adding the contents of the accompanying 100 mL vial of SWFI to the 100 mg vial of Activase.
  1. Use aseptic technique.
  2. Remove the protective flip-caps from one vial of Activase and one vial of SWFI.
  3. Open the package containing the transfer device by peeling the paper label off the package.
  4. Remove the protective cap from one end of the transfer device and keeping the vial of SWFI upright, insert the piercing pin vertically into the center of the stopper of the vial of SWFI.
  5. Remove the protective cap from the other end of the transfer device. DO NOT INVERT THE VIAL OF SWFI.
  6. Hold the vial of Activase upside down, position it so that the center of the stopper is directly over the exposed piercing pin of the transfer device, and push the vial of Activase down so that the piercing pin is inserted through the center of the Activase vial stopper.
  7. Invert the two vials so that the vial of Activase is on the bottom (upright) and the vial of SWFI is upside-down, allowing the SWFI to flow down through the transfer device. Allow the entire contents of the vial of SWFI to flow into the Activase vial (approximately 0.5 cc of SWFI will remain in the diluent vial).
  8. Remove the transfer device and the empty SWFI vial from the Activase vial and discard.
  9. Swirl gently to dissolve the Activase powder. DO NOT SHAKE.

Preparation of Bolus Dose

  • Prepare the bolus dose in one of the following ways: Remove the appropriate volume from the vial of reconstituted (1 mg/mL) Activase using a syringe and needle. If this method is used with the 50 mg vials, the syringe should not be primed with air and the needle should be inserted into the Activase vial stopper. If the 100 mg vial is used, the needle should be inserted away from the puncture mark made by the transfer device.
  • Remove the appropriate volume from a port (second injection site) on the infusion line after the infusion set is primed.
  • Program an infusion pump to deliver the appropriate volume as a bolus at the initiation of the infusion

Administration

Following bolus dose, if indicated [see Dosage and Administration (2.1, 2.2)]:

  • 50 mg vials - administer using either a polyvinyl chloride bag or glass vial and infusion set.
  • 100 mg vials - remove from the vial any quantity of drug in excess of that specified for patient treatment [see Dosage and Administration (2.1, 2.2)]. Insert the spike end of an infusion set through the same puncture site created by the transfer device in the stopper of the vial of reconstituted Activase. Peel the clear plastic hanger from the vial label. Hang the Activase vial from the resulting loop.

Activase is for intravenous administration only. Extravasation of Activase infusion can cause ecchymosis or inflammation. If extravasation occurs, terminate the infusion at that IV site and apply local therapy.

Do not add any other medication to infusion solutions containing Activase.

Adverse Reactions

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

  • Bleeding [see Contraindications (4), Warnings and Precautions (5.1)]
  • Orolingual Angioedema [see Warnings and Precautions (5.2)]
  • Cholesterol Embolization [see Warnings and Precautions (5.3)]
  • Reembolization of Deep Venous Thrombi during Treatment for Acute Massive Pulmonary Embolism [see Warnings and Precautions (5.4)].

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-Value*
* Fisher's Exact Test. † 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.
All-Cause 90-day Mortality 64 (20.5%) 54 (17.3%) 0.36
Total ICH† 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

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.

Clinical Studies

Acute Ischemic Stroke (AIS)

Two placebo-controlled, double-blind trials (Studies 1 and 2) were conducted in patients with AIS. Both studies enrolled patients with measurable neurological deficit who could complete screening and begin study treatment within 3 hours from symptom onset. A cranial computerized tomography (CT) scan was performed prior to treatment to rule out the presence of intracranial hemorrhage. Blood pressure was actively controlled (185/110 mm Hg or lower) for 24 hours.

Patients were randomized (1:1) to receive either 0.9 mg/kg Activase (maximum of 90 mg) or placebo. Activase was administered as a 10% initial IV bolus over 1 minute followed by continuous IV infusion of the remainder over 60 minutes. Study treatment was initiated prior to the availability of coagulation study results in patients without recent use of oral anticoagulants and/or heparin and was discontinued if the pretreatment prothrombin time (PT) was greater than 15 seconds or the activated partial thromboplastin time (aPTT) was elevated. Patients with prior aspirin use were included. Administration of anticoagulants and antiplatelet agents was prohibited for the first 24 hours following symptom onset.

Study 1 (n=291) evaluated neurological improvement at 24 hours after stroke onset. The primary endpoint, the proportion of patients with a 4 point or greater improvement in the National Institutes of Health Stroke Scale (NIHSS) score or complete recovery (NIHSS score of 0), was not significantly different between treatment groups. A prespecified secondary analysis suggested improved 3-month outcome associated with Activase treatment using the following stroke assessment scales: Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale, and the NIHSS.

Study 2 (n=333) assessed clinical outcome at 3 months. A favorable outcome was defined as minimal or no disability using four stroke assessment scales: Barthel Index (score of 95 or greater), Modified Rankin Scale (score of 1 or less), Glasgow Outcome Scale (score of 1), and NIHSS (score of 1 or less). The results comparing Activase- and placebo-treated patients for the four outcome scales together (Generalized Estimating Equations) and individually are presented in Table 7. In this study, depending upon the scale, the favorable outcome of minimal or no disability occurred in at least 11 per 100 more patients treated with Activase than those receiving placebo. Study results demonstrated consistent functional and neurological improvement within all four stroke scales as indicated by median scores. These results were consistent with the 3-month outcome treatment effects observed in Study 1.

Table 7 Study 2 Three-Month Efficacy Outcomes
Analysis Frequency of Favorable Outcome*
Placebo
(n=165)
Activase
(n=168)
Absolute Difference
(95% CI)
Odds Ratio†
(95% Cl)
p-Value‡
* Favorable Outcome is defined as recovery with minimal or no disability. † Value greater than 1 indicates odds of recovery in favor of Activase treatment. ‡ p-Value for Odds Ratio is from Generalized Estimating Equations with logit link.
Generalized Estimating Equations (Multivariate) - - - 1.71
(1.15, 2.56)
0.02
Barthel Index 37.6% 50.0% 12.4%
(3.0, 21.9)
1.66
(1.07, 2.57)
0.02
Modified Rankin Scale 26.1% 38.7% 12.6%
(3.7, 21.6)
1.79
(1.12, 2.85)
0.02
Glasgow Outcome Scale 31.5% 44.0% 12.5%
(3.3, 21.8)
1.71
(1.09, 2.68)
0.02
NIHSS 20.0% 31.0% 11.0%
(2.6, 19.3)
1.79
(1.06, 2.96)
0.02

In a prespecified subgroup analysis of patients receiving aspirin prior to onset of stroke symptoms, the favorable outcome for Activase-treated patients was preserved.

Acute Myocardial Infarction (AMI)

Two Activase dose regimens have been studied in patients experiencing acute myocardial infarction [see Dosage and Administration (2.2)]. The comparative efficacy of these two regimens has not been evaluated.

Accelerated Infusion in AMI Patients

Accelerated infusion of Activase was studied in an international, multi-center trial that randomized 41,021 patients with AMI to four thrombolytic regimens (Study 3). Entry criteria included onset of chest pain within 6 hours of treatment and ST-segment elevation of ECG. The four treatment regimens included accelerated infusion of Activase (≤100 mg over 90 minutes) plus intravenous (IV) heparin (n = 10,396); Streptokinase (1.5 million units over 60 minutes) plus IV heparin (SK [IV], n =10,410); Streptokinase plus subcutaneous (SQ) heparin (SK [SQ] n= 9841). A fourth regimen combined Activase and Streptokinase (n =10,374). All patients received 160 mg chewable aspirin administered as soon as possible, followed by 160-325 mg daily. Bolus IV heparin 5000 U was initiated as soon as possible, followed by a 1000 U/hour continuous IV infusion for at least 48 hours; subsequent heparin therapy was at the physician's discretion. Heparin SQ 12,500 U was administered 4 hours after initiation of SK therapy, followed by 12,500 U twice daily for 7 days or until discharge, whichever came first. Many of the patients randomized to receive SQ heparin received some IV heparin, usually in response to recurrent chest pain and/or the need for a medical procedure. Some received IV heparin on arrival to the emergency room prior to enrollment and randomization.

Key results from Study 3 are shown in Table 8. The incidence of 30-day mortality for Activase accelerated infusion was 1.0% lower than for either Streptokinase plus heparin regimen. The incidence of combined 30-day mortality or nonfatal stroke for the Activase accelerated infusion was 1.0% lower than for SK (IV) and 0.8% lower than for SK (SQ).

Table 8 Efficacy and Safety Results for Study 3
Event Accelerated Activase SK (IV) p-Value* SK (SQ) p-Value*
* Two-tailed p-value is for comparison of Accelerated Activase to the respective SK control arm.
30-Day Mortality 6.3% 7.3% 0.003 7.3% 0.007
30-Day Mortality
or Nonfatal Stroke
7.2% 8.2% 0.006 8.0% 0.036
24-Hour Mortality 2.4% 2.9% 0.009 2.8% 0.029
Any Stroke 1.6% 1.4% 0.32 1.2% 0.03
Intracerebral Hemorrhage 0.7% 0.6% 0.22 0.5% 0.02

Subgroup analysis of patients by age, infarct location, time from symptom onset to thrombolytic treatment, and treatment in the U.S. or elsewhere showed consistently lower 30-day mortality on Activase.

For patients who were over 75 years of age, a predefined subgroup consisting of 12% of patients enrolled, the incidence of stroke was 4.0% for the Activase accelerated infusion group, 2.8% for SK (IV), and 3.2% for SK (SQ); the incidence of combined 30-day mortality or nonfatal stroke was 20.6% for accelerated infusion of Activase, 21.5% for SK (IV), and 22.0% for SK (SQ).

3-Hour Infusion in AMI Patients

In a double-blind, randomized trial (n = 138) comparing 3-hour infusion of Activase to placebo (Study 4), patients infused with Activase within 4 hours of onset of symptoms experienced improved left ventricular function at Day 10 compared to the placebo group, when ejection fraction was measured by gated blood pool scan (53.2% vs. 46.4%, p =0.018). Relative to baseline (Day 1) values, the net changes in ejection fraction were + 3.6% and -4.7% for the treated and placebo groups, respectively (p=0.0001). The treated group had a reduced incidence of clinical heart failure (14%) compared to the placebo group (33%) (p = 0.009).

In a double-blind, randomized trial (n =5013) comparing 3-hour infusion of Activase to placebo (Study 5), patients infused with Activase within 5 hours of AMI symptom onset experienced improved 30-day survival compared to the placebo arm. At 1 month, the overall mortality rates were 7.2% for the Activase group and 9.8% for the placebo group (p = 0.001). At 6 months, the overall mortality rate for Activase-treated patients was 10.4% compared to the placebo arm (13.1%, p= 0.008).

Acute Massive Pulmonary Embolism (PE)

Study 6 was a comparative randomized trial (n =45) in which 59% of patients (n =22) treated with Activase (100 mg over 2 hours) experienced moderate or marked lysis of pulmonary emboli when assessed by pulmonary angiography 2 hours after treatment initiation. Activase-treated patients also experienced a significant reduction in pulmonary embolism-induced pulmonary hypertension within 2 hours of treatment (p=0.003). Pulmonary perfusion at 24 hours, as assessed by radionuclide scan, was significantly improved (p= 0.002).

Side effects

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

  • Bleeding [see CONTRAINDICATIONS , WARNINGS AND PRECAUTIONS]
  • Orolingual Angioedema [see WARNINGS AND PRECAUTIONS]
  • Cholesterol Embolization [see WARNINGS AND PRECAUTIONS]
  • Reembolization of Deep Venous Thrombi during Treatment for Acute Massive Pulmonary Embolism [see WARNINGS AND PRECAUTIONS].

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.

Uses of Activase

Activase is a prescription medication used to treat:

  • Acute myocardial infarction (heart attack)
  • Acute ischemic stroke (loss of blood flow to the brain)
  • Pulmonary embolism (blood clot that has traveled to the lungs)

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Activase Usage

Take Activase exactly as prescribed.

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Activase Overdose

If Activase is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

In Summary

More frequent side effects include: gastrointestinal hemorrhage and genitourinary tract hemorrhage. See below for a comprehensive list of adverse effects.

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