No Information Provided
Do not administer %medicine_name% to treat acute ischemic stroke in the following situations in which the risk of bleeding is greater than the potential benefit :
Do not administer %medicine_name% for treatment of AMI or PE in the following situations in which the risk of bleeding is greater than the potential benefit :
The following adverse reactions are discussed in greater detail in the other sections of the label:
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 %medicine_name% 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 %medicine_name%-treated patients than in placebo patients. A dose-finding study of %medicine_name% 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 %medicine_name% 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 %medicine_name% treatment, particularly symptomatic intracranial hemorrhage within 36 hours. There was no increase in the incidences of 90-day mortality or severe disability in %medicine_name%-treated patients compared to placebo.
Table 3: Combined Safety Outcomes for Studies 1 and 2
| Placebo (n= 312) |
%medicine_name% (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 %medicine_name%. In Studies 1 and 2, the frequency of bleeding requiring red blood cell transfusions was 6.4% for %medicine_name%-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 %medicine_name% 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 %medicine_name% 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 %medicine_name% treatment of AMI patients receiving the 3-hour infusion regimen.
Allergic ReactionsAllergic-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 ExperienceThe following adverse reactions have been identified during post-approval use of %medicine_name%. 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 %medicine_name% on the incidence of these events is unknown.
Acute Ischemic StrokeCerebral edema, cerebral herniation, seizure, new ischemic stroke. These events may be life threatening and may lead to death.
Acute Myocardial InfarctionArrhythmias, 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 EmbolismPulmonary reembolization, pulmonary edema, pleural effusion, thromboembolism, hypotension. These events may be life threatening and may lead to death. Fever has also been reported.
%medicine_name% 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. Initiate treatment as soon as possible but within 3 hours after symptom onset.
Acute Myocardial Infarction%medicine_name% is indicated for use in acute myocardial infarction (AMI) for the reduction of mortality and reduction of the incidence of heart failure.
Limitation Of UseThe 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%medicine_name% is indicated for the lysis of acute massive pulmonary embolism, defined as:
Following administration of 100 mg %medicine_name%, there is a decrease (16%-36%) in circulating fibrinogen. In a controlled trial, 8 of 73 patients (11%) receiving %medicine_name% (1.25 mg/kg body weight over 3 hours) experienced a decrease in fibrinogen to below 100 mg/dL.
Alteplase in acute myocardial infarction (AMI) patients is rapidly cleared from the plasma with an initial half-life of less than 5 minutes. There is no difference in the dominant initial plasma half-life between the 3-hour and accelerated regimens for AMI. The plasma clearance of alteplase is 380-570 mL/min, primarily mediated by the liver. The initial volume of distribution approximates plasma volume.
%medicine_name% is embryocidal in rabbits when intravenously administered in doses of approximately two times (3 mg/kg) the human dose for AMI. No maternal or fetal toxicity was evident at 0.65 times (1 mg/kg) the human dose in pregnant rats and rabbits dosed during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women.
%medicine_name% is supplied as a sterile, lyophilized powder in 50 mg vials containing vacuum and in 100 mg vials without vacuum.
Each 50 mg %medicine_name% vial (29 million IU) is packaged with diluent for reconstitution (50 mL Sterile Water for Injection, USP): NDC 50242-044-13.
Each 100 mg %medicine_name% vial (58 million IU) is packaged with diluent for reconstitution (100 mL Sterile Water for Injection, USP), and one transfer device: NDC 50242-085-27.
Stability And StorageStore lyophilized %medicine_name% at controlled room temperature not to exceed 30°C (86°F), or under refrigeration (2-8°C/36-46°F). Protect the lyophilized material during extended storage from excessive exposure to light. If stored between 2-30°C (36-86°F), %medicine_name% may be used within 8 hours following reconstitution. Discard any unused solution after administration is complete.
Do not use beyond the expiration date stamped on the vial.
Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990. Revised: Jan 2017
Included as part of the PRECAUTIONS section.
PRECAUTIONS Bleeding%medicine_name% can cause internal bleeding (intracranial, retroperitoneal, gastrointestinal, genitourinary, respiratory) or external bleeding, especially at arterial and venous puncture sites. Avoid intramuscular injections and trauma to the patient while on %medicine_name%. Perform venipunctures carefully and only as required. To minimize bleeding from noncompressible sites, avoid internal jugular and subclavian venous punctures. If an arterial puncture is necessary during %medicine_name% infusion, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely.
Because of the higher risk of intracranial hemorrhage in patients treated for acute ischemic stroke, limit treatment to facilities that can provide timely access to appropriate evaluation and management of intracranial hemorrhage.
Fatal cases of hemorrhage associated with traumatic intubation in patients administered %medicine_name% have been reported.
Aspirin and heparin have been administered concomitantly with and following infusions of %medicine_name% in the management of acute myocardial infarction and pulmonary embolism, but the concomitant administration of heparin and aspirin with and following infusions of %medicine_name% for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or %medicine_name% may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of %medicine_name%, while patients are still receiving anticoagulant therapy. If serious bleeding occurs, terminate the %medicine_name% infusion.
In the following conditions, the risks of bleeding with %medicine_name% therapy for all approved indications are increased and should be weighed against the anticipated benefits:
Orolingual angioedema has been observed during and up to 2 hours after %medicine_name% infusion in patients treated for acute ischemic stroke and acute myocardial infarction. In many cases, patients received concomitant angiotensin-converting enzyme inhibitors. Monitor patients treated with %medicine_name% during and for several hours after infusion for orolingual angioedema. If angioedema develops, discontinue the %medicine_name% infusion and promptly institute appropriate therapy (e.g., antihistamines, intravenous corticosteroids, epinephrine).
Cholesterol EmbolizationCholesterol embolism has been reported rarely in patients treated with thrombolytic agents; the true incidence is unknown. Cholesterol embolism may present with livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, or rhabdomyolysis and can be fatal. It is associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.
Reembolization Of Deep Venous Thrombi during Treatment For Acute Massive Pulmonary Embolism%medicine_name% has not been shown to treat adequately underlying deep vein thrombosis in patients with PE. Consider the possible risk of reembolization due to the lysis of underlying deep venous thrombi in this setting.
Coagulation Tests May Be Unreliable During %medicine_name% TherapyCoagulation tests and measures of fibrinolytic activity may be unreliable during %medicine_name% therapy, unless specific precautions are taken to prevent in vitro artifacts. When present in blood at pharmacologic concentrations, %medicine_name% remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityLong-term studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility. Short-term studies, which evaluated tumorigenicity of %medicine_name% and effect on tumor metastases in rodents, were negative.
Studies to determine mutagenicity (Ames test) and chromosomal aberration assays in human lymphocytes were negative at all concentrations tested. Cytotoxicity, as reflected by a decrease in mitotic index, was evidenced only after prolonged exposure and only at the highest concentrations tested.
Use In Specific Populations Pregnancy Pregnancy Category C%medicine_name% is embryocidal in rabbits when intravenously administered in doses of approximately two times (3 mg/kg) the human dose for AMI. No maternal or fetal toxicity was evident at 0.65 times (1 mg/kg) the human dose in pregnant rats and rabbits dosed during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women.
Nursing MothersIt is not known whether %medicine_name% is excreted in human milk. Many drugs are excreted in human milk.
Pediatric UseSafety and effectiveness of %medicine_name% in pediatric patients have not been established.
Geriatric Use Acute Ischemic StrokeIn exploratory, multivariate analyses of Studies 1 and 2, age greater than 77 years was one of several interrelated baseline characteristics associated with an increased risk of intracranial hemorrhage. Efficacy results suggest a reduced but still favorable clinical outcome for %medicine_name%-treated elderly.
Acute Myocardial InfarctionIn a large trial of accelerated-infusion %medicine_name% that enrolled 41,021 patients with AMI to one of four thrombolytic regimens , patients over 75 years of age, a predefined subgroup, comprised 12% of enrollment. In these patients, the incidence of stroke was 4.0% for the %medicine_name% accelerated infusion group, 2.8% for streptokinase IV [SK (IV)], and 3.2% for streptokinase SQ [SK (SQ)]. The incidence of combined 30-day mortality or nonfatal stroke was 20.6% for accelerated infusion of %medicine_name%, 21.5% for SK (IV), and 22.0% for SK (SQ).
Administer %medicine_name% 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 %medicine_name% administration for the treatment of acute ischemic stroke, frequently monitor and control blood pressure.
In patients without recent use of oral anticoagulants or heparin, %medicine_name% treatment can be initiated prior to the availability of coagulation study results. Discontinue %medicine_name% if the pretreatment International Normalized Ratio (INR) is greater than1.7 or the activated partial thromboplastin time (aPTT) is elevated.
Acute Myocardial InfarctionAdminister %medicine_name% 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 %medicine_name% 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.
Accelerated InfusionThe recommended accelerated infusion dose consists of an IV bolus 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 %medicine_name% have only been investigated with concomitant administration of heparin and aspirin.
3-Hour InfusionFor 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 |
The recommended dose is 100 mg administered by IV infusion over 2 hours.
Institute parenteral anticoagulation near the end of or immediately following the %medicine_name% infusion when the partial thromboplastin time or thrombin time returns to twice normal or less.
Preparation For Administration ReconstitutionUse 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 %medicine_name%. Reconstitute %medicine_name% no more than 8 hours before use, as it contains no antibacterial preservatives.
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.
%medicine_name% 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 %medicine_name%, 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 %medicine_name%.
Following bolus dose, if indicated :
%medicine_name% is for intravenous administration only. Extravasation of %medicine_name% 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 %medicine_name%.
The following adverse reactions are discussed in greater detail in the other sections of the label:
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 %medicine_name% 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 %medicine_name%-treated patients than in placebo patients. A dose-finding study of %medicine_name% 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 %medicine_name% 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 %medicine_name% treatment, particularly symptomatic intracranial hemorrhage within 36 hours. There was no increase in the incidences of 90-day mortality or severe disability in %medicine_name%-treated patients compared to placebo.
Table 3: Combined Safety Outcomes for Studies 1 and 2
| Placebo (n= 312) |
%medicine_name% (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 %medicine_name%. In Studies 1 and 2, the frequency of bleeding requiring red blood cell transfusions was 6.4% for %medicine_name%-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 %medicine_name% 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 %medicine_name% 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 %medicine_name% treatment of AMI patients receiving the 3-hour infusion regimen.
Allergic ReactionsAllergic-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 ExperienceThe following adverse reactions have been identified during post-approval use of %medicine_name%. 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 %medicine_name% on the incidence of these events is unknown.
Acute Ischemic StrokeCerebral edema, cerebral herniation, seizure, new ischemic stroke. These events may be life threatening and may lead to death.
Acute Myocardial InfarctionArrhythmias, 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 EmbolismPulmonary reembolization, pulmonary edema, pleural effusion, thromboembolism, hypotension. These events may be life threatening and may lead to death. Fever has also been reported.
DRUG INTERACTIONSThe interaction of %medicine_name% 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 %medicine_name% 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..
