DRUG PROFILE OF ALTEPLASE

1) INTRODUCTION:

Alteplase is a tissue plasminogen activator indicated for the treatment of;

 Acute Ischemic stroke.

 Acute Myocardial Infarction ( AMI) to reduce mortality and incidence of heart failure.
 Acute Massive Pulmonary Embolism (PE) for lysis.

Alteplase is a tissue plasminogen activator produced by recombinant DNA technology. It is a

sterile, purified glycoprotein of 527 amino acids. It is synthesized using the complementary
DNA (cDNA) for natural human tissue-type plasminogen activator obtained from a human
melanoma cell line. Alteplase is sterile, white to off-white, lyophilized powder for
intravenous administration after reconstitution with sterile water for injection, USP.
Biological potency is determined by an in vitro clot lysis assay and is expressed in
international Units. The reconstituted preparation results In a colourless to pale yellow
transparent solution containing Alteplase 1mg/mL at approximately pH 7.3. The osmolality
of this solution is approximately 215 mOsm/kg.

2) CLINICAL PHARMACOLOGY:
2.1) MECHANISM OF ACTION:
Alteplase is a serine protease responsible for fibrin-enhanced conversion of plasminogen to plasmin.
It produces limited conversion of plasminogen in the absence of fibrin. When introduced into the
systemic circulation at pharmacologic concentration, alteplase binds to fibrin in a thrombus and
converts the entrapped plasminogen to plasmin. The initiates local fibrinolysis with limited systemic
proteolysis.

2.2) PHARMACODYNAMICS:
Following administration of 100 mg alteplase, there is a decrease (16%-36%) in circulating
fibrinogen. In a controlled trial, 8 of 73 patients (11%) receiving alteplase (1.25 mg/kg body weight
over 3 hours) experienced a decrease in fibrinogen to below 100 mg/ dal.

2.3) PHARMACOKINETICS:
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.

3) INDICATION AND USAGE:

3.1) ACUTE ISCHEMIC STROKE:
Alteplase 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 symptoms
onset.

3.2) ACUTE MYOCARDIAL INFARCTION:

Alteplase is indicated for use in acute myocardial infarction for the reduction of mortality and
reduction of incidence of heart failure.

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

3.3) PULMONARY EMBOLISM:

Alteplase 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.
4) DOSAGE AND ADMINISTRATION:
4.1) FOR ACUTE ISCHEMIC STROKE
Administer Alteplase 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 the following alteplase administration for the treatment of acute Ischemic stroke, frequently
monitor and control blood pressure.

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

4.2) FOR ACUTE MYOCARDIAL INFARCTION:

Administer Alteplase 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 Alteplase dose regimens ( accelerated and 3-hour) for use in the
management of AMI;

 ACCELERATED INFUSION:
 The recommended accelerated infusion dose consists of an IV bolus followed by an IV infusion
as given below;
 For patient weighing > 67 kg, the recommended intravenous bolus is 15 mg administered as 50
mg in the first 30 minutes, 35 mg in the next 60 minutes.
 For patient weighing ≤ 67 kg, the recommended intravenous bolus is 15 mg administered as
0.75 mg/kg in the first 30 minutes, 0.50 mg/kg in the next 60 minutes.
The safety Mad efficacy of accelerated infusion of Alteplase have only been investigated with
concomitant administration of heparin and aspirin.
 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 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.
4.3) PULMONARY EMBOLISM:
The recommended dose is 100 mg administered by IV infusion over 2 hours.

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

5)PREPARATION AND DIRECTION 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 Alteplase.

Reconstitute Alteplase 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.

Alteplase 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 Alteplase, 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 Alteplase.

1. Use aseptic technique.

2. Remove the protective flip-caps from one vial of Alteplase 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.
4. Hold the vial of Alteplase 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 Alteplase down so that
the piercing pin is inserted through the center of the Alteplase vial stopper.
5. . Invert the two vials so that the vial of Alteplase 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 Alteplase vial (approximately 0.5 cc of SWFI will
Remain in the diluent vial).
6. Remove the transfer device and the empty SWFI vial from the Activase vial and discard.
7. Swirl gently to dissolve the Alteplase powder. DO NOT SHAKE.

6)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.

6.1)ADMINISTRATION:
Following bolus dose, if indicated;

• 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. 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 Alteplase. Peel the clear plastic hanger from
the vial label. Hang the Alteplase vial from the resulting loop.

Alteplase is for intravenous administration only. Extravasation of Alteplase 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 Alteplase.

7) DOSAGE FORMS AND STRENGTHS:

• 50 mg lyophilized powder per single use vial with 50 mL SWFI USP for reconstitution

• 100 mg lyophilized powder per single use vial with 100 mL SWFI USP for reconstitution

EFFICACY OF INTRAVENOUS THROMBOLYSIS

In 1995, the National Institute of Neurological Disorders and Stroke (NINDS) study group reported that
patients with acute ischemic stroke who received alteplase (0.9mg per kilogram of body weight,
maximum dose 90mg, 10% given as a bolus with the remainder given over one hour) within three
hours after the onset of symptoms were at least 30% more likely to have minimal or no disability at
three months than those who received placebo.

Subsequent study demonstrated that patients treated with rt-PA were also more likely to have
minimal or no disability at one-year follow-up.13 One year after the publication of the NINDS study,
the US Food and Drug Administration approved intravenous rt-PA as a treatment for acute ischemic
stroke and this treatment is the only approved medical therapy for patients with acute ischemic
stroke to date and is recommended as first-line treatment by most national and international stroke
associations.

The widespread adoption of treatme”t with rt-PA has not been without controversy, at least in part
because other studies with rt-PA in ischemic stroke have been negative, because of concerns that
baseline imbalances in the NINDS report might explain the benefit of this treatment, and because the
overall benefit in the trial included a 10-fold increase in the proportion of patients treated with
alteplase suffering from sICH (6.4% versus 0.6% in the placebo group), which could compromise the
benefit when used in routine clinical practice.

Negative thrombolytic studies differed from the NINDS trial in fundamental and important aspects,
such as different thrombolytic drugs, different doses of rt-PA, and longer intervals between symptom
onset and treatment. Among negative trials of intravenous rt-PA there was the first European
Cooperative Acute Stroke Study (ECASS I), in which a higher dose of rt-PA was used and patients were
randomized up to six hours after the onset of symptoms.17 In the ECASS II trial, the dose of rt-PA was
identical to that used in the NINDS trial, but there was a six-hour treatment window, with most
patients treated after three hours. In this second trial, the results were not in favor of treatment with
alteplase.
The Alteplase Thrombolysis for Acute Non-interventional Therapy in Ischemic Stroke (ATLANTIS) study
used a treatment protocol identical to that of the NINDS trial but randomized patients from three to
five hours after stroke and also showed negative results.

Despite these findings, Hacke and colleagues reported positive results of an intention-to-treat analysis
of pooled data from randomized trials of rt-PA for ischemic stroke (NINDS, ECASS I, ECASS II, and
ATLANTIS) that included 2775 patients treated up to six hours after symptom onset in more than 300
hospitals located in 18 countries.

Results of major trials on use of endovenous rt-PA. Report of the 90-day outcome for patients treated
with alteplase

This analysis supported the results of the NINDS trial and demonstrated that treatment within three
hours (and possibly up to 4.5 hours) of symptom onset is associated with a greater chance of a
favorable outcome at three months. This pooled analysis also showed how crucial the time of
treatment is; in particular, alteplase is nearly twice as efficacious when administered within the first
1.5 hours after the onset of ischemic stroke as it is when administered within 1.5 to 3 hours after
stroke onset (odds ratio for good outcome: 2.81 for an interval of 0 to 90 minutes, 1.55 for 91 to 180
minutes, and 1.40 for 181 to 270 minutes). Moreover, the estimated number needed-to-treat (NNT) of
patients to identify clinical benefit is only three.

The second concern about alteplase”in clinical practice was that the baseline imbalance in stroke
severity between the rt-PA- and placebo-treated groups in the NINDS trial might explain the benefit
observed in clinical outcome. An independent group reanalyzed the trial data and confirmed a
statistically significant treatment benefit despite subgroup imbalances in stroke severity assessed with
National Institutes of Health Stroke Survey (NIHSS) score.

Finally, we doubt the possibility that the results reached in the NINDS trial would be generalizable to
nonstudy settings. This fear was reinforced by several observational studies that documented higher
rates of bleeding complications occurring when treatment protocols were violated. In contrast, other
observational studies reported that, in the “real world,” results similar to those found in the NINDS
trial could be achieved only if treatment protocols were carefully followed.23 Moreover, a great
number of studies asserted that successful clinical outcomes and low complication rates could be
achieved by treating patients with intravenous rt-PA beyond the clinical trial setting.24–27 In
particular, the Standard Treatment with Alteplase to Reverse Stroke (STARS) study conducted on
consecutive acute stroke patients treated with intravenous rt-PA showed results similar to the NINDS
study: 13.1% of patients died within 30 days of follow-up and 11.5% experienced an ICH.

On the basis of these different results the European Medicines Agency (EMEA) granted approval of
alteplase in 2002 under condition that a study be initiated in order to assess the safety and efficacy of
rt-PA in routine clinical practice; subsequently, the Safe Implementation of Thrombolysis in Stroke–
Monitoring Study (SITS-MOST) was undertaken.

SITS-MOST completed in 2007 and confirmed that alteplase is safe and effective when used in the first
three hours after the onset of stroke in a wide range of clinical settings.28 The primary aim of the
study was to establish whether the levels of safety seen in randomized controlled trial populations
could be reproduced in routine clinical practice, and mainly concerned ICH. The results of this
observational study showed that the proportion of patients who experience sICH was similar to that
observed in randomized controlled trials. Moreover there was a trend towards a reduced incidence of
ICH in SITS-MOST when compared to NINDS study, although confidence intervals (CI) overlapped. A
reduction in mortality within the first three months was also seen in SITS-MOST compared with
randomized controlled trials (11.3% vs 17.3%; 95% CI 10.5–12.1, 14.1–21.1, respectively). This study
was compared with the Canadian Alteplase for Stroke Effectiveness Study (CASES), an observational
cohort study on alteplase in ischemic stroke done between February 1999, and June 2001, where
mortality was 22.3%.29 Lower mortality in SITS-MOST could be explained with lower stroke severity
and lower age in study population in respect to randomized controlled trials and CASES.

Similar results were achieved by smaller observational multicenter studies, including a total of about
650 patients,24,27 although one case had a higher rate of sICH.30

Moreover the results of SITS-MOST regarding complete recovery at three months follow-up was the
same as in the pooled randomized controlled trials (39% vs 42% CI 36.9–39.7, 38.2–43.2, respectively).

Lyden and colleagues31 discussed the uncertainty shown by less experienced centers in including
thrombolysis in their routine clinical practice. At the end of SITS-MOST study, the recruitment of “no-
expertise” centers had increased to about 50%, thus demonstrating an increase in awareness and
growth in the ability to provide thrombolysis within the three-hour therapeutic window in clinical
practice. Moreover, compared with centers with more experience, sICH was almost the same, which
demonstrates that treatment safety could be maintained across all centers. Neither the proportion of
patients with sICH nor the degree of independence at three months was significantly different
between experienced and new centers. Mortality was a little higher in new centers but remained
lower than that seen previously in randomized controlled trials. This data could be explained by
higher stroke severity in new centers (one point higher median NIHSS score) than in experienced
centers.

It Is interesting to note that there has been a gradual decline in the overall initial severity of stroke
and in mortality rates among patients enrolled in major randomized studies of acute ischemic stroke
over the past two decades. This observation may reflect the trend toward the use of alteplase in
patients who have less severe neurologic impairments (as demonstrated by the results of the SITS-
MOST trial), as well as the increased number of stroke units in Europe and the improved care provided
by such units.

THROMBOLYSIS AFTER THREE HOURS

The second request of the EMEA was the initiation of a third randomized trial,
ECASS III, in which the therapeutic window was extended beyond three hours.
Before ECASS III, two European trials, the ECASS I and ECASS II, investigated a
larger time window (up to six hours) but failed to show efficacy of treatment
with alteplase.17,18 A subsequent analysis of the NINDS study32 and the
combined analysis20 of data from the six randomized trials,12,17–19,33 showed
a significant association between efficacy of treatment and the interval between
the onset of symptoms and drug administration. Data from the pooled analysis
showed a favorable outcome even if treatment was given between 3 and 4.5
hours, with an odds ratio of 1.4 for a good outcome with alteplase treatment as
compared with placebo. This analysis also suggested that a longer time window
was not associated with higher rates of sICH or with greater mortality.20

ECASS III is the second randomized trial (after the NINDS trial in 1995) to show
significant treatment efficacy with intravenous alteplase in the unadjusted
analysis of the primary end-point demonstrating that patients with acute
ischemic stroke benefited from treatment when administered 3 to 4.5 hours
after the onset of stroke symptoms.34 Moreover this benefit was maintained as
significant after adjustment for all prognostic baseline characteristics. In this
trial the overall rate of sICH was increased in patient treated with rt-PA as
compared with placebo, but mortality was not affected. All these findings are
consistent with results from other randomized controlled trials.12,20,35

Finally, the initial severity of stroke represented the most predictive factor for
the functional and neurologic outcome and for the risk of death. Previous trials
failed to show a significant advantage of alteplase therapy in patients who
received treatment within 0 to 6 hours after the onset of symptoms.It is likely
that the time window of up to six hours and the lack of statistical power are
responsible for the failure of these studies.

Although it is well known that thrombolysis for ischemic stroke is associated

with an increased risk of symptomatic intracranial hemorrhage, it is difficult to
compare the incidence of this complication in the various studies due to the
different definitions used for intracranial hemorrhage.
The classifications widely used in clinical trials to identify intracranial bleeding
are those reported in the NINDS and ECASS studies.12,17,18 In the former,
hemorrhagic transformations were divided into two radiological groups:
hemorrhagic cerebral transformation and intracerebral hematomas.
Hemorrhagic cerebral infarction is defined as computed tomography (CT)
findings of acute infarction with punctate or variable hypodensity/hyperdensity
with an indistinct border within the vascular territory suggested by acute
neurologic signs and symptoms. Intracerebral hematoma is defined as a typical
homogeneous, hyperdense lesion with a sharp border with or without edema or
mass effect within the brain. This hyperdense lesion could arise at a site remote
from the vascular territory of the ischemic stroke or within but not necessarily
limited to the territory of the presenting ischemic stroke. Also hemorrhage with
an intraventricular extension is considered an intracerebral hematoma. ECASS
classification is a purely radiological definition subdivided into four categories:
hemorrhagic infarction type 1 (HI-1; small petechiae along the margins of the
infarct); hemorrhagic infarction type 2 (HI-2; confluent petechiae within the
infracted area, but without space-occupying effect); parenchymal hematoma
type 1 (PH-1; an hematoma in less than 30% of infracted area with some slight
space-occupying effect); parenchymal hematoma type 2 (PH-2; a dense
hematoma in more than 30% of infarcted area with substantial space-occupying
effect, or any hemorrhagic lesion outside the infarcted area). In the ECASS III
trial, sICHs have been identified as the predominant cause of neurologic
deterioration. Considering this definition, a difference of 2.14% was found
between the two treatment arms. The authors also analyzed the incidence of
intracranial hemorrhage using the definition of the other trials12,17,37 and in
this case the rate of sICH was no higher than that reported in previous trials or
in SITS-MOST, despite the extended time window. In ECASS III the overall
mortality rate was approximately 8% and was lower than that reported in
previous trials and this fact could be also attributable to the inclusion of patient
with lower stroke severity (baseline NIHSS score: for ECAS-III, 9; for NINDS, 14).
In comparison with pooled analysis of previous randomized trials, in ECASS III,
the odds ratio for a good outcome was 1.34 (CI 181–270 minutes) and the NNT
for a good outcome is equal to 14. The effectiveness of alteplase in an extended
time window up to 4.5 hours is confirmed by evaluation of the data from the
Safe Implementation of Thrombolysis in Stroke–International Stroke
Thrombolysis Register (SITS-ISTR) registry which shows that the rates of sICH,
mortality, and independence at three-month follow-up in routine clinical
practice are similar in patients who received treatment between three and 4.5
hours and for those treated within three hours from stroke onset.38 In the SITS-
ISTR registry, a small group of patients (n = 664) received rt-PA after three
hours. In the three to four, five-hour cohort, any hemorrhage occurred in 17% of
patients whereas 8% had symptomatic intracranial bleeding according to the
NINDS definition. Moreover 41% of patients reached a score of 0–1 on the
modified Rankin score at three months follow-up. The results of both studies
(SITS-ISTR and ECASS III) are statistically significant and allow physicians to
extend the window of treatment up to 4.5 hours.

IMPORTANT SAFETY INFORMATION:

8) CONTRAINDICATIONS:
8.1) ACUTE ISCHEMIC STROKE:
Do not administer Alteplase to treat acute ischemic stroke in the following situations in which the risk of
bleeding is greater than the potential benefit;

• Current intracranial hemorrhage

• Subarachnoid hemorrhage

• Active internal bleeding

• Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma

• Presence of intracranial conditions that may increase the risk of bleeding (e.g., some neoplasms,
arteriovenous malformations, or aneurysms)

• Bleeding diathesis

* Current severe uncontrolled hypertension.

8.2) ACUTE MYOCARDIAL INFARCTION OR PULMONARY EMBOLISM:

Do not administer Activase for treatment of AMI or PE in the following situations in which the risk Of
bleeding is greater than the potential benefit [see Warnings and Precautions (5.1)]:
• Active internal bleeding

• History of recent stroke

*Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma

• Presence of intracranial conditions that may increase the risk of bleeding (e.g. some neoplasms,
arteriovenous malformations, or aneurysms)

• Bleeding diathesis

• Current severe uncontrolled hypertension.

9) WARNING AND PRECAUTIONS:

9.1) BLEEDING:
Alteplase 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 Alteplase. 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 Alteplase 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 Alteplase have been reported. Aspirin and heparin have been
administered concomitantly with and following infusions of Alteplase in the management of acute
myocardial infarction and pulmonary embolism, but the concomitant administration of heparin and
aspirin with and following infusions of Alteplase for the treatment of acute ischemic stroke during the
first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or Alteplase
may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites.
Hemorrhage can occur 1 or more days after administration of Alteplase, while patients are still receiving
anticoagulant therapy. If serious bleeding occurs, terminate the Alteplase infusion.

In the following conditions, the risks of bleeding with Alteplase therapy for all approved indications are
increased and should be weighed against the anticipated benefits:

• Recent major surgery or procedure, (e.g., coronary artery bypass graft, obstetrical delivery, organ
biopsy, previous puncture of noncompressible vessels)

• Cerebrovascular disease

• Recent intracranial hemorrhage

• Recent gastrointestinal or genitourinary bleeding

• Recent trauma

• Hypertension: systolic BP above 175 mm Hg or diastolic BP above 110 mm Hg

• High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation • Acute pericarditis

• Subacute bacterial endocarditis

• Hemostatic defects including those secondary to severe hepatic or renal disease • Significant hepatic
dysfunction

• Pregnancy

 Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions.

• Septic thrombophlebitis or occluded AV cannula at seriously infected site

• Advanced age.

• Patients currently receiving anticoagulants (e.g., warfarin sodium)

• Any other condition in which bleeding constitutes a significant hazard or would be particularly
difficult to manage because of its location.

9.2) OROLINGUAL ENGIOEDEMA :

Orolingual angioedema has been observed during and up to 2 hours after Alteplase 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 Alteplase during
and for several hours after Infusion for orolingual angioedema. If angioedema develops, discontinue the
Alteplase infusion and Promptly institute appropriate therapy (e.g., antihistamines, intravenous
corticosteroids, epinephrine).

9.3) CHOLESTEROL EMBOLIZATION:

Cholesterol 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. 

9.4) REEMBOLIZATION OF DEEP VENOUS THROMBI DURING

TREATMENT FOR ACUTE MASSIVE;
  
*Pulmonary Embolism  
Alteplase 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.  

9.5) COAGULATION TESTS MAY BE UNRELIABLE DURING ALTEPLASE THERAPY:

 Coagulation tests and measures of fibrinolytic activity may be unreliable during Alteplase
therapy,  unless specific precautions are taken to prevent in vitro artifacts. When present
in blood at pharmacologic concentrations, Alteplase remains active under in vitro
conditions, which can result in  degradation of fibrinogen in blood samples removed for
analysis.
9.6) HYPERSENSITIVITY:
Hypersensitivity, including urticarial / anaphylactic reactions, have been reported after
administration of Activase. Rare fatal outcome for hypersensitivity was reported.
Angioedema has been observed during and up to 2 hours after Activase 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 Activase during and for several hours after infusion for hypersensitivity. If
signs of hypersensitivity occur, e.g. anaphylactoid reaction or angioedema develops,
discontinue the Activase infusion and promptly institute appropriate therapy (e.g.,
antihistamines, intravenous corticosteroids, epinephrine).
9.7) THROMBOEMBOLISM:
The use of thrombolytics can increase the risk of thrombo-embolic events in
patients with high likelihood of left heart thrombus, such as patients with mitral
stenosis or atrial fibrillation. Activase has not been shown to treat adequately
underlying deep vein thrombosis in patients with PE. Consider the possible risk of
re-embolization due to the lysis of underlying deep venous thrombi in this setting.
9.8) SIDE EFFECTS:
1). Serious bleeding:
gastrointestinal (1-10%), genitourinary (1-10%), epistaxis or other respiratory (1-10%),
retroperitoneal (less than 1%), pericardial (less than 1%), hepatic (less than 0.1%), eyes (less than
0.01%), This may present as shock ( falling blood pressure, tachycardia etc).
2) BRUISING OR SUPERFICIAL BLEEDING:
Occurs in greater than 10% of patients, particularly at sites of minor trauma or venipuncture.
3) ALLERGIC REACTIONS:
Have been reported in less than 1% of cases with Alteplase, and may range from mild to
anaphylactoid. Patient may develop swelling around the mouth and tongue during the There has been
an association with concurrent use of ACE inhibitors with Alteplase and the incidence of allergic
reactions.
OTHERS:
Blood pressure decreased ( greater than 10%), body temperature increased (1-10%), requiring
blood transfusion ( 1-10%), Embolism (less than1%), cholesterol Embolism (less than 0.1%), incidence
unknown; pulmonary re-embolisation, pulmonary oedema, pleural effusion, hypotension.

10) DRUG 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 Alteplase therapy. Some.of the examples are Aminophenazone,
Altretamine, Aminosalicylic Acid etc.
In the post-marketing setting, there have been reports of orolingual angioedema in
patients (primarily patients with AIS) receiving concomitant angiotensin-converting
enzyme inhibitors.
ACE INHIBITORS AND ANGIOTENSIN II ANTAGONISTS: increased risk of
experiencing anaphylactoid reaction with Alteplase.
GLYCERYL TRINITRATES: may increase hepatic blood flow, leading to increased
clearance of Alteplase. This may reduce the thrombolytic efficacy of Alteplase . Monitor
for adequate reperfusion and possible reocclusion. Use the lowest dose of glyceryl
trinitrate possible.
APROTININ: may decrease the therapeutic efficacy of Alteplase.

11) PRESCRIBING AND DISPENSING INFORMATION:

All Alteplase doses are to be prescribed by the ED, ICU, or medical
registrar under the supervision of a consultant. Maximum total dose 100
mg including loading dose.

 If 65 kg or Greater: 10 mg loading dose IV over 1 minute, then 90

mg IV infusion over 2 hours.
 If less than 65 kg: maximum 1.5 mg/kg with 10 mg loading dose IV
over 1 minute and remainder of dose by IV infusion over 2 hours.

PRESCRIBE AS:

Alteplase 10 mg undiluted IV over ONE minute, immediately followed by

alteplase X mg diluted to 100 ml sodium chloride 0.9% IV over two
hours. ( X represent the calculated dose required).

All doses require independent double check by nursing staff.

Select number of vials required to administer dose.

Reconstitute the required vials using the WFI diluent provided with the
vials to make a 1 mg/ml solution. Use the information provided in the
box. Swirl gently. Do not shake.

Prepare loading dose and infusion sequentially, with both prepared

before doses commence.
 Load: draw the loading (bolus) dose of 10 mg up in a 10 ml syringe and
attach an additive label. Do not dilute further.

12) MEDICINAL FORMS:

Generic name: Alteplase

Brand name: Activase, Cathflo Activase.

Injectable powder for injection (2 mg); intravenous powder for injection (100 mg; 50 mg)

13) USE IN SPECIFIC POPULATION:

 Pregnancy category C:
Alteplase 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.

 Lactation:
It is not known whether Alteplase is excreted in human
milk. Many drugs are excreted in human milk.
 Pediatric use:
Safety and effectiveness of Alteplase in pediatric patients
have not been established.
 Geriatric use:
Acute Ischemic Stroke

In 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 Activase-treated elderly.

Acute Myocardial Infarction

In a large trial of accelerated-infusion Activase that enrolled 41,021 patients

with AMI to one of four thrombolytic regimens [see Clinical Studies (14.2)],
patients over 75 years of age, a predefined Subgroup, comprised 12% of
enrolment. In these patients, the incidence of stroke was 4.0% for the
Alteplase 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 Activase,
21.5% for SK (IV), and 22.0% for SK (SQ).

14) HOW SUPPLIED/STORAGE AND HANDLING

14.1) How supplied:

Alteplase is supplied as a sterile, lyophilized powder in 50 mg vials containing

vacuum and in 100 mg vials without vacuum. Each 50 mg Activase vial (29 million IU) is
packaged with diluent for reconstitution (50 mL SterileWater for Injection, USP).Each 100 mg
Activase 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.

14.2) stability and storage:

Store lyophilized Activase 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), Alteplase 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.

15) PATIENT COUNSELING INFORMATION:

Following Alteplase administration, patients are at increased risk of bleeding internally or

externally. Advise patients to contact a health-care professional if they experience symptoms or
signs consistent with bleeding (e.g., unusual bruising, pink or brown urine, red or black or tarry
stools, coughing up Blood, vomiting blood or blood that looks like coffee grounds), headache, or
stroke.

CONCLUSIONS:
The introduction of rt-PA in clinical practice for the treatment of acute ischemic stroke has
represented an important step in the therapeutic approach to a difficult and once untreatable clinical
condition. Its major complication, ICH, describes complex and heterogeneous groups of phenomenon,
and involves multiple demographic, clinical, biological, and hemodynamic parameters, knowledge of
which remains partial. Identification of the risk factors for sICH will help in improved selection of
patients for thrombolysis.

The future of t-PA for the treatment of patients with acute ischemic stroke largely
depends on successfully attaining several goals including: (i) a better organization
of the health care system, (ii) improvement of the thrombolytic properties of t-
PA, (iii) inhibition of the deleterious effects of t-PA on the permeability of the
neurovascular unit without interfering with its thrombolytic properties, (iv)
attenuation of the neurotoxic effects of t-PA, and (v) extension of the time
window. The organization of the health care system should include educational
programs directed to the public and the development of dedicated acute stroke
units staffed by personnel with expertise in the diagnosis and treatment of acute
stroke.

The improvement of the efficiency of t-PA as a thrombolytic agent may be based

on the results of ongoing studies which are testing the effect of combined
intravenous and intra-arterial thrombolysis in addition to the simultaneous use of
t-PA and transcranial or local procedures; among these is the EKOS 1-catheter-
delivered ultrasound trial by EKOS Corporation.

Moreover, because the effect of t-PA on the BBB permeability seems to be have
an important role in the deleterious effects of t-PA itself in the ischemic brain, the
combined therapy of t-PA and protectors of the integrity of the neurovascular
unit might achieve promising results. The targets of neuroprotective experiments
have included calcium antagonists, sodium channel blockade, glutamate/NMDA
antagonists, free radical scavengers, apoptosis inhibitors, γ-aminobutyric acid-A
(GABAA) agonists, and agents that stabilize the neuronal membrane.
Unfortunately almost all the trials conducted with such neuroprotective agents
failed to shown a substantial benefit in ischemic stroke patients.

Based on the observation that the interaction of t-PA with the NMDA receptor
occurs through a particular kringle domain, new t-PA muteins lacking this domain
or containing mutations were developed with the aim to minimize the NMDA-
receptor-dependent neurotoxic effects of alteplase to be less harmful when
administered in ischemic stroke patients.

REFERENCE:

1)Center for drug evaluation and research

2) Ballarat health services and drug guidelines.