Retavase (Reteplase)

Transcription

Product Monograph
INTRODUCTION
The availability of RETAVASE® (Reteplase) marks an important advance in the
thrombolytic treatment of acute myocardial infarction (AMI). RETAVASE possesses
a unique molecular design and provides demonstrated reduction of mortality, a
documented safety profile, and has been angiographically proven to achieve high
rates of complete perfusion and patency. The correlation between patency and patient
outcome has not been established. In addition, RETAVASE offers the convenience of a
simple double-bolus dosing regimen.
This monograph is provided as a comprehensive informational reference to
RETAVASE. It includes a complete review of preclinical and clinical pharmacology
findings as well as clinical efficacy and safety data. The information presented has
been designed to aid in the evaluation of RETAVASE for use in clinical practice.
RETAVASE is manufactured and distributed by Centocor, Inc.
3
CONTENTS
I.
Brief overview of RETAVASE® (Reteplase):
a novel thrombolytic agent . . . . . . . . . . . . . . . . . . . . . 7
II.
Thrombolysis in the management
of acute myocardial infarction. . . . . . . . . . . . . . . . . . . . . . 9
III.
The open-artery hypothesis in thrombolysis . . . . . . . . . 13
IV.
RETAVASE preclinical pharmacology . . . . . . . . . . . . . . . 17
V.
RETAVASE clinical pharmacology. . . . . . . . . . . . . . . . . . 23
VI.
RETAVASE clinical efficacy and activity . . . . . . . . . . . . . 27
VII.
RETAVASE safety profile . . . . . . . . . . . . . . . . . . . . . . . . . 35
VIII.
RETAVASE angiographic trials . . . . . . . . . . . . . . . . . . . . 37
IX.
Summary of benefits of RETAVASE . . . . . . . . . . . . . . . . 41
X.
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
RETAVASE full prescribing information. . . . . . . . . . . . . 45
Please see full prescribing information on the last pages of this monograph.
5
SECTION I
Brief overview of
RETAVASE® (Reteplase):
a novel thrombolytic agent
R
ETAVASE is a modification of the tissuetype plasminogen activator (t-PA) protein
that maintains the kringle-2 and protease
domains of t-PA, but lacks its kringle-1, finger, and
growth-factor domains. In contrast to t-PA, the
RETAVASE molecule is nonglycosylated. These
modifications result in a molecule with a longer
half-life (13 to 16 minutes). RETAVASE lacks the
high-affinity fibrin binding characteristic of t-PA,
and is produced by recombinant DNA technology
in Escherichia coli for use as a thrombolytic agent
in the treatment of AMI. RETAVASE is a singlechain molecule consisting of 355 amino acids
and can be converted to the two-chain form
during fibrinolysis.
RETAVASE represents an important addition
to the therapeutic options to treat patients with
AMI. RETAVASE provides demonstrated reduction
of mortality, a documented safety profile, and
proven preservation of left ventricular function.
Additionally, RETAVASE has been angiographically
proven to achieve high rates of complete perfusion
and patency, and offers a fast, convenient doublebolus dosing regimen. The correlation between
patency and patient outcome has not been
established.
Table 1.—Selected Characteristics of
an Ideal Thrombolytic Agent
•
•
•
•
•
•
•
•
•
•
Rapid recanalization after administration
Approaches 100% efficacy for recanalization
Can be given as rapid IV bolus
Specific for recent thrombi
Assists in preventing reocclusion
– Should result in sustained patency within
the first 24 hours
– Appropriate half-life if fibrin-specific
Targets thrombus induced by plaque rupture
No effect on circulatory hemodynamics
No negative interactions with adjunctive therapies
No antigenicity
No significant side effects
– Adapted from Rapaport.1
thrombosis. Additional characteristics of an ideal
agent are listed in Table 1.
It is noteworthy that RETAVASE possesses
some of the attributes of the ideal agent:
administration as an intravenous bolus, relative
specificity for recent thrombi, and restoration of
complete flow in a high percentage of patients.
RETAVASE also has no effect on circulatory
hemodynamics, is not antigenic, and has no
known interactions with adjunctive therapies.
Pursuing the ideal thrombolytic agent
It was observed in 1992 that none of the
thrombolytic agents then available could be
considered ideal. Each had limitations. Therefore,
it is appropriate to define the characteristics
of an ideal thrombolytic drug to help guide the
direction of future research and development.1
Patient survival is the ultimate goal of thrombolytic
therapy. An agent should produce rapid
recanalization in patients with acute coronary
7
Pharmacokinetic properties
Results demonstrated that RETAVASE is
effective in reducing mortality in patients with
AMI. Patients treated with RETAVASE had a
significantly lower incidence of atrial fibrillation,
asystole, cardiogenic shock, congestive heart failure
(CHF), hypotension, and allergic reactions. Overall
bleeding and stroke rates were similar for both
agents. There was an increase in the incidence
of in-hospital intracranial hemorrhage in patients
treated with RETAVASE (0.77%) compared to those
in the Streptokinase group (0.37%, P=0.04). The
INJECT investigators concluded that RETAVASE
is an effective agent for the treatment of AMI
and has an acceptable safety profile.
In the Reteplase Angiographic Phase II
International Dose-finding (RAPID 1) Study,
infarct-related arteries were evaluated
angiographically in 606 patients after therapy with
RETAVASE administered by bolus injection (three
different regimens) or Alteplase administered as a
3-hour infusion.4 In the Reteplase vs Alteplase
Patency Investigation During Acute Myocardial
Infarction (RAPID 2) Study, 324 patients received
either RETAVASE or an accelerated-dose (90minute) Alteplase infusion.5 Patients in both trials
also received aspirin and heparin. In both
angiographic trials, RETAVASE achieved high
rates of complete perfusion and patency.4,5 The
correlation between patency and patient outcome
has not been established. These studies also
demonstrated the efficacy of RETAVASE in
preserving left ventricular function following AMI.
Deletion of the three N-terminal domains and
the absence of glycosylation present in native t-PA
improves the pharmacokinetic properties of
RETAVASE® (Reteplase) without sacrificing its
effectiveness as a plasminogen activator. These
modifications to the molecule result in a plasma
half-life of 13 to 16 minutes, which represents an
increase over the 3- to 6-minute half-life of native tPA.2 The longer half-life of RETAVASE permits fast,
convenient double-bolus intravenous dosing, with
the second dose given 30 minutes after the first.
Administration
The ease of administration afforded by bolus
dosing may permit an earlier start of life-saving
therapy in the hospital emergency department or
intensive care unit. Bolus dosing may also eliminate
the need for two intravenous lines during
coadministration with heparin, since the heparin
infusion can be interrupted during the injection of
RETAVASE. The intravenous line should be flushed
before and after administration of RETAVASE.
RETAVASE is supplied in glass vials as a sterile,
preservative-free, lyophilized powder. The contents
of the vial are reconstituted with Sterile Water for
Injection, USP (without preservatives), and
administered as an intravenous injection (10 U)
over 2 minutes. The second bolus (10 U) is given 30
minutes after initiation of the first bolus injection.
The dose of RETAVASE need not be adjusted for
patient weight.
Low risk of antigenicity
Clinical studies
RETAVASE is synthesized in transformed
E coli and is a modified endogenous protein
with a low risk for antigenic activity. Antibodies
to RETAVASE were not observed in any of
approximately 2,400 patients tested for
antibody formation.
The low risk of antigenicity with RETAVASE
contrasts with that of Streptokinase and its
derivatives. Since most patients have previously
been exposed to hemolytic streptococcal infection,
they may produce antibodies to Streptokinase, a
protein derived from Lancefield group C strains of
ß-hemolytic streptococci.
The clinical benefits and safety profile of
RETAVASE have been documented in wellcontrolled clinical trials in patients with AMI.
The International Joint Efficacy Comparison of
Thrombolytics (INJECT) trial was a randomized,
double-blind, multicenter comparison of
RETAVASE with Streptokinase in 6,010 AMI
patients that was conducted in Europe.3 The
study was powered to confirm that RETAVASE
was safe and effective in reducing mortality in
AMI patients.
8
SECTION II
Thrombolysis in the management
of acute myocardial infarction
Rationale for use of thrombolysis
The era of thrombolysis
C
The nature of the infarction process was not
well understood until comparatively recent years. In
1980, DeWood and colleagues provided definitive
proof that thrombosis occurs early in the infarction
process.7 These investigators angiographically
visualized total occlusion of the infarct-related
coronary artery within 4 hours of onset of
symptoms in 110 of 126 patients (87%) with acute
transmural (Q-wave) infarction. In addition, they
found that thrombi were present in 88% of patients
undergoing CABG. Since then, it has frequently
been observed that the arterial lumen is
considerably narrowed by dynamically changing
atheromatous plaque, which enables relatively small
thrombi to block antegrade flow and produce
ischemia and hypoxia. More than 85% of
myocardial infarctions result from formation of an
acute thrombus obstructing an atherosclerotic,
stenotic coronary artery.8 Thus, the development of
selective coronary angiography proved to be a vital
link in the development and acceptance of
thrombolytic therapy.
ardiovascular disease accounts for a large
proportion of all deaths in both men and
women in the United States. The ageadjusted death rate in 1991 was 186 per 100,000
individuals; for coronary heart disease, it was 99.1
per 100,000.6 Patients who survive the acute stage of
a myocardial infarction are at two to nine times
greater risk of subsequent cardiovascular morbidity
and mortality than the general population.6
Three perfusion methods are currently available
for the management of patients with AMI:
thrombolysis with pharmacologic agents,
percutaneous transluminal coronary angioplasty
(PTCA), and revascularization by coronary artery
bypass grafting (CABG). The effectiveness of
thrombolytic therapy in reducing mortality in
patients with AMI has been demonstrated in large,
multinational clinical trials. PTCA is an invasive
procedure that requires a catheterization laboratory
and expert teams for implementation. PTCA is
an option preferred by some physicians where
facilities are available, especially in patients with
contraindications to thrombolytic therapy or with
infarction complicated by cardiogenic shock.
9
Mechanisms of thrombolysis
symptoms.10 However, Streptokinase available at the
time was pyrogenic, and treatment was sometimes
delayed too long to salvage myocardium. Efficacy
could not be adequately documented by coronary
arteriography, left ventricular function (LVF) could
not be assessed with noninvasive modalities, and
even the correlation between infarct size and
prognosis was not apparent.
Despite these obstacles, several investigators
persisted with Streptokinase thrombolysis in the
1960s and 1970s. By 1983, Schröder and colleagues
had shown that intravenous administration of
Streptokinase could restore coronary blood flow
in patients with AMI.11
Like native tissue plasminogen activators, all
thrombolytic agents activate plasminogen into
plasmin, which splits the fibrin in the clot into
soluble fibrin degradation products; fibrinogen, a
precursor of fibrin, is also degraded by plasmin.
Plasminogen, which has high affinity for fibrin, is
activated much more efficiently when bound than
unbound because fibrin forms surface receptors that
allow plasminogen and plasminogen activator to
come into optimal contact (Fig 1). Thrombolytic
agents differ in their affinity for fibrin; this is
important because specificity for fibrin may result in
lysis of hemostatic plugs not only in coronary
thrombi but also elsewhere in the body, thus
promoting bleeding.
Early (exogenous) thrombolytic agents
Streptokinase. Rather than enzymatically
cleaving plasminogen (the mechanism of action
of t-PA, Alteplase, and RETAVASE® (Reteplase),
Streptokinase forms a complex that produces a
conformational change in the plasminogen
molecule. The plasminogen complex then converts
noncomplexed plasminogen molecules to plasmin.
The half-life of Streptokinase is approximately 30
minutes, with much of the circulating Streptokinase
catalyzed before it can bind to polymerized fibrin.12
Early history of thrombolytic therapy
The discovery in 1933 by Tillett and Garner that
the streptococcal protein Streptokinase lyses blood
clots did not translate into a tool for the cardiologist
until decades later.9 The first clinical indications for
Streptokinase were management of proximal deepvein thrombosis and severe pulmonary embolism.
The earliest attempt to treat AMI with coronary
fibrinolysis was a pilot study in 1959 by Fletcher and
colleagues, who infused Streptokinase intravenously
for 30 hours, starting 6 to 72 hours after onset of
Fig 1.—Binding of plasminogen to endogenous tissue plasminogen activator (t-PA)
and fibrin.
Fibrinolysis
Fibrin
Fibrin
Plasmin
t-PA
Pla
sm
ino
gen
A
t-P
10
Endogenous thrombolytic agents and
synthetic analogues
Streptokinase indiscriminately binds to both
circulating and thrombus-associated plasminogen;
this may result in plasminemia.13 While some excess
plasmin is inactivated by a2-antiplasmin, the rest
remains active. Thus, Streptokinase generates a
systemic lytic state by depleting concentrations of
circulating fibrinogen, plasminogen, procoagulant
proteins, and a2-antiplasmin while inducing high
plasma concentrations of fibrin degradation
products.
Equilibrium is normally reached between free
and bound plasminogen. By converting circulating
plasminogen into plasmin, Streptokinase may
create a systemic plasminogen deficit that draws
fibrin-associated plasminogen out of the clot.13
The hypothesis is that this “plasminogen steal”
may attenuate plasmin formation at the site of
the thrombus and hinder the reopening of
obstructed coronary arteries.14 The clinical
significance of plasminogen steal has not
been established.
Streptokinase use is associated with side
effects, allergic reactions, and circulating
antistreptokinase antibodies that have been
associated with patient reactions with repeat
administration of this agent.15,16
Anistreplase. Anistreplase is an anisoylated
derivative complex prepared from plasminogen and
purified Streptokinase.12 The anisoyl group blocks
activity until released by acylation in aqueous
solution (a first-order nonenzymatic reaction), after
which the complex forms. Deacylated Anistreplase
cleaves plasminogen with greater catalytic efficiency
within thrombi than in the circulation. Anistreplase
is indicated for management of AMI. After
reconstitution with sterile water, it is administered
as a single intravenous dose of 30 mg (either
directly into a vein or through an intravenous line)
over 2 to 5 minutes. Antibody formation against the
streptococcal protein may occur with Anistreplase.
Alteplase. Alteplase, a mixture of one-chain
and two-chain t-PA, is produced by means of
recombinant technology. Alteplase is activated in
the presence of fibrin. Therefore, it may elicit little
plasminogen from the clot to replenish plasma
levels. Moreover, plasmin formed in the thrombus
may be less accessible to inhibitors such as
a2-antiplasmin. Alteplase reduces plasma
fibrinogen levels only slightly. It was demonstrated
angiographically and clinically in the Global
Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary
Arteries (GUSTO-I) study that Alteplase recanalizes
arteries more frequently than Streptokinase.17,18
Effective thrombolysis requires that Alteplase
doses result in plasma levels of unbound drug
capable of saturating the endogenous inhibitors.
Alteplase is cleared rapidly by the liver, resulting
in a half-life of 3 to 6 minutes.2 The rapid
clearance of Alteplase from plasma is mediated
by two domains: the epidermal growth factor
and kringle-1 domains. Binding of these domains
to liver receptors promotes elimination of the
agent.19,20 Therefore, infusion is usually utilized
to sustain therapeutic plasma concentrations
of Alteplase.
11
Other issues and considerations for
current thrombolytic therapy
The addition of intravenous heparin to
Streptokinase in GUSTO-I produced results no
better than those with subcutaneous heparin.
In combination with either intravenous or
subcutaneous heparin, Streptokinase produced
a lower incidence of stroke without decreasing
mortality compared to accelerated-dose Alteplase
dosing with intravenous heparin.17 Aspirin, on the
other hand, is a valuable addition to Streptokinase,
as seen in ISIS-2.21 In ISIS-3, the addition of
heparin to aspirin was associated with an excess of
transfused or other major noncerebral bleeds and
of definite or probable cerebral hemorrhage.24
Cost-effectiveness of thrombolysis. Any
analysis of the cost-effectiveness of thrombolysis
must consider not only the price of the agent used
but also the total cost of care and the gain in
survival. Aggressive intervention, even with the
most expensive thrombolytic agents, may reduce
costs in the long run by lessening both short- and
long-term risks of CHF and other cardiac
complications.
Adjunctive anticoagulation. The activity of
thrombolytic agents can be potentiated by the
concurrent administration of aspirin for its
antiplatelet effect and heparin for its anticoagulant
effect. Aspirin has been recommended for
coadministration with thrombolytic therapy since
the Second International Study of Infarct Survival
(ISIS-2), which showed benefit for aspirin when
administered alone, as well as concurrently
with Streptokinase.21 Without heparin, ongoing
coagulation may outpace thrombolysis and
result in a lower patency rate.
Heparin in conventional doses has a narrow
therapeutic range. Whether used as the sole
antithrombotic agent, the initiating agent, or an
adjunctive anticoagulant, it is associated with a
risk of serious bleeding in 1% to 8% of patients.22
This risk is compounded by coadministration of
antiplatelet agents.
The Heparin-Aspirin Reperfusion Trial
(HART), which compared early intravenous
heparin with low-dose oral aspirin as adjunctive
treatment with recombinant tissue plasminogen
activator during AMI, found that t-PA and heparin
treatment resulted in a higher rate of arterial
patency (82%) after 7 to 24 hours than t-PA and
aspirin treatment (52%). These study results
suggest that early systemic heparin treatment
should be administered during thrombolytic
therapy with t-PA.23
12
SECTION III
The open-artery hypothesis in thrombolysis
Early reperfusion and reduction
in mortality
patency and complete perfusion than
Streptokinase.27
ECSG-1. The European Cooperative Study
Group (ECSG-1) observed a patency rate of 70% in
64 patients randomized to Alteplase and 55% in 65
patients randomized to Streptokinase (P=0.054).28
These data suggested that perfusion achieved late
after the onset of the symptoms of AMI may not
preserve ischemic myocardium, since prolonged
ischemia damages not only the muscle but also the
associated microvasculature.
A
ccording to the open-artery hypothesis,
reperfusion of ischemic areas as early
as possible after the appearance of
symptoms of AMI (ie, within 3 hours) is crucial
for limiting infarct size, preserving left ventricular
function, and improving the odds of survival.25
The rationale for rapid reopening is based on
animal experiments: a smaller area of infarction
was observed in animals in which transiently
induced coronary occlusion was relieved by
early reperfusion than in animals subjected to
permanent occlusion.26
As a corollary to the open-artery hypothesis,
early thrombolysis (with adjunctive treatment such
as aspirin, anticoagulants, or coronary angioplasty)
may recanalize obstructed coronary arteries and
salvage jeopardized myocardium, while reducing
progression to chronic CHF.
The open-artery hypothesis suggests that the
use of thrombolytic agents that reopen occluded
coronary arteries earlier and more completely in
patients with AMI may translate into lower
mortality. However, the correlation between
established.
Large-scale trials
GISSI-1. The Gruppo Italiano per lo Studio
della Streptochinasi nell’Infarto Miocardico
(GISSI-1) was a milestone study that established
the value of thrombolytic therapy for patients with
AMI. GISSI-1 was the first large-scale (N=11,806)
study to demonstrate a significant reduction in
mortality achieved with Streptokinase thrombolysis
compared to placebo.29
ISIS-2. In ISIS-2, another large-scale
(N=17,187) trial, a combination regimen of
Streptokinase and aspirin was shown to reduce
cumulative vascular mortality (deaths from cardiac,
cerebral, hemorrhagic, or other known vascular
disease) in the first 35 days more effectively than
either aspirin or Streptokinase monotherapy or
placebo.21
Early clinical trials
TIMI-1. The Thrombolysis in Myocardial
Infarction (TIMI-1) Study 27 in 1985 was the first
trial to demonstrate that Alteplase is more effective
than Streptokinase in reopening occluded coronary
arteries. In this randomized trial, 90-minute
angiography in 290 patients demonstrated that
Alteplase achieved significantly higher rates of
13
Clinical megatrials: implications for the
open-artery hypothesis
100 mg infused intravenously over 3 hours.30 In this
multicenter, randomized, open trial in 12,490
patients with AMI admitted to coronary care units
within 6 hours from onset of symptoms, half the
patients were also randomized to receive 12,500 U
of heparin subcutaneously twice daily, starting 12
hours after beginning thrombolytic therapy.
GISSI-2. The Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarto Miocardico (GISSI-2)
study was the first large-scale trial to assess the
comparative effects of Streptokinase 1.5 MU infused
intravenously over 30 to 60 minutes and Alteplase
Fig 2.—Cumulative mortality (%) in days 0 to 35 in ISIS-3 and GISSI-2.
(B) Death in ISIS-3
SK: 1,455/13,780 (10.6%)
rt-PA: 1,418/13,746 (10.3%)
(A) Death in ISIS-3
SK:
1,455/13,780 (10.6%)
APSAC: 1,448/13,773 (10.5%)
10
SK
Duteplase
10
SK, APSAC
%
P=NS
P=NS
%
5
5
0
0
0
0
7
14 21 28 35
Days from Randomization
(C) Death in GISSI-2
SK:
958/10,396 (9.2%)
rt-PA: 993/10,372 (9.6%)
(D) Death in ISIS-3 and GISSI-2
SK: 2,413/24,176 (10.0%)
rt-PA: 2,411/24,118 (10.0%)
Alteplase
10
7
14 21 28 35
10
SK, rt-PA
SK
%
P=NS
%
5
P=NS
5
0
0
0
0
7
14 21 28 35
7
14 21 28 35
SK = Streptokinase; APSAC = Anistreplase; rt-PA = Alteplase/Duteplase.
(A) All patients allocated SK vs all allocated APSAC in ISIS-3 only; (B, C, D) all patients allocated SK
vs all allocated rt-PA in (B) ISIS-3; (C) GISSI-2; (D) ISIS-3 and GISSI-2 combined.
– Adapted from ISIS-3.24
14
Atenolol (45.3%) and aspirin (87%) were
administered to patients without contraindications.
There was no significant difference in overall
mortality in the Alteplase-treated patients (9%) and
the Streptokinase group (8.6%). There was also no
significant difference in the combined end point of
death plus clinical CHF or extensive left ventricular
damage in the absence of CHF.30
International Study Group. The International
Study Group combined mortality data from the
12,490 patients in the GISSI-2 trial30 with data from
8,401 patients recruited in other countries. Again,
no significant differences in hospital mortality were
found between Alteplase (8.9%) or Streptokinase
(8.5%) or between subcutaneous heparin (8.5%)
and no heparin (8.9%) treatment.31
ISIS-3. In the Third International Study of
Infarct Survival (ISIS-3), 41,299 patients entering
914 hospitals up to 24 hours after the onset of
suspected AMI were randomized to Streptokinase,
1.5 MU infused over 1 hour; Duteplase (a doublechain t-PA), 0.04 MU/kg bolus over 1 minute,
0.36 MU/kg during the remainder of the first hour,
and 0.067 MU/kg/h over the next 3 hours; or
Anistreplase (30 U over 3 minutes).24 All patients
received aspirin, and half also received 12,500 IU
of calcium heparin, starting 4 hours after
randomization and given subcutaneously twice
daily for 7 days. Cumulative deaths during days
0 to 35 are shown in Fig 2. There were no
significant differences in mortality between
any two groups (10.6% Streptokinase, 10.5%
Anistreplase, 10.3% Duteplase). There were also no
significant differences in 35-day mortality between
the aspirin only (10.6%) and aspirin plus heparin
(10.3%) treated patients.24
GUSTO-I. The GUSTO-I study,17 the largest
megatrial comparing the effect of Alteplase and
Streptokinase on mortality (41,021 patients with
confirmed AMI treated at 1,081 hospitals in 15
countries), differed in several important respects
from the ISIS and GISSI trials.
In the GUSTO-I study, the accelerated-dose or
“front-loaded” Alteplase regimen was given as an
initial bolus, followed by a 90-minute infusion,
with two thirds of the dose given in the first 30
minutes. This dosing regimen was designed to
improve perfusion rates. In another departure
from previous megatrials, heparin was given by
bolus followed by intravenous infusion, rather
than subcutaneously, and was continued for at least
48 hours to limit fibrin formation that might
produce reocclusion. Similar to GISSI-2, patients
in GUSTO-I were admitted within 6 hours after
the onset of symptoms. In ISIS-2 and ISIS-3,
however, patients were included up to 24 hours
after onset of symptoms.
Patients in the GUSTO-I trial were randomized
to one of four treatment regimens:
• Alteplase (bolus dose of 15 mg, followed by an
infusion of 0.75 mg/kg over 30 minutes, not to
exceed 50 mg, and 0.5 mg/kg, up to 35 mg,
over the next 60 minutes) plus intravenous
heparin
• Streptokinase and intravenous heparin
• Streptokinase and subcutaneous heparin
• Both thrombolytics together plus intravenous
heparin
The primary clinical end point of 30-day
mortality was 6.3% in patients receiving accelerateddose Alteplase plus intravenous heparin, compared
to 7.2% and 7.4% for the two Streptokinase groups
(Table 2 and Fig 3).17 There was a significant
reduction in mortality with accelerated-dose
Alteplase compared with the two Streptokinase
regimens (10 lives saved per 1,000 patients treated;
risk reduction, 14%). The GUSTO-I trial adds
to a growing body of evidence in support of the
open-artery hypothesis.
In the GUSTO-I Angiographic Investigators
substudy, 2,431 of the patients randomized to the
four treatment regimens were assigned to undergo
cardiac angiography at 90 minutes, 180 minutes,
24 hours, or 5 to 7 days after the initiation of
thrombolytic therapy; angiography was repeated
after 5 to 7 days in the 90-minute group.18 The rate
15
Table 2.—Major Clinical Outcomes in GUSTO-I
Percentage of Patients
Streptokinase
and
Subcutaneous
Heparin
(n = 9,796)
Streptokinase
and
IV Heparin
(n = 10,377)
Accelerated-Dose
Alteplase and
IV Heparin
(n = 10,344)
Both
Thrombolytic
Agents and
IV Heparin
(n = 10,328)
P Value,
Accelerated-Dose
Alteplase vs Both
Streptokinase
Groups
24-hour mortality
2.8
2.9
2.3
2.8
0.005
30-day mortality
Or nonfatal stroke
Or nonfatal
hemorrhagic stroke
Or nonfatal
disabling stroke
7.2
7.9
7.4
8.2
6.3
7.2
7.0
7.9
0.001
0.006
7.4
7.6
6.6
7.4
0.004
7.7
7.9
6.9
7.6
0.006
Outcome
– From GUSTO Investigators.17
of patency of the infarct-related artery at 90 minutes
was highest in the Alteplase plus heparin group
(81%), compared with the Streptokinase and
subcutaneous heparin group (54%, P<0.001), the
Streptokinase and intravenous heparin group (60%,
P<0.001), and the combination therapy group
(73%, P=0.032). By 180 minutes, the four groups
had similar patency rates and reocclusion rates. Left
ventricular function, which paralleled patency rate at
90 minutes, was best in the Alteplase group and in
patients with normal flow, regardless of treatment.
Mortality at 30 days was lowest (4.4%) among
patients with complete coronary flow at 90 minutes
and highest (8.9%) among patients with no flow
in the infarct-related artery (P=0.009). The
investigators suggested that the mechanism by
which accelerated-dose Alteplase therapy produced
a superior outcome in the GUSTO-I trial was its
more complete restoration of flow through the
infarct-related artery than Streptokinase, which in
turn resulted in improved ventricular performance
and lower mortality due to AMI.18
Fig 3.—Mortality (30 days) in the four treatment groups of GUSTO-I.
10
9
8
7
6
Mortality 5
(%)
4
3
2
1
0
Streptokinase and IV heparin
Streptokinase and SC heparin
Alteplase and Streptokinase
Accelerated-dose Alteplase
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Days After Randomization
– Adapted from GUSTO Investigators.17
16
SECTION IV
RETAVASE® (Reteplase)
preclinical pharmacology
RETAVASE: a novel thrombolytic agent for
acute myocardial infarction
Biochemistry: a recombinant
plasminogen activator
V
RETAVASE is a nonglycosylated recombinant
plasminogen activator. It is a single-chain molecule
that consists of 355 amino acids corresponding
to coding sequences 1 to 3 and 176 to 527 of
native t-PA. Expression in E coli results in a
nonglycosylated protein, which accumulates
inside cells as inactive inclusion bodies that
must be refolded in vitro and purified to restore
the native structure.19,32
The RETAVASE gene lacks the complementary
DNA sequence coding for the three N-terminal
(finger, epidermal growth factor, and kringle-1)
domains found in native t-PA but retains the
kringle-2 and serine protease domains in a
functional form.32 The domain structures of the
Alteplase and RETAVASE molecules are shown in
Fig 4 on page 18, and the structure-function
relationships of these domains are shown in
Table 3 on page 19.
Alteplase retains the kringle-1 and epidermal
growth factor domains deleted from RETAVASE.20,32
Alteplase binds to liver receptors by means of these
domains, thereby facilitating hepatic clearance.20
Oligosaccharide side chains retained by Alteplase
and not by RETAVASE also influence clearance.
These deletions from the RETAVASE molecule
provide a longer half-life than that of Alteplase,33
with two consequences: (1) less drug is required
to maintain therapeutic levels and (2) RETAVASE
can be administered by intravenous bolus over a
period of 2 minutes.
arious thrombolytic agents are in
development for potential improvements
in half-life, mode of administration, fibrin
specificity, and proteolytic activity. RETAVASE is
the first available agent using selected domains
from the native t-PA molecule.16 The molecule
consists of the kringle-2 and protease domains
of native t-PA and shows predilection for
fibrin-bound plasminogen. RETAVASE possesses
important pharmacokinetic and mechanistic
features that contribute to the feasibility of a
double-bolus dosing regimen and restoration
of flow in AMI patients.
Description
RETAVASE is a plasminogen activator whose
design was based on naturally occurring t-PA and
is produced by recombinant genetic technology in
E coli.19 It is prepared as a white, sterile, lyophilized
powder for intravenous bolus injection after
reconstitution with Sterile Water for Injection, USP
(without preservatives). The potency standard for
RETAVASE, expressed in units (U), is not
comparable to that for other thrombolytics.
RETAVASE is supplied as a 10.8 U vial to ensure
sufficient drug for administration of each 10 U
dose. Each vial of the lyophilized product contains
18.8 mg of RETAVASE, along with arginine,
phosphoric acid, and polysorbate 20 as inactive
ingredients.
17
Fig 4.—Molecular structures of Alteplase and RETAVASE ®(Reteplase).
Alteplase
RETAVASE
Kringle 1
Kringle 2
EGF
Finger
Protease
RETAVASE differs further from Alteplase in
that it lacks the finger domain, a fibronectin-like
projection that promotes high-affinity fibrin
binding.16 The RETAVASE molecule is also specific
for plasminogen bound to fibrin, but its affinity to
fibrin is lower than that of Alteplase. RETAVASE may
activate plasminogen at the surface as well as in the
interior of the thrombus.
In vitro catalytic activity and
fibrin binding
RETAVASE has approximately 20% to 30% of
the in vitro plasminogenolytic potency of Alteplase
as determined by a standard in vitro assay in which
each activator is incubated with plasminogen in
the presence of cyanogen bromide (CNBr) split
products (fragments) of fibrinogen that serve as
a stimulator.32
RETAVASE, like Alteplase, is cleaved by plasmin
specifically at the Arg275-Ile276 bond, indicating that
the protease and kringle-2 domains have the same
structure as in native t-PA.32 Both RETAVASE and
Alteplase lose activity in a similar manner when
incubated with increasing levels of PAI-1.
18
Table 3.—Structure-Function Relationships of Native t-PA Domains
Structure
Function
F domain
(finger, fibronectin-like)
High-affinity fibrin binding
E domain (epidermal growth factor-like domain)
Receptor binding (liver)
K1 domain (kringle-1)
Liver receptor binding(?) Fibrin binding(?)
K2 domain (kringle-2)
Low-affinity interaction with fibrin
(stimulation effect by fibrin)
P domains
Protease function (plasminogen specific)
Carbohydrates
Mediation of t-PA plasma clearance (half-life)
Besides its lower plasminogenolytic activity
in the presence of a stimulator, RETAVASE®
(Reteplase) does not bind to fibrin like Alteplase.32 In
vitro fibrin binding was analyzed by adding
RETAVASE or Alteplase to a newly forming clot in a
test tube and measuring binding in response to
increasing amounts of fibrin. As shown in Fig 5,
Alteplase is nearly 100% bound by 200 µg of fibrin,
while only 20% of RETAVASE is found in the clot
fraction. The amount of RETAVASE in the clot
fraction increases at higher fibrin concentrations,
possibly because of a nonspecific protein-protein
interaction. Thus, throughout the range of fibrin
concentration
from 0 to 1,000 µg, the binding of RETAVASE
ranges from about 10% to 30% of that of Alteplase.
The lower catalytic activity and fibrin binding
of RETAVASE relative to Alteplase may be due to
the missing finger domain. This leaves only the
kringle-2 lysine-binding site as the focus of the
interaction between RETAVASE and fibrin.20,32
Fig 5.—In vitro fibrin binding of RETAVASE ®(Reteplase) and Alteplase in the presence of
increasing fibrin concentrations.
100
Alteplase
80
Relative
Binding
(%)
60
40
RETAVASE
20
0
250
500
Fibrin (µg)
750
1,000
– Data on file.34
19
Fig 6.—Concentration-dependent lysis of 125I-labeled human platelet-poor plasma clots by
Alteplase, melanoma t-PA, RETAVASE ® (Reteplase), and Urokinase.
100
Alteplase
Melanoma t-PA
RETAVASE
Urokinase
80
Clot Lysis
(%)
60
40
20
0
Vehicle
0.1
1
Concentration (nmol)
10
100
Mean values.
– Adapted from Martin et al.32
Fig 6 is a comparison of concentrationdependent in vitro clot lysis by RETAVASE,
Alteplase, melanoma t-PA (which differs from
Alteplase in carbohydrate side chains), and
Urokinase, based on the method of Collen et al.35
Lytic activity is represented by the percentage
of radioactivity released from iodine 125 (125I)
radiolabeled fibrinogen plasma clots after 4 hours
of incubation with RETAVASE or one of the three
comparative agents.32 These data show that
RETAVASE had the same maximal lytic activity as
Alteplase at equipotent concentrations, despite a
lower in vitro potency. RETAVASE is less active than
Alteplase in lysis of platelet-rich plasma clots and
aged clots.36 This diminished activity of RETAVASE
toward old thrombi may reduce lysis of hemostatic
plugs, which are thought to be older clots that seal
small vessel wall injuries.37
In vivo animal studies showed greater
potency of RETAVASE than Alteplase
Jugular vein thrombolysis in rabbits. The in
vivo thrombolytic activity of RETAVASE was studied
in rabbits and dogs. In the rabbit model of jugular
vein thrombosis, the RETAVASE effective dose for
50% lysis (ED50) was 5.3-fold more potent per
unit than the Alteplase ED50.32 The investigators
attributed the greater in vivo potency of RETAVASE
to its lower clearance rate. An important conclusion
of this study is that the relative in vitro potencies of
Alteplase and RETAVASE are reversed in animals.
The paradox: in vivo and in vitro profile reversal
• The in vitro potency (specific activity) of RETAVASE as determined by plasminogenolytic assay
is lower than that of Alteplase by a factor of 2 or 3
• RETAVASE is significantly more potent than Alteplase in in vivo models
• The slower hepatic clearance and longer plasma half-life of RETAVASE may explain this reversal
20
Fig 7.—More rapid coronary reperfusion in a canine model.
120
*
100
*
*
80
*
Time to
Reperfusion 60
(min)
40
20
0
RETAVASE®
(Reteplase)
*P < 0.05 vs Reteplase.
Mean ± SEM.
n = 3 to 6 per group.
Alteplase
Anistreplase Streptokinase Urokinase
At Dose Corresponding to Clinical Practice
(Alteplase by standard infusion)
– Adapted from Martin et al.32
significantly more rapidly than Alteplase,
Anistreplase, Streptokinase, and Urokinase when
administered at clinically equivalent doses (Fig 7).32
Pharmacokinetics: clearance through liver and
kidneys. The pharmacokinetic properties of
RETAVASE were extensively studied in rats, rabbits,
dogs, and nonhuman primates.32 Half-life and total
plasma clearance parameters for RETAVASE in
comparison with Alteplase in humans are shown in
Table 4. Based on the mean liver uptake of the
respective injected doses, hepatic clearance accounts
for much less of the total plasma clearance of
RETAVASE than for Alteplase in all species studied.
RETAVASE is cleared mainly by the kidneys,
although inhibitory proteins in the blood contribute
to RETAVASE clearance through biochemical
inactivation.
Greater activity in coronary thrombolysis
in dogs. The activity of RETAVASE in inducing
coronary reperfusion was investigated in openchested anesthetized dogs in which electrical injury
to the intima of the left circumflex coronary artery
was used to simulate AMI.32 A double-bolus
intravenous regimen of RETAVASE proved to be
superior (P<0.05) to a single bolus in stabilizing
coronary artery blood flow and reducing
reocclusion, but doubling the dose of a single bolus
did not have this effect.32 The total plasma clearance
rate of RETAVASE was at least three times lower
than that of Alteplase, suggesting that this
contributed to the greater thrombolytic potency
of RETAVASE.32
In another study utilizing the same canine
model, RETAVASE was shown to induce reperfusion
Table 4.—Pharmacokinetic Properties of RETAVASE ® (Reteplase) in Plasma
Following Intravenous Bolus Injection
Dose
N
t½α (min)
t½β (min)
CL (mL/min)
6 U (10.4 mg)
7
13.9 ± 0.7
173 ± 33
183 ± 15
10 U (18 mg)
4
19.2 ± 1.0
375 ± 34
104 ± 11
15 U (27 mg)
10
18.8 ± 0.8
377 ± 20
139 ± 21
– From Martin et al.32
Mean ± SEM.
t½ = half-life; CL = total plasma clearance.
21
Toxicology showed no internal bleeding, even
at highest dose. The effect of RETAVASE®
(Reteplase) on platelets, bleeding times, and plasma
proteins was studied in rats, rabbits, and dogs.
Pharmacologically effective doses produced a dosedependent reduction in fibrinogen, plasminogen,
and a2-antiplasmin 2 hours post-injection.32 In a
14-day subchronic toxicity study in cynomolgus
monkeys, all dose levels induced unilateral focal
hemorrhages that correlated with low red blood cell
counts, but internal hemorrhaging did not develop,
even at the highest dose.
Mutagenicity was not detectable in Salmonella
typhimurium or in rat bone marrow erythrocytes
tested in vivo for 2 weeks with daily intravenous
administration of doses up to 1.4 U/kg.32 No adverse
effects on reproduction or fetal development were
seen at doses of 4.3 U/kg in rats. The minimum
lethal dose of RETAVASE (from hemorrhage and/or
hypotension) in rats, rabbits, and monkeys exceeds
8.4 U/kg given as a single injection; no deaths
occurred in animals receiving 4.2 U/kg.32
Summary of preclinical findings. The
preclinical pharmacology studies demonstrate that
RETAVASE has more potent in vivo thrombolytic
activity than Alteplase on both a dose and molar
basis, which contrasts with the results of in vitro
studies. RETAVASE induces more rapid reperfusion
than other thrombolytic agents in animal models of
coronary thrombosis. Reperfusion is significantly
more rapid after intravenous bolus injection than
after infusion, and a double bolus is significantly
more active in stabilizing coronary artery blood flow
and preventing reocclusion.
22
SECTION V
clinical pharmacology
Well-tolerated hemostatic and
fibrinolytic effects
Dose-response restoration of coronary flow
in patients with AMI
T
The hemostatic and fibrinolytic effects of
RETAVASE doses were evaluated in patients with
AMI. The effects of RETAVASE on fibrinogen,
plasminogen, a2-antiplasmin, fibrin degradation
products (FDP, as represented by fibrin-specific
D-dimers), and fibrinogen degradation products
(FgDP) in the two German Recombinant
Plasminogen Activator Studies in patients with
AMI (GRECO39 and GRECO-DB40) are summarized
in Table 5. At 2 hours after administration (2-hour
values were chosen because they represent the
strongest effects), mean values of fibrinogen were
approximately 45% of baseline for the 15 U and
10 + 5 U regimens and 60% of baseline for the
10 U regimen. The higher doses used in the
GRECO studies resulted in a greater reduction in
plasminogen and a2-antiplasmin and a greater
increase in D-dimers and FgDP. The 15 U and the
10 + 5 U regimens had a greater effect on these
parameters than the 10-U regimen, suggesting
dose dependency.
Administration of RETAVASE in the GRECO-DB
(double bolus) study caused the median fibrinogen
level to decrease from a baseline of 286 mg/dL to 63%
of this value at 24 hours (Fig 8).40
he hemostatic and fibrinolytic properties of
RETAVASE were investigated in a Phase I
dose-ranging study in 18 healthy male
volunteers.38 Intravenous bolus doses ranging from
0.11 U to 5.5 U given over 2 minutes did not alter
plasma fibrinogen levels except at the higher doses.
However, a2-antiplasmin and fibrin D-dimers
decreased in a dose-dependent fashion. RETAVASE
was well tolerated, and antibodies to RETAVASE did
not appear in plasma samples taken up to 1 year
after the study.
A single intravenous bolus dose of 6 U
(10.4 mg) of RETAVASE or placebo was given over 2
minutes to seven healthy male volunteers in another
Phase I study, this time using a randomized, singleblind, placebo-controlled, crossover design.20
Fibrinogen levels were unchanged by RETAVASE.
Plasminogen and a2-antiplasmin levels, however,
were reduced to 83% and 64%, respectively, of
baseline values, probably reflecting a systemic
activation of the fibrinolytic system. RETAVASE
was well tolerated, and antibodies to RETAVASE
were not detected.20
Table 5.—Hemostatic and Fibrinolytic Parameters at 2 Hours in the GRECO
and GRECO-DB Studies
2–Hour Values as a Mean Percentage of Baseline
Parameter
10 U RETAVASE
(n = 38-41)
15 U RETAVASE
(n = 66-99)
10 + 5 U RETAVASE
(n = 43-49)
Fibrinogen
60
44
45
Plasminogen
55
41
42
α2-antiplasmin
30
26
19
2,940
5,709
5,986
10,449
19,507
42,611
D-dimers
FgDP
– Data on file.34
FgDP = fibrinogen degradation products.
23
Fig 8.—Fibrinogen profile over time following a 10 + 5 U intravenous
double bolus of RETAVASE ® (Reteplase) in GRECO-DB.
100
80
Percentage 60
of
Baseline 40
20
0
0
2
4
8
24
Time (hours)
– Adapted from Tebbe et al.40
Pharmacokinetics in healthy volunteers
In another study, 18 volunteers received
sequential doses of RETAVASE between 0.11 U
and 5.5 U.38 Plasma AUC and Cmax showed dosedependent linear increases. Clearance was 406±40
mL/min (4 mL/min/kg), and half-life for the 5.5 U
dose was 14.4±1 min.
Data from the studies in healthy subjects
demonstrate that RETAVASE pharmacokinetics are
linear over the dose range of 0.11 to 5.5 U. Plasma
concentrations of RETAVASE antigen persist for a
longer period of time than do those of activity.
The pharmacokinetics of RETAVASE were
evaluated in three studies in healthy volunteers.
Drug was administered by IV injection over
2 minutes in each study. Plasma concentrations
of RETAVASE antigen, ie, protein, were measured
using a monoclonal antibody enzyme-linked
immunosorbent assay. A plasminogenolytic
activity assay based on the method of Verheijen
et al41 was used to measure the more relevant
active concentrations.
In one of the studies, seven subjects received
a single intravenous 6.0 U bolus dose of
RETAVASE.20 The activity half-life was 11.2±0.4 min
and the antigen half-life was 13.9±0.7 min
(2.4 mL/min/kg), followed by a terminal antigen
half-life of 173±33 min. Plasma clearance was
371±13 mL/min (4.9 mL/min/kg) for activity in
plasma (ie, effect on fibrin) and 183±5 mL/min
(2.4 mL/min/kg) for antigen. The half-life and
clearance of RETAVASE activity were 3.3-fold longer
and 3.3-fold lower, respectively, than in volunteers
who received Alteplase in a study by Seifried et al.42
In addition, the half-life and clearance for antigen
were 4.2-fold longer and 3.9-fold lower, respectively.42
Pharmacokinetics in AMI
The pharmacokinetics of RETAVASE in patients
with AMI were evaluated using subsets of patients
in two trials. In the GRECO study, doses were
administered as single boluses of 10 U or 15 U39;
in MF4292, patients received a single bolus of 15 U
or a double bolus of either 10 + 5 U or 10 + 10 U.34
The mean RETAVASE plasma concentrations
(activity) for the two studies are shown in Fig 9
and Fig 10.
24
Fig 9.—Mean RETAVASE ® (Reteplase) plasma concentrations (activity) after
administration of 10 U and 15 U doses in patients with AMI in the GRECO study.
3,500
3,000
2,500
RETAVASE
(U/mL)
2,000
10 U
15 U
1,500
1,000
500
0
0
0.5
1
1.5
2
Time (hours)
– Data on file.34
Linear pharmacokinetics
effective half-life of RETAVASE is 13 to 16 minutes.
Plasma antigen concentrations persist for a longer
period than plasma activity. This is not unexpected,
since the antigen assay measures all RETAVASErelated protein, not all of which is active RETAVASE.
The pharmacokinetics of RETAVASE in patients
with AMI as well as in healthy volunteers are linear
over the dose range of 0.11 to 20 U and do not
appear to be affected by the target disease. The
Fig 10.—Mean RETAVASE plasma concentrations (activity)
after administration of 10 + 5 U, 10 + 10 U, and 15 U doses in patients
with AMI in MF4292.
2,000
10 + 5 U
10 + 10 U
15 U
1,500
RETAVASE
(U/mL)
1,000
500
0
0
0.5
1
1.5
2
Time (hours)
– Data on file.34
25
SECTION VI
clinical efficacy and activity
RETAVASE: an effective
thrombolytic agent
evaluating the activity of RETAVASE in restoring
blood flow through the infarct-related artery
(Table 6). Three comparative studies were
performed to compare RETAVASE with
Streptokinase (INJECT) or Alteplase (RAPID 1
and RAPID 2) (Table 7). Two of these, RAPID 2
and INJECT, were Phase III studies, while RAPID 1
was a Phase II study.
S
ix clinical trials of significance have
identified the appropriate dose and
demonstrated the efficacy and safety of
RETAVASE as therapy for AMI. Three were Phase II
dose-finding studies (without comparative agents)
Table 6.—Non-Comparative Studies in Patients With AMI
Protocol
Location
Study Design
Population
Dose Strength
and Form
Frequency,
Duration
Number
of Patients
Primary
Evaluation
Key Entry
Criteria
GRECO39
Germany
OL
10 U RP
Single bolus
42
ST segment
elevation
AMI patients
15 U RP
Single bolus
100
90-minute
patency and
TIMI 3 rates
Onset of
ischemic
pain within
6 hours
18-75 years old
GRECODB40
Germany
OL
10 + 5 U RP
Double bolus
51
AMI patients
90-minute
patency and
TIMI 3 rates
ST segment
elevation
Onset of
ischemic pain
within 6 hours
18-75 years old
MF429234
Germany
R, OL
15 U RP
Single bolus
9
AMI patients
10 + 5 U RP
Double bolus
8
10 + 10 U RP
Double bolus
8
90-minute
ST segment
patency and
elevation
TIMI 3 rates,
pharmacokinetics,
Onset of
hemostasis
ischemic pain
parameters
within 6 hours
18-75 years old
OL = open label; R = randomized; RP = Reteplase.
27
Table 7.—Comparative Studies in Patients With AMI
Protocol
Location
Study Design
Population
RAPID 1 United States
R, OL
(Phase II)4 Germany
(angiograms
United Kingdom
read
Austria
blinded)
Dose Strength
and Form
Frequency,
Duration
Number
of Patients
Primary
Evaluation
Key Entry
Criteria
15 U RP
Single bolus
146
90-minute
patency
ST segment
elevation
10 + 5 U RP
Double bolus
152
10 + 10 U RP
Double bolus
154
100 mg AP
(standard dose)
Bolus +
3-hour
infusion
154
10 + 10 U RP
Double bolus
169
100 mg AP
(accelerated
dose)
Bolus +
1.5-hour
infusion
155
Onset of
ischemic pain
within 6 hours
AMI patients
RAPID 25 United States
Germany
R, OL
(angiograms
read blinded)
18-75 years old
90-minute
TIMI grade
AMI patients
ST segment
elevation or
bundle branch
block
Onset of
ischemic pain
within 12 hours
≥18 years old
R, DB
INJECT3 United Kingdom
Germany
Poland
AMI patients
Sweden
Hungary
Finland
Spain
Lithuania
Austria
10 + 10 U RP
Double bolus
3,004*
1.5 MU SK
1-hour infusion
3,006*
35-day
mortality
ST segment
elevation or
bundle branch
block
Onset of
ischemic pain
within 12 hours
≥18 years old
*74 patients were randomized but were not treated. Overall, 2,965 RETAVASE® (Reteplase) patients and 2,971 Streptokinase patients received treatment. AP =
Alteplase; DB = double-blind; INJECT= International Joint Efficacy Comparison of Thrombolytics; OL = open label; R = randomized;
RAPID 1 = Reteplase Angiographic Phase II International Dose-finding Study; RAPID 2 = Reteplase vs Alteplase Patency Investigation During Acute Myocardial
Infarction Study; RP = RETAVASE; SK = Streptokinase.
The six studies evaluated four different
dosage regimens of RETAVASE™ (Reteplase):
• Single 10 U bolus
• Single 15 U bolus
• 10 U bolus followed by a 5 U bolus
30 minutes later (10 + 5 U)
• 10 U bolus followed by a 10 U bolus
30 minutes later (10 + 10 U).
Each bolus was administered as a slow
intravenous injection over an interval not
exceeding 2 minutes. Of the 3,805 patients
treated with RETAVASE, 3,292 received the
10 + 10 U regimen.
Dose-finding trials determined patency of
infarct-related arteries
GRECO. This was a sequential rising-dose study
that enrolled 142 patients with AMI who presented
less than 6 hours after the onset of symptoms.39
RETAVASE was given as a single 10 U bolus to the
first 42 patients and as a 15 U bolus to the next
100 patients. Patients also received an intravenous
bolus of heparin immediately after the bolus
dose of RETAVASE, and aspirin was given daily
throughout the study. Nitroglycerin was
administered intravenously unless
hemodynamically contraindicated.
28
Fig 11.—Patency of infarct-related arteries in the GRECO study.
100
TIMI 3
TIMI 2
80
73
65
Patients
(%)
75
74
66
92
92
88
85
89
90
86
85
66
69
60
58
40
52
48
46
38
20
0
Dose 10 U
15 U
(n = 32) (n = 62)
Angiogram
at 30 min
10 U
15 U
(n = 41) (n = 99)
10 U
15 U
(n = 42) (n = 99)
10 U
15 U
(n = 42) (n = 95)
10 U
15 U
(n = 38) (n = 85)
Angiogram
at 60 min
Angiogram
at 90 min
Angiogram
at 24 to 48 hr
Angiogram
at 14 to 21 days
– Adapted from Neuhaus et al.39
Activity was evaluated by means of
angiographically determined patency of infarctrelated arteries. Coronary arteriography of the
presumed infarct-related artery was conducted
30 and 90 minutes after the bolus injection of
RETAVASE™ (Reteplase, recombinant) and repeated
at 24 to 48 hours and prior to discharge at 14 to 21
days. Patency was assessed by TIMI flow grade and
had to be rated as grade 2 or 3 by two independent,
experienced investigators.
The patency rate (TIMI 2 + 3 flow) at 90
minutes for the single-bolus 10 U dose group was
66%.39 Since the 66% was below the predetermined
70% lower limit of activity for Alteplase in the TIMI
trial,43 the next 100 patients received a single bolus of
15 U.39 The 90-minute patency rate in these patients
was increased to 75% and the TIMI 3 rate alone was
69% (Fig 11), a result similar to that associated with
Alteplase thrombolysis.39
GRECO-DB. A second bolus of RETAVASE
maintained patency of coronary arteries. While the
GRECO study demonstrated that single-bolus
administration of RETAVASE could lead to high
patency rates in patients with AMI, fluctuations were
observed in the early angiograms.39 In some patients,
infarct-related arteries that were patent at 30 or 60
minutes became reoccluded at 90 minutes.
In GRECO-DB, patients received an initial
10 U bolus of RETAVASE followed by 5 U of
RETAVASE 30 minutes later.40 The purpose of this
double bolus was to optimize perfusion of the
infarct-related artery and maintain patency during
The TIMI flow grades
Since the TIMI trial, coronary flow after reperfusion therapy has been classified by TIMI
angiographic grade.27
• TIMI 0: no penetration of contrast medium beyond the thrombus
• TIMI 1: minimal penetration; no significant flow
• TIMI 2: restored but sluggish flow
• TIMI 3: brisk flow
29
Table 8.—Patency of Infarct-Related Arteries in GRECO-DB
Patency Rate
Angiogram at 30 minutes (n = 48)
TIMI grade 2 or 3
TIMI grade 3
50%
31%
TIMI grade 2 or 3
TIMI grade 3
72%
50%
TIMI grade 2 or 3
TIMI grade 3
78%
58%
Angiogram at 24 to 48 hours (n = 50)
TIMI grade 2 or 3
TIMI grade 3
94%
84%
Angiogram at 14 to 21 days (n = 49)
TIMI grade 2 or 3
TIMI grade 3
90%
82%
– From Tebbe et al.40
TIMI = Thrombolysis in Myocardial Infarction trial.
INJECT establishes efficacy of
RETAVASE™ (Reteplase, recombinant)
in reducing mortality
the early phase of thrombolysis by sustaining
the RETAVASE™ (Reteplase, recombinant)
plasma level.40 Otherwise, the protocol was
similar to GRECO.
Fifty-one patients were treated with the
10 + 5 U RETAVASE regimen, and 50 underwent
angiography (Table 8).40 The 90-minute patency rate
(TIMI 2 + 3 flow) of 78% was slightly higher than
the 75% observed with the 10 + 5 U regimen in
GRECO; the TIMI 3 rate was 58%, compared with
69% in GRECO.
INJECT was a randomized, double-blind,
Phase III multicenter study designed to confirm
that RETAVASE was effective in reducing mortality
in AMI. In INJECT, RETAVASE was compared to
Streptokinase, the standard thrombolytic agent
in Europe.3 The trial was not powered, however,
to statistically detect modest differences between
the two agents. The goal of the study was to
demonstrate the efficacy and safety of RETAVASE.
The 35-day mortality rate of RETAVASE was
compared to the standard Streptokinase regimen.
A total of 5,936 patients in nine European
countries received thrombolytic therapy no later
than 12 hours after the onset of symptoms of AMI.3
There was no upper age limit. A total of 2,965
patients randomized to RETAVASE 10 + 10 U (the
second injection given 30 minutes after the first) and
2,971 patients randomized to a 1.5 MU infusion of
Streptokinase over 60 minutes were assessable. All
patients received intravenous heparin for at least 24
hours. Patients were given 250 mg to 350 mg
aspirin, then 75 mg to 150 mg daily.
Comparative clinical trials
The safety and efficacy of RETAVASE were
evaluated in three controlled clinical trials in which
RETAVASE was compared to other thrombolytic
agents. INJECT compared RETAVASE to
Streptokinase to assess the relative effects on 35-day
mortality rates. RAPID 1 and RAPID 2 were both
angiographic trials comparing the effect on coronary
patency of RETAVASE and Alteplase (see Section VIII
beginning on page 37).
30
Fig 12.—35-day mortality rates in the INJECT study.
P=NS
10
9.43%
8.90%
8
6
Patients
(%)
4
2
0
RETAVASETM
Streptokinase
(Reteplase, recombinant) 1.5 MU/60 min
(n = 2,971)
10 U + 10 U
(n = 2,965)
Difference in mortality: RETAVASE – Streptokinase = –0.53% (90% CI: –1.76% to 0.71%).
– Adapted from INJECT.3
Results
These data provide confirmation that RETAVASE
is effective in reducing mortality after AMI.
At 6 months, mortality rates (Kaplan-Meier
estimate) were 11.02% for RETAVASE and 12.05%
for Streptokinase, a difference of 1.03%.3 These
results provide further evidence that RETAVASE is
effective in reducing mortality after AMI.3
The 35-day study mortality rates are shown in
Fig 12, and the Kaplan-Meier survival curves over
the 35-day interval are depicted in Fig 13.3 Mortality
at day 35 in patients who received study medication
was 8.90% in the RETAVASE group and 9.43% in
the Streptokinase group, a difference of 0.53%.
Fig 13.—Kaplan-Meier survival curves from day 0 to 35 in INJECT.
Streptokinase
10
8
Mortality
(%)
RETAVASE
6
4
2
0
0
7
14
21
Days in Study
28
35
– Adapted from INJECT.3
31
INJECT substudy demonstrates early
resolution of ST segment elevation
Results irrespective of therapy showed that
the 35-day mortality rate in 1,398 patients with
infarct age ≤6 hours for complete, partial, or
no ST resolution was 2.5%, 4.3%, and 17.5%,
respectively (P<0.0001).44 As can be seen in Table 9,
RETAVASE™ (Reteplase, recombinant) achieved
complete or partial ST segment resolution in 82%
of patients at 3 hours.44 Although the authors
concluded that resolution of ST segment elevation
may correlate with mortality, the correlation with
mortality and other patient outcomes was not
established.
INJECT investigators conducted an exploratory
substudy among the 1,909 patients in Germany to
evaluate the prognostic power of early resolution
of ST segment elevation.44
ST segment elevation was classified as achieving
complete (≥70%), partial (30% to 70%), or no (0%
to 30%) resolution after 3 hours of thrombolytic
therapy.44
Table 9.—Percentages of RETAVASE ® (Reteplase) Patients in INJECT With
Complete, Partial, or No ST Segment Elevation Resolution
All Patients
RETAVASE
(n = 692)
Anterior MI
RETAVASE
(n = 318)
Inferior MI
RETAVASE
(n = 374)
Complete
51
36
65
Partial
31
43
22
No
17
22
14
ST resolution (%)
– From Schröder et al.44
MI = myocardial infarction.
32
GUSTO-III: a large-scale, mortality trial
versus Alteplase
As discussed in Section VIII beginning on page
37, the RAPID 2 trial showed differences in patency
between RETAVASE™ (Reteplase, recombinant) and
Alteplase.5 Direct comparison of these two agents for
their effects on mortality was the logical next step.
In recognition of the need for additional study,
the GUSTO-III (Global Use of Strategies to Open
Occluded Coronary Arteries) trial was initiated in
October 1995 with plans of enrolling approximately
15,000 patients of any age who present within 6
hours of the onset of symptoms of an AMI. Patients
were randomized in a 2:1 ratio, 10,000 to the
double-bolus RETAVASE regimen and 5,000 to the
accelerated-dose Alteplase regimen (Fig 14).
The accelerated-dose Alteplase regimen
provided a 14% relative reduction in mortality from
AMI over Streptokinase in the GUSTO (now known
as GUSTO-I) trial in 1993.17 The most plausible
explanation is that Alteplase achieved a higher TIMI
3 flow rate in infarct-related coronary arteries, thus
supporting the open-artery hypothesis.18 Impressive
as these results may seem, however, analysis of
angiograms taken 90 minutes after the start of
therapy reveals that only 54% of the Alteplasetreated patients actually attained TIMI 3 flow.
This suggests that further increases in 30-day
survival may be achieved if greater reopening
of occluded arteries is also achieved. Moreover,
once achieved, the patency should be sustained,
since the initial benefit may be attenuated by
subsequent reocclusion.45
Fig 14.—GUSTO-III protocol algorithm.
Identify eligible patient
Aspirin 150-325 mg
2:1 Randomization
2
IV Reteplase
10 U bolus 32
30 min apart
N = 15,000
1
Heparin
5,000 U bolus
For patients ≥ 80 kg: 1,000 U/hr
For patients < 80 kg: 800 U/hr
IV heparin 3 ≥ 24 hours
IV Alteplase
15 mg bolus
0.75 mg/kg over 30 min
not to exceed 50 mg
0.50 mg/kg over 60 min
not to exceed 35 mg
Total dose ≤100 mg
Primary end point: 30-day mortality
– Data on file.34
33
SECTION VII
RETAVASE® (Reteplase) safety profile
Double-bolus safety profile established
The incidence of bleeding varied widely among
the clinical trials and was influenced by the use of
arterial catheterization and other highly invasive
procedures, and whether the study was performed
in Europe or the United States. The overall incidence
of bleeding in patients who received the RETAVASE
10 + 10 U double-bolus regimen in INJECT,3
RAPID 1,4 and RAPID 2 5 was 21.1%. This percentage
was similar to that of Streptokinase and Alteplase.
The rates of bleeding in the INJECT trial are
summarized in Table 10.
T
he safety of RETAVASE was evaluated in
3,805 patients with AMI and 45 healthy
volunteers. Most of the patients (3,296)
participating in the clinical trials received the
10 + 10 U double-bolus regimen. These studies
demonstrated that the safety profile of RETAVASE is
similar to that of other available thrombolytic agents
with respect to
• Cardiac events
• Allergic events
• Other adverse events
Strokes
Bleeding is the most common complication
encountered during the use of thrombolytics.
Internal bleeding can occur at intracranial or
retroperitoneal sites or in the gastrointestinal,
genitourinary, or respiratory tracts. Superficial
bleeding occurs mainly at sites of invasion or
disturbance (eg, venous cutdowns, arterial
punctures, or recent surgical incisions). Intracranial
bleeding is the most important safety concern
associated with the use of thrombolytic agents.
The overall incidence for RETAVASE was 0.71%.
In-hospital stroke rates for the 10 + 10 U
RETAVASE regimen in the INJECT trial is
summarized in Table 11.
There were no significant differences in overall
stroke rates between RETAVASE and Streptokinase
in the INJECT study.3 Overall in-hospital stroke
rates for the RETAVASE and Streptokinase treatment
groups were 1.23% and 1.00%, respectively. There
was an increase in the incidence of in-hospital
intracranial hemorrhage for RETAVASE (0.77%)
versus Streptokinase (0.37%, P=0.04). The
percentage of patients requiring transfusion was
similar in the two groups (0.7% for RETAVASE and
1.0% for Streptokinase).
Table 10.—Bleeding Incidence (%) in
INJECT Trial
Table 11.—In-Hospital Cerebrovascular
Events (%) in INJECT Trial 3
Bleeding
Bleeding Site
RETAVASE
(n = 2,965)
Event
All in-hospital strokes
RETAVASE
(n = 2,965)
Streptokinase
(n = 2,971)
1.21
1.01*
Injection site
4.6
Gastrointestinal
2.5
Intracranial hemorrhage
0.77
0.37†
Genitourinary
1.6
Nonhemorrhagic stroke
0.30
0.30
Anemia, site unknown
2.6
Unknown etiology
0.13
0.34
*P = 0.45;
35
†P
= 0.04.
No dosing adjustment is required based on
patient’s weight
Other cardiovascular events in INJECT
The incidence of hypotension, pulmonary
edema, atrial fibrillation or flutter, and asystole were
all significantly lower for patients treated with
RETAVASE.3 While a variety of additional
cardiovascular events had similar rates for both
agents, there were no cardiac complications for
which the incidence rate was significantly lower
in the Streptokinase group. Overall, 60.3% of
RETAVASE-treated patients and 63.0% of
Streptokinase-treated patients experienced at least
one cardiovascular adverse event, while 20.0%
and 22.2%, respectively, had at least one serious
cardiovascular adverse event.
In low-weight (<65 kg) and higher-weight
(>65 kg) RETAVASE® (Reteplase)-treated patients,
the rates of cerebrovascular events, total strokes, and
hemorrhagic strokes were similar. In the INJECT
study,3 hemorrhagic stroke rates were 0.7% for both
subgroups.
For hemorrhages of any type, combined data
from INJECT3 and the RAPID4,5 studies showed
that 25.8% of low-weight patients and 21.0% of
higher-weight patients experienced at least one
hemorrhage. For hemorrhages requiring a
transfusion, the low-weight and higher-weight
groups were more similar (3.8% vs 3.1%,
respectively).3,4
Because of these results, and particularly
because the incidence of hemorrhagic strokes was
similar in both low-weight and higher-weight
patients, it was concluded that dose adjustment
based on a patient’s weight is not necessary for
RETAVASE use.
RETAVASE, therefore, can be administered
rapidly in a convenient double-bolus dosing
regimen, with no dosage adjustment necessary
regardless of weight.
Allergic events
The incidence of allergic events in the INJECT
study was lower in the RETAVASE group (1.1%)
than in the Streptokinase group (2.0%). Serious
events occurred more often in patients receiving
Streptokinase (0.5%) than in those receiving
RETAVASE (0.1%).
Across all studies, 42 of 3,288 RETAVASEtreated patients (1.3%) experienced an allergic
event, compared to 59 of 2,971 Streptokinase-treated
patients (2.0%).
Congestive heart failure and cardiogenic
shock in INJECT
Other adverse events
There were no major differences between
RETAVASE and the control agents in the incidence
of other events. The higher incidences of minor
bleeding and other events in RAPID 1 and 2 than
in INJECT are due to angiographic intervention
and are consistent with rates in other angiographic
trials. There was also a more detailed reporting
scheme in the RAPID trials, since INJECT focused
on major clinical end points (mortality, stroke,
cardiovascular events, allergic reactions) appropriate
for a mortality trial.
As can be seen in Table 12, significantly fewer
patients treated with RETAVASE in the INJECT
trial had new or worsening CHF (P=0.004) and
cardiogenic shock (P=0.03) than patients treated
with Streptokinase. These results demonstrate that
the rate of CHF reduced by Streptokinase can be
further reduced by RETAVASE.
Table 12.—Patients (%) Reported With CHF and Cardiogenic Shock in INJECT
Congestive heart failure
Cardiogenic shock
RETAVASE
(n = 2,965)
Streptokinase
(n = 2,971)
P Value
24.8
28.1
0.004
4.6
5.8
0.03
36
SECTION VIII
angiographic trials
RAPID 1 and RAPID 2 clinical trials
establish activity of bolus dosing
trials were not designed or powered to compare
RETAVASE and Alteplase with respect to the
outcomes of mortality or stroke, consequently
comparisons of mortality or stroke cannot be made.
RAPID 1. The RAPID 1 study compared three
doses of RETAVASE to Alteplase in patients with
AMI.4 A total of 606 patients treated within 6 hours
of the onset of symptoms of AMI were randomized
to one of four treatment groups:
• 146 had a 15 U single RETAVASE bolus
• 152 had a 10 + 5 U RETAVASE
double-bolus dose
• 154 had a 10 + 10 U RETAVASE
double-bolus dose
• 154 had a 3-hour infusion of Alteplase
(100 mg)
Both the RAPID 14 and RAPID 25 clinical
trials were angiographic studies designed to
test the hypothesis that bolus dosing of RETAVASE
was superior to administration of Alteplase in
achieving complete perfusion (TIMI 3 flow) and
patency (TIMI 2 + 3 flow) of the infarct-related
artery 90 minutes after initiation of thrombolytic
therapy in patients with AMI.
Secondary end points in RAPID 1 and RAPID 2
were patency at 60 minutes after the initiation of
therapy, patency prior to hospital discharge (in 5 to
14 days), and LVF prior to discharge.4,5
The correlation between patency and patient
outcome has not been established. The angiographic
Fig 15.—Summary of infarct-related artery patency rates in RAPID 1.
Patency at 90 minutes
TIMI 3
100
Patency at hospital discharge
TIMI 2
100
85.2
80
77.2
66.7†
60
62.7†
49.0
40.9
45.7
60
70.7
71.0
80.5
87.8‡
73.2
Patients
(%) 40
20
20
0
85.5
80
62.8*
Patients
(%) 40
95.1†
87.8
Alteplase
3 hr
(n = 145)
RETAVASE
15 U
(n = 137)
RETAVASE
10 + 5 U
(n = 138)
0
RETAVASE
10 + 10 U
(n = 142)
Alteplase
3 hr
(n = 123)
RETAVASE RETAVASE RETAVASE
15 U
10 + 5 U
10 + 10 U
(n = 123)
(n = 124) (n = 123)
*P <0.01 compared to Alteplase.
†P <0.05 compared to Alteplase.
‡P <0.001 compared to Alteplase.
The P-values represent a comparison of the multiple RETAVASE groups to the single Alteplase group without adjustment for multiple comparisons.
– Adapted from Smalling et al.4
37
Aspirin was given at a dose of 200 to
325 mg immediately before administration of
each thrombolytic agent and continued daily
until hospital discharge. Heparin was started
as an intravenous bolus just before the start of
thrombolytic therapy and then infused at the
rate of 1,000 U/hr for at least 24 hours.
Coronary arteriography was performed at
30 and 60 minutes after initiation of thrombolytic
therapy (when possible) and at 90 minutes. Left
ventriculography was also performed after coronary
arteriography, and TIMI grade was estimated at
90 minutes. The complete angiographic procedure
was repeated between 5 days after admission and
discharge from the hospital.
Results of RAPID 1. Patency data in the
RAPID 1 study are summarized in Fig 15 on
page 37.4 The 10 + 10 U RETAVASE™ (Reteplase,
recombinant) group achieved patency (TIMI 2 + 3
flow) in 85% of patients at 90 minutes compared
to 77% of patients treated with Alteplase. This
difference was not statistically significant. At 5 to 14
days after treatment, however, RETAVASE achieved
significantly higher patency rates than the Alteplase
group (95% vs 88%, P<0.05). Bolus administration
of 10 + 10 U of RETAVASE resulted in improved
complete flow, both at 90 minutes and before
hospital discharge, compared with standard-dose
Alteplase. These findings were associated with
improved global and regional function at hospital
discharge. Patients in the RETAVASE 10 + 10 U and
Alteplase groups exhibited similar global ventricular
function in the acute stage of treatment. There was,
however, a significant difference in favor of
RETAVASE at hospital discharge in left ventricular
ejection fraction and regional wall motion.4 The
bleeding risk of RETAVASE was similar to that
associated with standard-dose Alteplase.
RAPID 1 provided dose-finding data that
supported the use of the 10 + 10 U double-bolus
regimen as the standard for subsequent studies.
outcome has not been established. This trial was
not designed or powered to make comparisons of
mortality or stroke.
The need for coronary interventions within
6 hours of thrombolysis was also evaluated in
RAPID 1. There were no significant differences in
the incidence of early rescue PTCAs (14.9% versus
22.1%),4 or the overall in-hospital incidences of
PTCAs (RETAVASE 46.8%, Alteplase 50.6%).34
RAPID 2. In the RAPID 2 study, 324 patients
treated within 12 hours of the onset of symptoms
of AMI were randomized to receive either a
10 + 10 U double bolus of RETAVASE 30 minutes
apart (n=169) or the accelerated (front-loaded)
90-minute Alteplase regimen (n=155). Patients
also received aspirin and heparin.5 Angiographic
procedures were conducted as in RAPID 1.
Results of RAPID 2. Patency (TIMI 2 + 3 flow)
and complete perfusion (TIMI 3 flow) rates were
significantly higher for the 10 + 10 U RETAVASE
regimen than for Alteplase at 60 minutes and 90
minutes5 (Fig 16). At the primary time point of 90
minutes, the patency rate in the RETAVASE group
was 10% higher and the complete perfusion rate
(TIMI 3) was 15% higher (P=0.011) than in the
Alteplase group.
In RAPID 2, patients who received treatment
within 6 hours after onset of symptoms had better
overall patency and complete perfusion in both
groups than did patients who presented between
6 and 12 hours. Notably, patients treated with
RETAVASE had better patency in all time-totreatment categories. RETAVASE achieved
90-minute patency (TIMI 2 + 3 flow) in 86.5%
and complete perfusion (TIMI 3 flow) in 62.4% of
patients treated within 6 hours. The corresponding
rates for Alteplase were 77.2% and 47.2%.5
outcome has not been established. This trial was
not designed or powered to make comparisons of
mortality or stroke.
38
Fig 16.—Patency profile at 60, 90 minutes and 5 to 14 days in RAPID 2.
100
TIMI 3
TIMI 2
90
89
77
75
83†
82*
80
73
66
60
60†
Patients
(%)
51†
40
45
37
20
0
*P <0.01 RETAVASE vs Alteplase.
†P <0.05 RETAVASE vs Alteplase.
Alteplase RETAVASETM
(n = 146) (Reteplase,
recombinant)
(n = 157)
recombinant)
(n = 121)
60 min
90 min
recombinant)
(n = 128)
5-14 days
The correlation between patency and patient outcome has not been established. Due to different numbers of patients in the
60- and 90-minute groups and nonrandomization to these time points, no comparison can be made between 60- and 90-minute data.
– Adapted from Bode et al.5
The need for coronary interventions within
6 hours of thrombolysis was also evaluated in
RAPID 2. There were significantly fewer early
rescue PTCAs for patients treated with RETAVASE
compared to accelerated-dose Alteplase. There were
no differences in the overall in-hospital incidences
of PTCAs (Fig 17).5
Fig 17.—Incidence of PTCA interventions in RAPID 2.
Within 6 hours
60
Overall
57.4
52.7†
50
40
Patients
(%)
30
23.9
20
12.4*
10
0
*P < 0.01 vs Alteplase.
†P =NS vs Alteplase.
Alteplase
1.5 hr
(n = 155)
RETAVASE
10 + 10 U
(n = 169)
Alteplase
1.5 hr
(n = 155)
RETAVASE
10 + 10 U
(n = 169)
– Adapted from Bode et al.5
39
SECTION IX
Summary of benefits of
RETAVASE ® (Reteplase)
Demonstrated mortality reduction/
documented safety profile
Simple, convenient administration
The unique molecular structure of RETAVASE
and its long therapeutic half-life permit a
convenient double-bolus dosing regimen.
Administration of RETAVASE as a double-bolus
regimen—intravenous injections 30 minutes
apart—may permit an earlier start of life-saving
therapy in the hospital emergency department or
intensive care unit, and the dose does not have to be
adjusted for the patient’s weight. The greater ease of
RETAVASE administration may reduce time and
staff required for administration and may also
obviate the need for two intravenous lines, since
heparinization can be interrupted during
RETAVASE bolus injections. Intravenous lines,
however, should be flushed between administration
of RETAVASE and other agents.
A
double-blind mortality trial has
demonstrated that RETAVASE is effective
in reducing mortality following an AMI.3
Furthermore, patients treated with RETAVASE had
a significantly lower incidence of atrial fibrillation,
asystole, cardiogenic shock, CHF, and hypotension,
and significantly fewer allergic reactions than
patients treated with Streptokinase.3
With the exception of intracranial hemorrhage
in which the incidence with RETAVASE was higher,
the incidence of serious complications, such as
cerebrovascular and cardiovascular events, was
similar to that of control agents.
Restoration of coronary flow
in more patients
RETAVASE has been angiographically proven
to achieve complete perfusion and patency in
significantly more patients than the accelerateddose Alteplase regimen.5 The correlation between
established. In addition, RETAVASE is proven
to preserve left ventricular function.4,5
The GUSTO-III trial with 15,000 patients was
designed to study 30-day mortality with RETAVASE
compared to Alteplase. Enrollment was completed
in January 1997. Secondary end points included
in-hospital rates of reinfarction, CHF, stroke, and
intracranial hemorrhage.
41
SECTION X
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19. Kohnert U, Rudolph R, Verheijen JH, et al. Biochemical properties of the
kringle 2 and protease domains are maintained in the refolded t-PA
deletion variant BM 06.022. Protein Eng. 1992;5:93-100.
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20 891 patients with suspected acute myocardial infarction randomised
between alteplase and streptokinase with or without heparin. Lancet.
1990;336:71-75.
12. Handin RI, Loscalzo J. Hemostasis, thrombosis, fibrinolysis, and
cardiovascular disease. In: Braunwald E, ed. Heart Disease: A Textbook of
Cardiovascular Medicine. 4th ed. Philadelphia, Pa: WB Saunders Co;
1992:1767-1789.
32. Martin U, Bader R, Böhm E, et al. BM 06.022: a novel recombinant
plasminogen activator. Cardiovasc Drug Rev. 1993;11:299-311.
33. Tanswell P, Seifried E, Su PCAF, et al. Pharmacokinetics and systemic
effects of tissue-type plasminogen activator in normal subjects. Clin
Pharmacol Ther. 1989;46:155-162.
13. Sobel BE, Hirsh J. Principles and practice of coronary thrombolysis and
conjunctive treatment. Am J Cardiol. 1991;68:382-388.
34. Data on file, Boehringer Mannheim Corporation–Therapeutics Division.
14. Sobel BE, Nachowiak DA, Fry ETA, et al. Paradoxical attenuation of
fibrinolysis attributable to “plasminogen steal” and its implications for
coronary thrombolysis. Coron Artery Dis. 1990;1:111-119.
35. Collen D, De Cock F, Demarsin E, et al. Absence of synergism between
tissue-type plasminogen activator (t-PA), single-chain urokinase-type
plasminogen activator (scu-PA) and urokinase on clot lysis in a plasma
milieu in vitro. Thromb Haemost. 1986;56:35-39.
15. Pasternak RC, Braunwald E, Sobel BE. Acute myocardial infarction. In:
Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 4th
ed. Philadelphia, Pa: WB Saunders Co; 1992: 1200-1291.
36. Martin U, Sponer G, Strein K. Differential fibrinolytic properties of the
recombinant plasminogen activator BM 06.022 in human plasma and
blood clot systems in vitro. Blood Coagul Fibrinolysis. 1993;4:235-242.
16. Agnelli G. The pharmacological basis of thrombolytic therapy. In:
Agnelli G, ed. Thrombolysis Yearbook 1995. Amsterdam: Excerpta Medica;
1995:31-61.
37. Kanamasa K, Watanabe I, Cercek B, et al. Selective decrease in lysis of old
thrombi after rapid administration of tissue-type plasminogen activator.
J Am Coll Cardiol. 1989;14:1359-1364.
17. The GUSTO Investigators. An international randomized trial comparing
four thrombolytic strategies for acute myocardial infarction. N Engl J Med.
1993;329:673-682.
38. Martin U, von Möllendorff E, Akpan W, et al. Dose-ranging study of the
novel recombinant plasminogen activator BM 06.022 in healthy volunteers.
Clin Pharmacol Ther. 1991;50:429-436.
43
was significantly higher with Retavase® than with Alteplase at 90 minutes after the initiation of therapy. In both
clinical trials the reocclusion rates were similar for Retavase® and Alteplase. The relationship between coronary
artery patency and clinical efficacy has not been established.
Table 2
RAPID 1 and RAPID 2 TRIALS
Arteriographic Results
DESCRIPTION
Retavase® (Reteplase) is a non-glycosylated deletion mutein of tissue plasminogen activator (tPA), containing
the kringle 2 and the protease domains of human tPA. Retavase® contains 355 of the 527 amino acids of
native tPA (amino acids 1-3 and 176-527). Retavase® is produced by recombinant DNA technology in
E. coli. The protein is isolated as inactive inclusion bodies from E. coli, converted into its active form by an
in vitro folding process and purified by chromatographic separation. The molecular weight of Reteplase is
39,571 daltons.
Potency is expressed in units (U) using a reference standard which is specific for Retavase® and is not
comparable with units used for other thrombolytic agents.
Retavase® is a sterile, white, lyophilized powder for intravenous bolus injection after reconstitution with
Sterile Water for Injection, USP (without preservatives) provided as part of a kit. Following reconstitution, the
pH is 6.0 ± 0.3. Retavase® is supplied as a 10.4 U vial to ensure sufficient drug for administration of each
10 U dose. Each single-use vial contains:
18.1 mg
8.32 mg
18.1
136.24
8.32 mg
51.27 mg
136.24
364.0 mg
51.27
5.20 mg
35 Day mortality
6 Month mortality†
Combined outcome of
35 day mortality or
nonfatal stroke
within 35 days
Heart failure
Retavase®
n = 2,965
Streptokinase
n = 2,971
90 minute patency rates
TIMI 2 or 3
TIMI 3
Follow-up patency rates
TIMI 2 or 3
TIMI 3
mean %
Follow-up regional wall motion
Standard deviation from
mean normal value
CLINICAL PHARMACOLOGY
General
Retavase® is a recombinant plasminogen activator which catalyzes the cleavage of endogenous plasminogen to
generate plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic
action.1,2 In a controlled trial, 36 of 56 patients treated for an acute myocardial infarction (AMI) had a decrease
in fibrinogen levels to below 100 mg/dL by 2 hours following the administration of Retavase® as a doublebolus intravenous injection
(10 + 10 U) in which 10 U (17.4 mg) was followed 30 minutes later by a second
3
bolus of 10 U (17.4 mg). The mean fibrinogen level returned to the baseline value by 48 hours.
Pharmacokinetics
Based on the measurement of thrombolytic activity, Retavase® is cleared from plasma at a rate of 250-450
mL/min, with an effective half-life of 13-16 minutes. Retavase® is cleared primarily by the liver and kidney.
Clinical Studies
The safety and efficacy of Retavase® were evaluated in three controlled clinical trials in which Retavase® was
compared to other thrombolytic agents. The INJECT study was designed to assess the relative effects of
Retavase® or the Streptase® brand of Streptokinase upon mortality rates at 35 days following an AMI. The
other studies (RAPID 1 and RAPID 2) were arteriographic studies which compared the effect on coronary
patency of Retavase® to two regimens of Alteplase (a tissue plasminogen activator; Activase® in the USA and
Actilyse® in Europe) in patients with an AMI. In all three studies, patients were treated with aspirin (initial
doses of 160 mg to 350 mg and subsequent doses of 75 mg to 350 mg) and heparin (a 5,000 U IV bolus
prior to the3,4,5administration of Retavase®, followed by a 1000 U/hour continuous IV infusion for at least
24 hours). The safety and efficacy of Retavase® have not been evaluated using antithrombotic or
antiplatelet regimens other than those described above.
Retavase® (10 + 10 U) was compared to Streptokinase (1.5 million units over 60 minutes) in a doubleblind, randomized, European study (INJECT), which studied 6,010 patients treated within 12 hours of the
onset of symptoms of AMI. To be eligible for enrollment, patients had to have chest pain consistent with
coronary ischemia and ST segment elevation, or a bundle branch block pattern on the EKG. Patients with
known cerebrovascular or other bleeding risks or those with a systolic blood pressure >200 mm Hg or a
diastolic blood pressure >100 mm Hg were excluded from enrollment. The results of the primary endpoint
(mortality at 35 days), six month mortality and selected other 35 day endpoints are shown in Table 1 for
patients receiving study medications.
Table 1
INJECT TRIAL
Incidence of Selected Outcomes
Retavase®-Streptokinase
difference (95% CI)
p
Value
8.9%
9.4%
-0.5 (-2.0, 0.9)
0.49*
11.0%
12.1%
-1.1 (-2.7, 0.6)
0.22
9.6%
10.2%
-0.6 (-2.1, 1.0)
0.47
24.8%
28.1%
-3.3 (-5.6, -1.1)
0.004
Cardiogenic shock
4.6%
5.8%
-1.2 (-2.4, -0.1)
0.03
Any stroke
1.4%
1.1%
0.3 (-0.3, 0.8)
0.34
Intracranial hemorrhage
0.8%
0.4%
0.4 (0.0, 0.8)
0.04
*p value for the exploratory analysis comparing Retavase® versus Streptokinase.
Kaplan-Meier estimates.
†
For mortality, stroke and the combined outcome of mortality or stroke, the 95% confidence intervals in
Table 1 reflect the range within which the true difference in outcomes probably lies and includes the possibility
of no difference. The incidences of congestive heart failure and of cardiogenic shock were significantly lower
among patients treated with Retavase®.
The total incidence of stroke was similar between the groups. However, more patients treated with
Retavase® experienced hemorrhagic strokes than patients treated with Streptokinase. An exploratory analysis
indicated that the incidence of intracranial hemorrhage was higher among older patients or those with elevated
blood pressure. The incidence of intracranial hemorrhage among the 698 patients treated with Retavase® who
were older than 70 years was 2.2%. Intracranial hemorrhage occurred in 8 of the 332 (2.4%) patients treated
with Retavase® who had an initial systolic blood pressure >160 mm Hg and in 15 of the 2,629 (0.6%)
Retavase® patients who had an initial systolic blood pressure <160 mm Hg.
Two arteriographic studies (RAPID 1 and RAPID 2) were performed utilizing open-label administration
of the study agents and a blinded review of the arteriograms. In RAPID 1, patients were treated within 6 hours
of the onset of symptoms, and in RAPID 2, patients were treated within 12 hours of the onset of symptoms.
Both studies evaluated coronary artery perfusion through the infarct-related artery 90 minutes after the initiation of therapy as the primary endpoint. Some patients in each study also had perfusion through the infarctrelated artery evaluated at 60 minutes after the initiation of therapy. In RAPID 1, Retavase® (in doses of 10 +
10 U, 15 U, or 10 + 5 U) was compared to a 3 hour regimen of Alteplase (100 mg administered over 3 hrs). In
RAPID 2, Retavase® (10 + 10 U) was compared to an accelerated regimen of Alteplase (100 mg administered
over 1.5 hrs). The percentages of patients with partial or complete flow (TIMI grades 2 or 3) and complete
flow (TIMI grade 3), are shown along with ventricular function assessments in Table 2. The follow-up
arteriogram was performed at a median of 8 (RAPID 1) and 5 (RAPID 2) days following the administration of
the thrombolytics. In RAPID 1 the best patency results were obtained with the 10 + 10 U dose. In RAPID 2,
the percentage of patients with partial or complete flow and the percentage of patients with complete flow
RAPID 2
Retavase® Alteplase
(10 +10 U) (Accelerated
regimen)
Follow-up ejection fraction
10.4 U (18.1 mg) Vial
Reteplase
10.4 U (18.1 mg) Vial
Tranexamic Acid
Reteplase
DipotassiumAcid
Hydrogen Phosphate
Tranexamic
Phosphoric Acid
Dipotassium
Hydrogen Phosphate
Sucrose
Phosphoric Acid
Polysorbate 80
Endpoint
Outcome
n = 157
n = 146
83%
60%
73%
45%
n = 128
n = 113
89%
75%
90%
77%
n = 89
n = 77
52%
54%
n = 87
n = 72
-2.3
-2.3
RAPID 1*
p
0.03
0.01
0.76
0.72
0.25
0.96
Retavase® Alteplase
(10 +10 U) (Standard
regimen)
n = 142
n = 145
85%
63%
77%
49%
n = 123
n = 123
95%
88%
88%
71%
n = 91
n = 84
53%
49%
n = 84
n = 80
-2.2
-2.6
p
0.08
0.02
0.040
0.001
0.03
0.02
*p values represent one of multiple dose comparisons.
Approximately 70% (RAPID 1) and 78% (RAPID 2) of the patients in the arteriographic studies underwent optional arteriography at 60 minutes following the administration of the study agents. In both trials the
percentage of patients with complete flow at 60 minutes was significantly higher with Retavase® than with
Alteplase. Neither RAPID clinical trial was designed nor powered to compare the efficacy or safety of
Retavase® and Alteplase with respect to the outcomes of mortality and stroke.
INDICATIONS AND USAGE
Retavase® (Reteplase) is indicated for use in the management of acute myocardial infarction (AMI) in adults
for the improvement of ventricular function following AMI, the reduction of the incidence of congestive heart
failure and the reduction of mortality associated with AMI. Treatment should be initiated as soon as possible
after the onset of AMI symptoms (see CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
Because thrombolytic therapy increases the risk of bleeding, Retavase® is contraindicated in the following
situations:
•
Active internal bleeding
•
History of cerebrovascular accident
•
Recent intracranial or intraspinal surgery or trauma (see WARNINGS)
•
Intracranial neoplasm, arteriovenous malformation, or aneurysm
•
Known bleeding diathesis
•
Severe uncontrolled hypertension
WARNINGS
Bleeding
The most common complication encountered during Retavase® therapy is bleeding. The sites of bleeding include both internal bleeding sites (intracranial, retroperitoneal, gastrointestinal, genitourinary, or respiratory) and superficial bleeding sites (venous cutdowns, arterial punctures, sites of recent surgical intervention).
The concomitant use of heparin anticoagulation may contribute to bleeding. In clinical trials some of the hemorrhage episodes occurred one or more days after the effects of Retavase® had dissipated, but while heparin
therapy was continuing.
As fibrin is lysed during Retavase® therapy, bleeding from recent puncture sites may occur. Therefore,
thrombolytic therapy requires careful attention to all potential bleeding sites (including catheter insertion sites,
arterial and venous puncture sites, cutdown sites, and needle puncture sites). Noncompressible arterial puncture must be avoided and internal jugular and subclavian venous punctures should be avoided to minimize
bleeding from noncompressible sites.
Should an arterial puncture be necessary during the administration of Retavase®, it is preferable to
use an upper extremity vessel that is accessible to manual compression. Pressure should be applied for at
least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.
Intramuscular injections and nonessential handling of the patient should be avoided during treatment
with Retavase®. Venipunctures should be performed carefully and only as required.
Should serious bleeding (not controllable by local pressure) occur, concomitant anticoagulant therapy
should be terminated immediately. In addition, the second bolus of Retavase® should not be given if serious
bleeding occurs before it is administered.
Each patient being considered for therapy with Retavase® should be carefully evaluated and anticipated benefits weighed against the potential risks associated with therapy. In the following conditions, the risks
of Retavase® therapy may be increased and should be weighed against the anticipated benefits:
•
Recent major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy
•
Previous puncture of noncompressible vessels
•
Cerebrovascular disease
•
Recent gastrointestinal or genitourinary bleeding
•
Recent trauma
•
Hypertension: systolic BP ≥180 mm Hg and/or diastolic BP ≥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
•
Severe hepatic or renal dysfunction
•
Pregnancy
•
Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions
•
Septic thrombophlebitis or occluded AV cannula at a seriously infected site
•
Advanced age
•
Patients currently receiving oral 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
Cholesterol Embolization
Cholesterol embolism has been reported rarely in patients treated with thrombolytic agents; the true incidence
is unknown. This serious condition, which can be lethal, is also associated with invasive vascular procedures
(e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. Clinical features of
cholesterol embolism may include livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous
digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal
artery occlusion, bowel infarction, and rhabdomyolysis.
Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such as
sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) are not different from those often seen in the ordinary course of acute myocardial infarction and
should be managed with standard antiarrhythmic measures. It is recommended that antiarrhythmic therapy
for bradycardia and/or ventricular irritability be available when Retavase® is administered.
PRECAUTIONS
General
Standard management of myocardial infarction should be implemented concomitantly with Retavase®
treatment. Arterial and venous punctures should be minimized (see WARNINGS). In addition, the second
bolus of Retavase® should not be given if the serious bleeding occurs before it is administered. In the event
of serious bleeding, any concomitant heparin should be terminated immediately. Heparin effects can be
reversed by protamine.
Readministration
There is no experience with patients receiving repeat courses of therapy with Retavase®. Retavase® did not
induce the formation of Retavase® specific antibodies in any of the approximately 2,400 patients who were
tested for antibody formation in clinical trials. If an anaphylactoid reaction occurs, the second bolus of
Retavase® should not be given, and appropriate therapy should be initiated.
Drug Interactions
The interaction of Retavase® with other cardioactive drugs has not been studied. In addition to bleeding
associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as aspirin, dipyridamole, and abciximab) may increase the risk of bleeding if administered prior to or after Retavase® therapy.
Drug/Laboratory Test Interactions
Administration of Retavase® may cause decreases in plasminogen and fibrinogen. During Retavase® therapy,
if coagulation tests and/or measurements of fibrinolytic activity are performed, the results may be unreliable
unless specific precautions are taken to prevent in vitro artifacts. Retavase® is an enzyme that when present
in blood in pharmacologic concentrations remains active under in vitro conditions. This can lead to
degradation of fibrinogen in blood samples removed for analysis. Collection of blood samples in the presence
of PPACK (chloromethylketone) at 2 µM concentrations was used in clinical trials to prevent in vitro
fibrinolytic artifacts.6
Use of Antithrombotics
Heparin and aspirin have been administered concomitantly with and following the administration of
Retavase® in the management of acute myocardial infarction. Because heparin, aspirin, or Retavase® may
cause bleeding complications, careful monitoring for bleeding is advised, especially at arterial puncture sites.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Retavase®.
Studies to determine mutagenicity, chromosomal aberrations, gene mutations, and micronuclei induction
were negative at all concentrations tested. Reproductive toxicity studies in rats revealed no effects on fertility
at doses up to 15 times the human dose (4.31 U/kg).
Pregnancy Category C
Reteplase has been shown to have an abortifacient effect in rabbits when given in doses 3 times the human
dose (0.86 U/kg). Reproduction studies performed in rats at doses up to 15 times the human dose (4.31
U/kg) revealed no evidence of fetal anomalies; however, Reteplase administered to pregnant rabbits resulted
in hemorrhaging in the genital tract, leading to abortions in mid-gestation. There are no adequate and wellcontrolled studies in pregnant women. The most common complication of thrombolytic therapy is bleeding
and certain conditions, including pregnancy, can increase this risk. Reteplase should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether Retavase® is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when Retavase® is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Retavase® in pediatric patients have not been established.
ADVERSE REACTIONS
Bleeding
The most frequent adverse reaction associated with Retavase® is bleeding (see WARNINGS). The types of
bleeding events associated with thrombolytic therapy may be broadly categorized as either intracranial hemorrhage or other types of hemorrhage.
•
Intracranial hemorrhage (see CLINICAL PHARMACOLOGY)
In the INJECT clinical trial the rate of in-hospital, intracranial hemorrhage among all patients
treated with Retavase® was 0.8% (23 of 2,965 patients). As seen with Retavase® and other thrombolytic agents, the risk for intracranial hemorrhage is increased in patients with advanced age or with
elevated blood pressure.
•
Other types of hemorrhage
The incidence of other types of bleeding events in clinical studies of Retavase® varied depending
upon the use of arterial catheterization or other invasive procedures and whether the study was performed in Europe or the USA. The overall incidence of any bleeding event in patients treated with
Retavase® in clinical studies (n = 3,805) was 21.1%. The rates for bleeding events, regardless of
severity, for the 10 + 10 U Retavase® regimen from controlled clinical studies are summarized
in Table 3.
Table 3
Retavase® Hemorrhage Rates
Bleeding Site
INJECT
RAPID 1 and RAPID 2
Europe
n = 2,965
USA
n = 210
Europe
n =113
Injection Site*
4.6%
48.6%
19.5%
Gastrointestinal
2.5%
9.0%
1.8%
Genitourinary
1.6%
9.5%
0.9%
Anemia, site unknown
2.6%
1.4%
0.9%
*includes the arterial catheterization site (all patients in the RAPID studies underwent arterial catheterization).
In these studies the severity and sites of bleeding events were comparable for Retavase® and the
comparison thrombolytic agents.
Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial)
occur, any concomitant heparin should be terminated immediately. In addition, the second bolus of
Retavase® should not be given if the serious bleeding occurs before it is administered. Death and permanent
disability are not uncommonly reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.
Fibrin which is part of the hemostatic plug formed at needle puncture sites will be lysed during
Retavase® therapy. Therefore, Retavase® therapy requires careful attention to potential bleeding sites (e.g.,
catheter insertion sites, arterial puncture sites).
Allergic Reactions
Among the 2,965 patients receiving Retavase® in the INJECT trial, serious allergic reactions were noted in 3
patients, with one patient experiencing dyspnea and hypotension. No anaphylactoid reactions were observed
among the 3,856 patients treated with Retavase® in initial clinical trials. In an ongoing clinical trial two anaphylactoid reactions have been reported among approximately 2,500 patients receiving Retavase®.
Other Adverse Reactions
Patients administered Retavase® as treatment for myocardial infarction have experienced many events which
are frequent sequelae of myocardial infarction and may or may not be attributable to Retavase® therapy.
These events include cardiogenic shock, arrhythmias (e.g., sinus bradycardia, accelerated idioventricular
rhythm, ventricular premature depolarizations, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation), AV block, pulmonary edema, heart failure, cardiac arrest, recurrent ischemia, reinfarction,
myocardial rupture, mitral regurgitation, pericardial effusion, pericarditis, cardiac tamponade, venous thrombosis and embolism, and electromechanical dissociation. These events can be life-threatening and may lead
to death. Other adverse events have been reported, including nausea and/or vomiting, hypotension, and fever.
DOSAGE AND ADMINISTRATION
Retavase® (Reteplase) is for intravenous administration only. Retavase® is administered as a 10 + 10 U
double-bolus injection. Each bolus is administered as an intravenous injection over 2 minutes. The second
bolus is given 30 minutes after initiation of the first bolus injection. Each bolus injection should be given via an
intravenous line in which no other medication is being simultaneously injected or infused. No other medication
should be added to the injection solution containing Retavase®. There is no experience with patients receiving
repeat courses of therapy with Retavase®.
Heparin and Retavase® are incompatible when combined in solution. Do not administer heparin and
Retavase® simultaneously in the same intravenous line. If Retavase® is to be injected through an intravenous
line containing heparin, a normal saline or 5% dextrose (D5W) solution should be flushed through the line
prior to and following the Retavase® injection.
Although the value of anticoagulants and antiplatelet drugs during and following administration of
Retavase® has not been studied, heparin has been administered concomitantly in more than 99% of patients.
Aspirin has been given either during and/or following heparin treatment. Studies assessing the safety and efficacy of Retavase® without adjunctive therapy with heparin and aspirin have not been performed.
Reconstitution
Reconstitution should be carried out using the diluent, syringe, needle and dispensing pin provided with
Retavase®. It is important that Retavase® be reconstituted only with Sterile Water for Injection, USP (without
preservatives). The reconstituted preparation results in a colorless solution containing Retavase® 1 U/mL.
Slight foaming upon reconstitution is not unusual; allowing the vial to stand undisturbed for several minutes
is usually sufficient to allow dissipation of any large bubbles.
Because Retavase® contains no antibacterial preservatives, it should be reconstituted immediately
before use. When reconstituted as directed, the solution may be used within 4 hours when stored at 2-30˚C
(36-86˚F). Prior to administration, the product should be visually inspected for particulate matter and
discoloration.
Reconstitution Instructions
Use aseptic technique throughout.
Step 1: Remove the protective flip-cap from one vial of Sterile Water for Injection, USP (SWFI).
Open the package containing the 10 cc syringe with attached needle.
Remove the protective cap from the needle and withdraw 10 mL of SWFI from the vial.
Step 2: Open the package containing the dispensing pin. Remove the needle from the syringe, discard
the needle.
Remove the protective cap from the luer lock port of the dispensing pin and connect the syringe to
the dispensing pin.
Remove the protective flip-cap from one vial of Retavase®.
Step 3: Remove the protective cap from the spike end of the dispensing pin, and insert the spike into the vial
of Retavase® until the security clips lock onto the vial.
Transfer the 10 mL of SWFI through the dispensing pin into the vial of Retavase®.
Step 4: With the dispensing pin and syringe still attached to the vial, swirl the vial gently to dissolve the
Retavase®. DO NOT SHAKE.
Step 5: Withdraw 10 mL of Retavase® reconstituted solution back into the syringe. A small amount of solution
will remain in the vial due to overfill.
Step 6: Detach the syringe from the dispensing pin, and attach the sterile 20 gauge needle provided.
Step 7: The 10 mL bolus dose is now ready for administration.
Safely discard all used reconstitution components and the empty Retavase® vial according to institutional
procedures.
HOW SUPPLIED
Retavase®, is supplied as a sterile, preservative-free, lyophilized powder in 10.4 U (18.1 mg) vials without a
vacuum, in a kit with components for reconstitution. Each kit contains a package insert, 2 single-use
Retavase® vials 10.4 U (18.1 mg), 2 single-use diluent vials for reconstitution (10 mL Sterile Water for
Injection, USP), 2 sterile 10 cc syringes with 20 G needle attached, 2 sterile dispensing pins, 2 sterile 20 G
needles for dose administration, and 2 alcohol swabs. NDC 57894-040-01.
Storage
Store the kit containing Retavase® at 2-25˚C (36-77˚F). Kit should remain sealed until use to protect the
lyophilisate from exposure to light. Do not use beyond expiration date printed on the kit.
References
1.
Martin U, Sponer G, Strein K. Evaluation of thrombolytic and systemic effects of the novel recombinant plasminogen activator BM 06.022 compared with alteplase, anistreplase, streptokinase and
urokinase in a canine model of coronary artery thrombosis. JACC. 1992;19:433-440.
2.
Kohnert U, Rudolph R, Verheijen JH. Biochemical properties of the kringle 2 and protease domains are
maintained in the refolded t-PA deletion variant BM 06.022. Protein Engineering. 1992;5:93-100.
3.
Smalling R, Bode C, Kalbfleisch J, et al. More rapid, complete, and stable coronary thrombolysis with
bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction.
Circulation. 1995;91:2725-2732.
4.
Bode C, Smalling R, Gunther B, et al. Randomized comparison of coronary thrombolysis achieved
with double bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated
alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction.
Circulation. 1996;94:891-898.
5.
INJECT Study Group. Randomised, double-blind comparison of reteplase double-bolus administration
with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet.
1995;346:329-336.
6.
Martin U, Gärtner D, Markl HJ, et al. D-PHE-PRO-ARGCHLOROMETHYLKETONE prevents in vitro fibrinogen reduction by the novel recombinant plasminogen activator BM 06.022. Ann Hematol. 1992;
64(suppl)A47.
Retavase®,
Reteplase,
recombinant
Manufactured by:
Boehringer Mannheim GmbH
Nonnenwald 2
D-82377 Penzberg
Germany
For:
Centocor, Inc.
Malvern, PA 19355
U.S. License Number 1242
© 1999 Centocor, Inc.
January 1999
Printed in U.S.A.
January 1999
RP-98041
RP-98041

Retavase (Reteplase)

Transcription

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European Nienhuis Montessori Retreat 2014

Megatouch 2011.

Medtronic to Animas® Insulin Pump Switch Guide

The Bucks County Jewish Community presents