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). Following reconstitution, the pH is 6.0 ± 0.3. Retavase® is supplied as a 10.4 unit vial to ensure sufficient drug for administration of each 10 unit injection. Each single-use vial contains:
Reteplase 18.1 mg
Tranexamic Acid 8.32 mg
Dipotassium Hydrogen Phosphate 136.24 mg
Phosphoric Acid 51.27 mg
Sucrose 364.0 mg
Polysorbate 80 5.20 mg
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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 double-bolus intravenous injection (10 + 10 unit) in which 10 units (17.4 mg) was followed 30 minutes later by a second bolus of 10 units (17.4 mg).3 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 unit IV bolus prior to the administration of Retavase®, followed by a 1000 unit/hour continuous IV infusion for at least 24 hours).3,4,5 The safety and efficacy of Retavase® have not been evaluated using antithrombotic or antiplatelet regimens other than those described above.
Retavase® (10 + 10 unit) was compared to Streptokinase (1.5 million units over 60 minutes) in a double-blind, 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
|
Endpoint
|
Retavase®
n = 2,965
|
Streptokinase
n = 2,971
|
Retavase®-Streptokinase
difference (95% CI)
|
p
Value
|
| *p value for the exploratory analysis comparing Retavase® versus Streptokinase.
|
|
† Kaplan-Meier estimates.
|
| 35 Day mortality |
8.9% |
9.4%
|
-0.5 (-2.0, 0.9)
|
0.49* |
| 6 Month mortality†
|
11.0% |
12.1%
|
-1.1 (-2.7,0.6)
|
0.22 |
| Combined outcome of 35 day mortality or nonfatal stroke within 35 days |
9.6% |
10.2%
|
-0.6 (-2.1,1.0)
|
0.47 |
| Heart failure |
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 |
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 infarct-related artery evaluated at 60 minutes after the initiation of therapy. In RAPID 1, Retavase® (in doses of 10 + 10 unit, 15 unit, or 10 + 5 unit) was compared to a 3 hour regimen of Alteplase (100 mg administered over 3 hrs).In RAPID 2, Retavase® (10 + 10 unit) 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 unit dose. In RAPID 2, the percentage of patients with partial or complete flow and the percentage of patients with complete flow 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.
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.
Table 2 RAPID 1 and RAPID 2 TRIALS Arteriographic Results
|
Outcome
|
RAPID 2
|
RAPID 1*
|
|
Retavase®
(10 +10 unit)
|
Alteplase
(Accelerated regimen)
|
p
|
Retavase®
(10 +10 unit)
|
Alteplase
(Standard regimen)
|
p
|
| *p values represent one of multiple dose comparisons.
|
| 90 minute patency rates |
n = 157
|
n = 146
|
|
n = 142
|
n = 145
|
|
TIMI 2 or 3
TIMI 3 |
83%
60%
|
73%
45%
|
0.03
0.01 |
85%
63%
|
77%
49% |
0.08
0.02 |
| Follow-up patency rates |
n = 128
|
n = 113
|
|
n = 123
|
n = 123
|
|
TIMI 2 or 3
TIMI 3 |
89%
75%
|
90%
77% |
0.76
0.72 |
95%
88%
|
88%
71% |
0.04
0.001 |
| Follow-up ejection fraction |
n = 89
|
n =77 |
|
n = 91
|
n = 84 |
|
| mean % |
52%
|
54%
|
0.25 |
53%
|
49% |
0.03 |
| Follow-up regional wall motion |
n = 87
|
n =72 |
| n = 84
|
n = 80 |
|
| Standard deviation from mean normal value |
-2.3
|
-2.3
|
0.96 |
-2.2
|
-2.6 |
0.02 |
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