A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Retavase Warnings, Precautions, Pregnancy, Nursing, Abuse - Reteplase
Retavase Warnings, Precautions, Pregnancy, Nursing, Abuse - Reteplase
WARNINGS
Bleeding
The most common complication encountered during RetavaseŽ 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 RetavaseŽ had dissipated, but while heparin therapy was continuing.
As fibrin is lysed during RetavaseŽ 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 RetavaseŽ,
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 RetavaseŽ. 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 RetavaseŽ should not be given if serious bleeding occurs before it
is administered.
Each patient being considered for therapy with RetavaseŽ should be carefully
evaluated and anticipated benefits weighed against the potential risks associated
with therapy. In the following conditions, the risks of RetavaseŽ 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 RetavaseŽ is administered.
PRECAUTIONS
General
Standard management of myocardial infarction should be implemented concomitantly
with RetavaseŽ treatment. Arterial and venous punctures should be minimized
(see WARNINGS
). In addition, the second bolus of RetavaseŽ 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
RetavaseŽ. RetavaseŽ did not induce the formation of RetavaseŽ 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
RetavaseŽ should not be given, and appropriate therapy should be initiated.
Drug Interactions
The interaction of RetavaseŽ 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 RetavaseŽ
therapy.
Drug/Laboratory Test Interactions
Administration of RetavaseŽ may cause decreases in plasminogen and fibrinogen.
During RetavaseŽ 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. RetavaseŽ 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 ľM concentrations was used in clinical trials of prevent in vitro fibrinolytic
artifacts. 6
Use of Antithrombotics
Heparin and aspirin have been administered concomitantly with and following
the administration of RetavaseŽ in the management of acute myocardial infarction.
Because heparin, aspirin, or RetavaseŽ 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 RetavaseŽ. 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 well-controlled 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 RetavaseŽ is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when RetavaseŽ is administered
to a nursing woman.
Pediatric Use
Safety and effectiveness of RetavaseŽ in pediatric patients have not been established.
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