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UROKINASE
(Angikinase®) |
Description:
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Urokinase is a
thrombolytic agent obtained from human neonatal kidney cells grown in tissue
culture. The principle active ingredient of
Angikinase is
the low molecular weight form of urokinase, and consists of an A chain of 2,000
Daltons linked by a sulfhydryl bond to a B chain of 30,400 Daltons.
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| Clinical pharmacology: |
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Urokinase is an
enzyme (protein) produced by the kidney, and found in the urine. There are two
forms of urokinase which differ in molecular weight but have similar clinical
effects.
Angikinase is the
low molecular weight form.
Angikinase acts on the endogenous fibrinolytic system.
It converts plasminogen to the enzyme plasmin. Plasmin degrades fibrin clots as
well as fibrinogen and some other plasma proteins.
Information about
the pharmacokinetic properties in man is limited. Urokinase administered by
intravenous infusion is rapidly cleared by the liver with an elimination
half-life for biologic activity of 12.6 + /- 6.2 minutes and a distribution
volume of 11.5 L. Small fractions of the administered dose are excreted in bile
and urine.
Although the pharmacokinetics of exogenously administered urokinase
have not been characterized in patients with hepatic impairment, endogenous
urokinase-type plasminogen activator plasma levels are elevated 2- to 4-fold in
patients with moderate to severe cirrhosis. Thus, reduced urokinase clearance in
patients with hepatic impairment might be expected.
Intravenous
infusion of
Angikinase in doses recommended for lysis of pulmonary embolism is
followed by increased fibrinolytic activity in the circulation. This effect
disappears within a few hours after discontinuation, but a decrease in plasma
levels of fibrinogen and plasminogen and an increase in the amount of
circulating fibrin and fibrinogen degradation products may persist for 12-24
hours. There is a lack of correlation between embolus resolution and
changes in coagulation and fibrinolytic assay results.
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Treatment with urokinase demonstrated more improvement on: |
►Pulmonary angiography
►Lung perfusion scanning
►Haemo-dynamic
Measurements within 24 hours than did
treatment with heparin. Lung perfusion
scanning showed no significant
treatment-associated difference by day 7.
Information based on patients treated with
fibrinolytic for pulmonary embolus suggests
that improvement in angiographic and lung
perfusion scans is lessened when treatment
is instituted more than several days (e.g.,
4 to 6 days) after onset.
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Indications and usages: |
Angikinase is indicated in
adults:
►For the lysis of acute massive pulmonary
emboli, defined as obstruction of blood flow
to a lobe or multiple segments.
►For the lysis of pulmonary emboli
accompanied by unstable hemodynamics, i.e.,
failure to maintain blood pressure without
supportive measures.
The diagnosis should be confirmed by
objective means, such as pulmonary
angiography or non-invasive procedures such
as lung scanning.
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Contraindications:
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The use of Angikinase is
contraindicated in patients with a history
of hypersensitivity to the product.
Because thrombolytic therapy increases the
risk of bleeding.
Sedonase is contraindicated in the
situations listed below:
►Recent (e.g., within two months)
cerebrovasular accident
►Active internal bleeding
►Recent (e.g., within two months)
intracranial or intraspinal surgery
►Recent trauma including cardiopulmonary
resuscitation
►Intracranial neoplasm, arteriovenous
malformation, or aneurysm
►Known bleeding diatheses
►Severe uncontrolled arterial hypertension
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Warning: |
Bleeding:
The risk of serious bleeding is increased
with use of Angikinase. Fatalities due to
hemorrhage, including intracranial and
retroperitoneal, have been reported in
association with urokinase therapy.
Concurrent administration of Angikinase with
other thrombolytic agents, anticoagulants,
or agents inhibiting platelet function may
further increase the risk of serious
bleeding.
Angikinase therapy requires careful
attention to all potential bleeding sites
(including catheter insertion sites,
arterial and venous puncture sites, cut down
sites, and other needle puncture sites).
Intramuscular injections and nonessential
handling of the patient must be avoided
during treatment with Angikinase.
Venipunctures should be performed as
infrequently as possible and with care to
minimize bleeding.
Should an arterial puncture be necessary,
upper extremity vessels are preferable.
Direct pressure should be applied for at
least 30 minutes, a pressure dressing
applied, and the puncture site checked
frequently for evidence of bleeding.
In the following conditions, the risk of
bleeding may be increased and should be
weighed against the anticipated benefits:
►Recent (within 10 days) major surgery,
obstetrical delivery, organ biopsy, previous
puncture of non-compressible vessels.
►Recent (within 10 days) serious
gastrointestinal bleeding.
►High likelihood of a left heart thrombus,
for example, mitral stenosis with arterial
fibrillation.
►Subacute bacterial endocarditis.
►Haemostatic defects including those
secondary to severe hepatic or renal
disease.
►Pregnancy.
►Cerebrovasular disease.
►Diabetic hemorrhagic retinopathy
Any other condition in which bleeding might
constitute a significant hazard or be
particularly difficult to manage because of
its location
When internal bleeding occurs, it may be
more difficult to manage than that which
occurs with conventional anticoagulant
therapy. Should potentially serious
spontaneous bleeding (not controllable by
direct pressure) occur, the infusion of
Angikinase should be terminated immediately,
and measures to manage the bleeding
implemented. Serious blood loss may be
managed with volume replacement, including
packed red blood cells.
Dextran should not be used. When
appropriate, fresh frozen plasma and/or
cryoprecipitate may be considered to reverse
the bleeding tendency.
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Anaphylaxis and Other Infusion Reactions : |
Post-marketing reports of hypersensitivity
reactions have included:
►Anaphylaxis (with rare reports of fatal
anaphylaxis)
►Bronchospasm
►Orolingual edema
►Urticaria.
There have also been reports of other
infusion reactions which have included one
or more of the following:
| ►Fever
and/or chills/rigors |
►Hypotension |
| ►Hypoxia |
►Hypertension |
| ►Cyanosis |
►Acidosis |
| ►Dyspnea |
►Back
pain |
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►Tachycardia |
►Vomiting
& Nausea |
Reactions
generally occurred within one hour of
beginning Angikinase infusion. Patients who
exhibit reactions should be closely
monitored and appropriate therapy
instituted.
Infusion reactions generally respond to
discontinuation of the infusion and/or
administration of intravenous
antihistamines, corticosteroids, or
adrenergic agents.
Antipyretics which inhibit platelet function
(aspirin and other non-steroidal
anti-inflammatory agents) may increase the
risk of bleeding and should not be used for
treatment of fever.
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Cholesterol Embolization: |
Cholesterol embolism has
been reported rarely in patients treated
with all types of 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:
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►Myocardial
infarction |
►Cerebral
infarction |
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►Acute
renal failure |
►Spinal
cord infarction |
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►Gangrenous
digits |
►Retinal
artery occlusion |
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►Hypertension |
►Bowel
infarction |
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►Pancreatitis |
►Rhabdomyolysis |
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►livedo reticularis(bluish-black patch of discolored skin) "Purple Toe"
syndrome |
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