UROKINASE
DESCRIPTION:
UNI-KINASE (UROKINASE FOR INJECTION) SHOULD BE USED IN HOSPITALS WHERE THE
RECOMMENDED DIAGNOSTIC AND MONITORING TECHNIQUES ARE AVAILABLE. THROMBOLYTIC
THERAPY SHOULD BE CONSIDERED IN ALL SITUATIONS WHERE THE BENEFITS TO BE ACHIEVED
OUTWEIGH THE RISK OF POTENTIALLY SERIOUS HEMORRHAGE. WHEN INTERNAL BLEEDING DOES
OCCUR, IT MAY BE MORE DIFFICULT TO MANAGE THAN THAT WHICH OCCURS WITH
CONVENTIONAL ANTICOAGULANT THERAPY.
UROKINASE TREATMENT SHOULD BE INSTITUTED AS SOON AS POSSIBLE AFTER ONSET OF
PULMONARY EMBOLISM, PREFERABLY NO LATER THAN SEVEN DAYS AFTER ONSET. ANY DELAY
IN INSTITUTING LYTIC THERAPY TO EVALUATE THE EFFECT OF HEPARIN DECREASES THE
POTENTIAL FOR OPTIMAL EFFICACY.(REF. 1)
WHEN UROKINASE IS USED FOR TREATMENT OF CORONARY ARTERY THROMBOSIS ASSOCIATED
WITH EVOLVING TRANSMURAL MYOCARDIAL INFARCTION, THERAPY SHOULD BE INSTITUTED
WITHIN SIX HOURS OF SYMPTOM ONSET.
Urokinase is an enzyme (protein) produced by the kidney, and found in the urine.
There are two forms of urokinase differing in molecular weight but having
similar clinical effects. UNI-KINASE (urokinase for injection) is a thrombolytic
agent obtained from human kidney cells by tissue culture techniques and is
primarily the low molecular weight form. It is supplied as a sterile lyophilized
white powder containing mannitol (25 mg/vial), Albumin (Human) (250 mg/vial),
and sodium chloride (50 mg/vial).
Thin translucent filaments may occasionally occur in reconstituted UNI-KINASE
vials, but do not indicate any decrease in potency of this product. No clinical
problems have been associated with these filaments. See "Dosage and
Administration" section.
Following reconstitution with 5 mL of Sterile Water for Injection, USP, it is a
clear, slightly straw-colored solution; each mL contains 50,000 IU of urokinase
activity, 0.5% mannitol, 5% Albumin (Human), and 1% sodium chloride. The pH is
adjusted with sodium hydroxide and/or hydrochloric acid prior to lyophilization.
UNI-KINASE is for intravenous and intracoronary infusion only.
ACTIONS/CLINICAL PHARMACOLOGY:
Urokinase acts on the endogenous fibrinolytic system. It converts plasminogen to
the enzyme plasmin. Plasmin degrades fibrin clots as well as fibrinogen and
other plasma proteins.
Intravenous infusion of urokinase in doses recommended for lysis of pulmonary
embolism is followed by increased fibrinolytic activity. 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
(ogen) degradation products may persist for 12-24 hours. (REF.2,3) There is a
lack of correlation between embolus resolution and changes in coagulation and
fibrinolytic assay results.
Information is incomplete about the pharmacokinetic properties in man. Urokinase
administered by intravenous infusion is cleared rapidly by the liver. The serum
half-life in man is 20 minutes or less. Patients with impaired liver function
(e.g., cirrhosis) would be expected to show a prolongation in half-life. Small
fractions of an administered dose are excreted in bile and urine.
INDICATIONS AND USAGE:
PULMONARY EMBOLISM
UNI-KINASE (urokinase for injection) 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 via an upper extremity vein, or non-invasive procedures such as lung
scanning.
Angiographic and hemodynamic measurements demonstrate a more rapid improvement
with lytic therapy than with heparin therapy. (REF.4-8)
CORONARY ARTERY THROMBOSIS
UNI-KINASE has been reported to lyse acute thrombi obstructing coronary
arteries, associated with evolving transmural myocardial infarction. (REF. 9)
The majority of patients who received UNI-KINASE by intracoronary infusion
within six hours following onset of symptoms showed recanalization of the
involved vessel.
IT HAS NOT BEEN ESTABLISHED THAT INTRACORONARY ADMINISTRATION OF UNI-KINASE
DURING EVOLVING TRANSMURAL MYOCARDIAL INFARCTION RESULTS IN SALVAGE OF
MYOCARDIAL TISSUE, NOR THAT IT REDUCES MORTALITY. THE PATIENTS WHO MIGHT BENEFIT
FROM THIS THERAPY CANNOT BE DEFINED.
I.V. CATHETER CLEARANCE
UNI-KINASE is indicated for the restoration of patency to intravenous catheters,
including central venous catheters, obstructed by clotted blood or fibrin. (REF.
l0,ll) (See separate section at end of insert concerning I.V. catheter clearance
for information regarding warnings, precautions, adverse reactions, and dosage
and administration.)
CONTRAINDICATIONS:
Because thrombolytic therapy increases the risk of bleeding, urokinase is
contraindicated in the following situations: (See WARNINGS.)
-- Active internal bleeding
-- History of cerebrovascular accident
-- Recent (within two months) intracranial or intraspinal surgery
-- Recent trauma including cardiopulmonary resuscitation
-- Intracranial neoplasm, arteriovenous malformation, or aneurysm
-- Known bleeding diathesis
-- Severe uncontrolled arterial hypertension
WARNINGS:
BLEEDING
THE AIM OF UROKINASE IS THE PRODUCTION OF SUFFICIENT AMOUNTS OF PLASMIN FOR
LYSIS OF INTRAVASCULAR DEPOSITS OF FIBRIN; HOWEVER, FIBRIN DEPOSITS WHICH
PROVIDE HEMOSTASIS, FOR EXAMPLE, AT SITES OF NEEDLE PUNCTURE, WILL ALSO LYSE,
AND BLEEDING FROM SUCH SITES MAY OCCUR.
Intramuscular injections and nonessential handling of the patient must be
avoided during treatment with urokinase. Venipunctures should be performed
carefully and as infrequently as possible.
Should an arterial puncture be necessary (except for intracoronary
administration), upper extremity vessels are preferable. 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 risks of therapy 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, e.g., mitral stenosis with atrial
fibrillation
-- Subacute bacterial endocarditis
-- Hemostatic defects including those secondary to severe hepatic or renal
disease
-- Pregnancy
-- Cerebrovascular 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
Should serious spontaneous bleeding (not controllable by local pressure) occur,
the infusion of urokinase should be terminated immediately, and treatment
instituted as described under ADVERSE REACTIONS.
USE OF ANTICOAGULANTS
Concurrent use of anticoagulants with intravenous administration of UNI-KINASE
is not recommended. However, concurrent use of heparin may be required during
intracoronary administration of UNI-KINASE. A clinical study (REF. 9) with
concurrent use of heparin and UNI-KINASE during intracoronary administration has
demonstrated no tendency toward increased bleeding that would not be
attributable to the procedure or UNI-KINASE alone. Nevertheless, careful
monitoring for excessive bleeding is advised.
ARRHYTHMIAS
Rapid lysis of coronary thrombi has been reported occasionally to cause atrial
or ventricular dysrhythmias as a result of reperfusion requiring immediate
treatment. Careful monitoring for arrhythmias should be maintained during and
immediately following intracoronary administration of UNI-KINASE.
PRECAUTIONS:
LABORATORY TESTS
Before commencing thrombolytic therapy, obtain a hematocrit, platelet count, and
a thrombin time (TT), activated partial thromboplastin time (APTT), or
prothrombin time (PT). If heparin has been given, it should be discontinued
unless it is to be used in conjunction with UNI-KINASE for intracoronary
administration. TT or APTT should be less than twice the normal control value
before thrombolytic therapy is started.
During the infusion, coagulation tests and/or measures of fibrinolytic activity
may be performed if desired. Results do not, however, reliably predict either
efficacy or a risk of bleeding. The clinical response should be observed
frequently, and vital signs, i.e., pulse, temperature, respiratory rate and
blood pressure, should be checked at least every four hours. The blood pressure
should not be taken in the lower extremities to avoid dislodgment of possible
deep vein thrombi.
Following the intravenous infusion, Before (re)instituting Heparin, the TT or
APTT should be less than twice the upper limits of normal. Following
intracoronary infusion of UNI-KINASE, blood coagulation parameters should be
determined and heparin therapy continued as appropriate.
DRUG INTERACTIONS
The interaction of urokinase with other drugs has not been studied. Drugs that
alter platelet function should not be used. Common examples are: aspirin,
indomethacin and phenylbutazone.
Although a bolus dose of heparin is recommended prior to intracoronary use of
urokinase, oral anticoagulants or heparin should not be given concurrently with
large doses of urokinase such as those used for pulmonary embolism. Concomitant
use of intravenous urokinase and oral anticoagulants or heparin may increase the
risk of hemorrhage. (See "WARNINGS" section.)
CARCINOGENICITY
Adequate data are not available on the long-term potential for carcinogenicity
in animals or humans.
PREGNANCY
Pregnancy category B. Reproduction studies have been performed in mice and rats
at doses up to 1,000 times the human dose and have revealed no evidence of
impaired fertility or harm to the fetus due to urokinase. There are, however, no
adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed.
NURSING MOTHERS
It is not known whether this drug is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when urokinase is
administered to a nursing woman.
PEDIATRIC USE
Safety and effectiveness in children have not been established.
DRUG INTERACTIONS:
The interaction of urokinase with other drugs has not been studied. Drugs that
alter platelet function should not be used. Common examples are: aspirin,
indomethacin and phenylbutazone.
Although a bolus dose of heparin is recommended prior to intracoronary use of
urokinase, oral anticoagulants or heparin should not be given concurrently with
large doses of urokinase such as those used for pulmonary embolism. Concomitant
use of intravenous urokinase and oral anticoagulants or heparin may increase the
risk of hemorrhage. (See "WARNINGS" section.)
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN ASSOCIATED WITH INTRAVENOUS THERAPY
BUT MAY ALSO OCCUR WITH INTRACORONARY ARTERY INFUSION.
BLEEDING
The type of bleeding associated with thrombolytic therapy can be placed into two
broad categories:
-- Superficial or surface bleeding, observed mainly at invaded or disturbed
sites (e.g., venous cutdowns, arterial punctures, sites of recent surgical
intervention, etc.).
-- Internal bleeding, involving, e.g., the gastrointestinal tract, genitourinary
tract, vagina, or intramuscular, retroperitoneal, or intracranial sites.
Several fatalities due to intracranial or retroperitoneal hemorrhage have
occurred during thrombolytic therapy.
Should serious bleeding occur, urokinase infusion should be discontinued and, if
necessary, blood loss and reversal of the bleeding tendency can be effectively
managed with whole blood (fresh blood preferable), packed red blood cells and
cryoprecipitate or fresh frozen plasma. Dextran should not be used. Although the
use of aminocaproic acid (ACA, AMICAR(R)) in humans as an antidote for urokinase
has not been documented, it may be considered in an emergency situation.
ALLERGIC REACTIONS
In Vitro tests with urokinase, as well as intradermal tests in humans, gave no
evidence of induced antibody formation. Relatively mild allergic type reactions,
e.g., bronchospasm and skin rash, have been reported. When such reactions occur,
they usually respond to conventional therapy. In addition, rare cases of
anaphylaxis have been reported.
MISCELLANEOUS
Fever and chills, including shaking chills (rigors), nausea and/or vomiting,
transient hypotension or hypertension, dyspnea, tachycardia, cyanosis, back
pain, hypoxemia, and acidosis have been reported together and separately. Rare
cases of myocardial infarction have also been reported. A cause and effect
relationship has not been established.
Aspirin is not recommended for treatment of fever.
DOSAGE AND ADMINISTRATION:
UNI-KINASE IS INTENDED FOR INTRAVENOUS AND INTRACORONARY INFUSION ONLY.
A. PULMONARY EMBOLISM:
PREPARATION
Reconstitute UNI-KINASE (urokinase for injection) by aseptically adding 5 mL of
Sterile Water for Injection, USP, to the vial. (It is important that UNI-KINASE
be reconstituted Only with Sterile Water for Injection, USP, Without
preservatives. Bacteriostatic Water for Injection should Not be used.) Each vial
should be visually inspected for discoloration (slightly straw- colored
solution) and for the presence of particulate material. Highly colored solutions
should not be used. Because UNI-KINASE contains no preservatives, it should not
be reconstituted until immediately before using. Any unused portion of the
reconstituted material should be discarded.
To minimize formation of filaments, avoid shaking the vial during
reconstitution. Roll and tilt the vial to enhance reconstitution. The solution
may be terminally filtered, e.g., through a 0.45 micron or smaller cellulose
membrane filter. No other medication should be added to this solution.
Reconstituted UNI-KINASE is diluted with 0.9% Sodium Chloride Injection, USP or
5% Dextrose Injection, USP, prior to intravenous infusion. (See Table I, DOSE
PREPARATION-PULMONARY EMBOLISM.)
ADMINISTRATION
Administer UNI-KINASE (urokinase for injection) by means of a constant infusion
pump that is capable of delivering a total volume of 195 mL. The following table
may be used as an aid in the preparation of UNI-KINASE (urokinase for injection)
for administration.
TABLE I
DOSE PREPARATION-PULMONARY EMBOLISM
Number Volume of
Total Vials UNI-KINASE
Dose* UNI-KINASE After Volume of Final
Weight Urokinase (urokinase Reconstitution Diluent Volume
(pounds) (IU) for injection) (mL)** + (mL) = (mL)
----------------------------------------------------------------------------
81-90 2,250,000 9 45 150 195
91-100 2,500,000 10 50 145 195
101-110 2,750,000 11 55 140 195
111-120 3,000,000 12 60 135 195
121-130 3,250,000 13 65 130 195
131-140 3,500,000 14 70 125 195
141-150 3,750,000 15 75 120 195
151-160 4,000,000 16 80 115 195
161-170 4,250,000 17 85 110 195
171-180 4,500,000 18 90 105 195
181-190 4,750,000 19 95 100 195
191-200 5,000,000 20 100 95 195
201-210 5,250,000 21 105 90 195
211-220 5,500,000 22 110 85 195
221-230 5,750,000 23 115 80 195
231-240 6,000,000 24 120 75 195
241-250 6,250,000 25 125 70 195
----------------------------------------------------------------------------
Priming Dose Dose for 12-Hour Period
Infusion Rate: ------------- -------------------
15 mL/10 min*/* 15 mL/hr for 12 hrs
----------------------------------------------------------------------------
*Priming dose +dose administered during 12-hour period.
**After addition of 5 mL of Sterile Water for Injection, USP, per vial. (See
Preparation.)
*/*Pump rate = 90 mL/hr
A priming dose of 2,000 IU/lb (4,400 IU/kg) of UNI-KINASE is given as the
UNI-KINASE-0.9% Sodium Chloride Injection or 5% Dextrose Injection admixture at
a rate of 90 mL/hour over a period of 10 minutes. This is followed by a
continuous infusion of 2,000 IU/lb/hr (4,400 IU/kg/hr) of UNI-KINASE at a rate
of 15 mL/hour for 12 hours. Since some UNI-KINASE admixture will remain in the
tubing at the end of an infusion pump delivery cycle, the following flush
procedure should be performed to insure that the total dose of UNI-KINASE is
administered. A solution of 0.9% Sodium Chloride Injection or 5% Dextrose
Injection approximately equal in amount to the volume of the tubing in the
infusion set should be administered via the pump to flush the UNI-KINASE
admixture from the entire length of the infusion set. The pump should be set to
administer the flush solution at the continuous infusion rate of 15 mL/hour.
ANTICOAGULATION AFTER TERMINATING
UROKINASE TREATMENT
At the end of urokinase therapy, treatment with heparin by continuous
intravenous infusion is recommended to prevent recurrent thrombosis. Heparin
treatment, without a loading dose, should not begin until the thrombin time has
decreased to Less Than Twice the normal control value (approximately 3 to 4
hours after completion of the infusion). See manufacturer's prescribing
information for proper use of heparin. This should then be followed by oral
anticoagulants in the conventional manner.
B. LYSIS OF CORONARY ARTERY THROMBI: (REF.9)
PREPARATION
Reconstitute three (3) 250,000 IU vials of UNI-KINASE by aseptically adding 5 mL
of Sterile Water for Injection, USP, to each vial. (It is important that
UNI-KINASE be reconstituted Only with Sterile Water for Injection, USP, without
preservatives. Bacteriostatic Water for Injection should Not be used.) Each vial
should be visually inspected for discoloration (slightly straw- colored
solution) and for the presence of particulate material. Highly colored solutions
should not be used. Because UNI-KINASE contains no preservatives, it should not
be reconstituted until immediately before using. Any unused portion of the
reconstituted material should be discarded.
To minimize formation of filaments, avoid shaking the vial during
reconstitution. Roll and tilt the vial to enhance reconstitution. The solution
may be terminally filtered, e.g., through a 0.45 micron or smaller cellulose
membrane filter.
Add the contents of the three (3) reconstituted UNI-KINASE vials to 500 mL of 5%
Dextrose Injection, USP. The resulting solution admixture will have a
concentration of approximately 1500 IU per mL. No other medication should be
added to the solution.
The admixture should be administered immediately as described under
Administration. Any solution remaining after administration should be discarded.
NOTE: Adsorption of drug from dilute protein solutions to various materials has
been reported in the literature. Therefore, the directions for Preparation and
Administration must be followed to assure that significant drug loss does not
occur.
ADMINISTRATION
Prior to the infusion of UNI-KINASE, a bolus dose of heparin ranging from 2500
to 10,000 units should be administered intravenously. Prior heparin
administration should be considered when calculating the heparin dose for this
procedure. Following the bolus dose of heparin, the prepared UNI-KINASE solution
should be infused into the occluded artery at a rate of 4 mL per minute (6000 IU
per minute) for periods up to 2 hours. In a clinical study, the average total
dose of UNI-KINASE utilized for lysis of coronary artery thrombi was 500,000
IU.(REF. 9)
To determine response to UNI-KINASE therapy, periodic angiography during the
infusion is recommended. It is suggested that the angiography be repeated at
approximately 15 minute intervals. UNI-KINASE therapy should be continued until
the artery is maximally opened, usually 15 to 30 minutes after the initial
opening. Following the infusion, coagulation parameters should be determined. It
is advisable to continue heparin therapy after the artery is opened by
UNI-KINASE.
When UNI-KINASE was administered selectively into thrombosed coronary arteries
via coronary catheter within 6 hours following onset of symptoms of acute
transmural myocardial infarction, 60% of the occlusions were opened. (REF. 9)
I.V. CATHETER CLEARANCE
Warnings
Excessive pressure should be avoided when UNI-KINASE is injected into the
catheter. Such force could cause rupture of the catheter or expulsion of the
clot into the circulation.
Precautions
Catheters may be occluded by substances other than blood products, such as drug
precipitate. UNI-KINASE is not effective in such a case, and there is the
possibility that the precipitate may be forced into the vascular system.
Adverse Reactions
Although there have been no adverse reactions reported as a result of using
UNI-KINASE for the removal of clot obstruction from I.V. catheters, the
possibility of reactions should nevertheless be considered.
Dosage And Administration
PREPARATION: Reconstitute UNI-KINASE (urokinase for injection) by aseptically
adding 5 mL of Sterile Water for Injection, USP, to the vial. (It is important
that UNI-KINASE be reconstituted Only with Sterile Water for Injection, USP,
Without preservatives. Bacteriostatic Water for Injection should Not be used.)
Add 1 mL of the reconstituted drug to 9 mL Sterile Water for Injection, USP, to
make a final dilution equivalent to 5,000 IU/mL. One mL of this preparation is
to be utilized for each catheter clearing procedure. BECAUSE UNI-KINASE CONTAINS
NO PRESERVATIVES, IT SHOULD NOT BE RECONSTITUTED UNTIL IMMEDIATELY BEFORE USING.
ADMINISTRATION: NOTE: When the following procedure is used to clear a central
venous catheter, the patient should be instructed to exhale and hold his breath
any time the catheter is not connected to I.V. tubing or a syringe. This is to
prevent air from entering the open catheter.
Aseptically disconnect the I.V. tubing connection at the catheter hub and attach
a 10 mL syringe. Determine occlusion of the catheter by Gently attempting to
aspirate blood from the catheter with the 10 mL syringe. If aspiration is not
possible, remove the 10 mL syringe and attach a 1mL tuberculin syringe filled
with prepared UNI-KINASE to the catheter. Slowly and gently inject an amount of
UNI-KINASE equal to the volume of the catheter. Aseptically remove the
tuberculin syringe and connect a 5 mL syringe to the catheter. Wait at least 5
minutes before attempting to aspirate the drug and residual clot with the 5 mL
syringe. Repeat aspiration attempts every 5 minutes. If the catheter is not open
within 30 minutes, the catheter may be capped allowing UNI-KINASE to remain in
the catheter for 30 to 60 minutes before again attempting to aspirate. A second
injection of UNI-KINASE may be necessary in resistant cases.
When patency is restored, aspirate 4 to 5 mL of blood to assure removal of all
drug and clot residual. Remove the blood-filled syringe and replace it with a 10
mL syringe filled with 0.9% Sodium Chloride Injection, USP. The catheter should
then be gently irrigated with this solution to assure patency of the catheter.
After the catheter has been irrigated, remove the 10 mL syringe and aseptically
reconnect sterile I.V. tubing to the catheter hub.
REFERENCES:
1. Sherry S, et al. Thrombolytic therapy in thrombosis: A National Institutes of
Health consensus development conference. Ann Intern Med. 1980;93:141-144.
2. Bang NU. Physiology and biochemistry of fibrinolysis. In: Bang NU, Beller FK,
Deutsch E, Mammen EF, eds. Thrombosis And Bleeding Disorders. New York, NY:
Academic Press; 1971:292-327.
3. McNicol GP. The fibrinolytic enzyme system. Postgrad Med J. August 1973;49
(suppl 5):10-12.
4. Sasahara AA, Hyers TM, Cole CM, et al. The urokinase pulmonary embolism
trial. Circulation. 1973;47 (suppl 2):1-108.
5. Urokinase pulmonary embolism trial study group: Urokinase-streptokinase
embolism trial. JAMA. 1974;229: 1606-1613.
6. Sasahara AA, Bell WR, Simon TL, et al. The Phase II urokinase-streptokinase
pulmonary embolism trial, Thrombos Diathes Haemorrh (Stuttg). 1975;33:464-476.
7. Bell WR. Thrombolytic therapy: A comparison between urokinase and
streptokinase, Sem Thromb Hemost. 1975;2:1-13.
8. Fratantoni JC, Ness P, Simon TL. Thrombolytic therapy: Current status. N Eng
J Med. 1975;293:1073-1078.
9. Tennant SN, Campbell WB, et al. Intracoronary thrombolysis in acute
myocardial infarction: Comparison of the efficacy of urokinase to streptokinase.
Circulation. 1984;69:756-760.
10. Lawson M, et al. The use of urokinase to restore the patency of occluded
central venous catheters. Am J Intravenous Therapy And Clinical Nutrition.
1982;9:29-32.
11. Glynn MFX, et al. Therapy for thrombotic occlusion of long-term intravenous
alimentation catheters. Journal Of Parenteral And Enteral Nutrition. 1980;4:387-
390.
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