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UROKINASE
(Angikinase®)    

Description:
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.

Clinical pharmacology:

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.

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.

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.

Contraindications:
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

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.

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
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.

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:
Myocardial infarction Cerebral infarction
Acute renal failure Spinal cord infarction
Gangrenous digits Retinal artery occlusion
Hypertension Bowel infarction
Pancreatitis Rhabdomyolysis
livedo reticularis (bluish-black patch of discolored skin) "Purple Toe" syndrome

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