Kinlytic Open-Cath Product Monograph

INDICATIONS AND CLINICAL USE

KINLYTIC® OPEN-CATH® (urokinase for catheter clearance) is indicated for the restoration of patency to intravenous catheters, including central venous catheters, obstructed by clotted blood or fibrin.^3,4,5,6,7,8

CONTRAINDICATIONS

This drug is contraindicated in individuals with a history of hypersensitivity to urokinase.

Because thrombolytic therapy increases the risk of bleeding, urokinase is contraindicated in the following situations: active internal bleeding, history of cerebrovascular accident, recent (within two months) intracranial or intraspinal surgery, recent traum a including cardio-pulmonary resuscitation, intracranial neoplasm, arteriovenous malformation, or aneurysm, known bleeding diathesis, severe uncontrolled arterial hypertension and aortic dissection.

There have been no reports however, which would suggest a contraindication for the use of urokinase for intravenous catheter clearance.

WARNINGS

KINLYTIC is produced from cultures of primary human neonatal kidney cells. Products manufactured from human source materials have the potential to transmit infectious agents. Procedures to control such risks can reduce but cannot completely eliminate the risk of transmitting infectious agents. The procedures used in the manufacture of currently available KINLYTIC raise concerns regarding the risk of transmission of infectious agents. In considering this risk, the prescriber should be aware of the following information regarding currently available lots of KINLYTIC:

The kidney cells used in the manufacture of this product were obtained from populations at high risk for a variety of infectious diseases, including tropical diseases. Although efforts were made to screen and test the mothers and neonate donors, the screening and testing measures were inadequate and were not consistently or reliably performed. For example, the screening of potential donors did not include the questioning of the mothers to determine infectious disease status or specific risk factors for infectious diseases, and donors were not tested for hepatitis C virus (HCV) infection. While Abbott has recently instituted a test for HCV in kidney cells used in the manufacture of currently available lots of KINLYTIC, this test has not been validated. A viral inactivation procedure that has been shown to substantially inactivate HIV and HCV in other biological products was used in the production of the currently available product. However, this process has variable effects on other infectious agents and has not been fully validated for viral inactivation of KINLYTIC.

Excessive pressure should be avoided when KINLYTIC® OPEN-CATH® (urokinase for catheter clearance) is injected into the catheter. Such force could cause rupture of the catheter or expulsion of the clot into the circulation. During attempts to determine catheter occlusion, vigorous suction should not be applied due to possible damage to the vascular wall or collapse of soft-wall catheters.

Catheters may be occluded by substances other than fibrin clots, such as precipitates. KINLYTIC® is not effective in such cases and there is the possibility that the substances may be forced into the vascular system.

PRECAUTIONS

Use in Pregnancy: 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.

Use in 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 of KINLYTIC® OPEN-CATH® in children have been established.^9,10,11,12

ADVERSE REACTIONS

The potential exists for adverse reactions to occur as a result of using urokinase for the removal of clot obstruction from I.V. catheters.

The following adverse reactions have been associated with intravenous therapy:

Bleeding: The type of bleeding associated with thrombolytic therapy can be placed into two broad categories: a) superficial or surface bleeding, observed mainly at invaded or disturbed sites (e.g., venous cutdowns, arterial punctures, sites of recent surgical intervention, etc.), and

1. b) internal bleeding, involving e.g., the gastrointestinal tract, genitourinary tract, vagina, or intramuscular, retroperitoneal, or intracerebral sites. Bleeding through Gore-Tex grafts has been reported.

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 epsilon aminocaproic acid (EACA. AMICAR*) 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 ^13,14,15. Relatively mild allergic type reactions, e.g., bronchospasm and skin rash, have been reported rarely. 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.

Febrile episodes have occurred in approximately 2-3% of treated patients. Symptomatic treatment of fever with acetaminophen is usually sufficient to alleviate discomfort. The use of acetaminophen rather than acetyl salicylic acid (ASA) is recommended.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

KINLYTIC® therapy should be discontinued if there is bleeding and fresh whole blood or fresh frozen plasma should be administered; if these fail to control bleeding, the use of epsilon aminocaproic acid (EACA) is suggested although there is not documented evidence for this use in humans.

Mild external bleeding is usually controlled by the application of local pressure.

DOSAGE AND ADMINISTRATION

Solution:

Reconstitute KINLYTIC® OPEN-CATH® according to the recommendations described under "Preparation of Solution". One mL or 1.8 mL of this preparation is to be utilized for each catheter clearing procedure. BECAUSE KINLYTIC® CONTAINS NO PRESERVATIVES, ANY UNUSED PORTION SHOULD BE DISCARDED.

Administration:

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 intravenous tubing or a syringe. This is to prevent air from entering the open catheter. As an added precaution, any central venous catheter not connected to I.V. tubing or a syringe should be clamped or connected to a closed stopcock.

Aseptically disconnect the I.V. tubing connection at the catheter hub and attach an empty 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 tuberculin syringe filled with prepared KINLYTIC® OPEN-CATH® equal to the internal volume of the catheter. Slowly and gently inject the KINLYTIC® solution into the catheter. Care must be taken to avoid rupture of the catheter or expulsion of the intact clot into the circulation. Aseptically remove the tuberculin syringe and connect an empty syringe (e.g., 5 mL) to the catheter. Wait at least 5 minutes before attempting to aspirate the KINLYTIC® solution and residual clot with the empty syringe. Repeat aspiration attempts every 5 minutes. If the catheter is not open within 30 minutes, the catheter may be capped allowing KINLYTIC® to remain in the catheter for 30 to 60 minutes before again attempting to aspirate. A second injection of KINLYTIC® into the catheter may be necessary in resistant cases.

When patency is restored, aspirate 4 to 5 mL of blood to assure removal of all KINLYTIC® solution and clot residue. 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.

PHARMACEUTICAL INFORMATION

Drug Substance

Name: Urokinase for catheter clearance

Description: 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.

Composition

Urokinase is a thrombolytic agent obtained from human kidney cells by tissue culture techniques and is primarily the low molecular weight form. It is a sterile lyophilized white powder. Each mL of reconstituted KINLYTIC® OPEN-CATH® (urokinase for catheter clearance) contains 5000 IU of urokinase activity, 5 mg gelatin, 15 mg mannitol, 1.7 mg sodium chloride and 4.6 mg monobasic sodium phosphate anhydrous.

Sodium hydroxide and/or hydrochloric acid have been added prior to lyophilization for pH adjustment.

Stability and Storage Recommendations

Store powder below 25°C. Avoid freezing.

Preparation of Solution: DIL-U-VIAL*:

1. 1. Remove protective cap. Turn plunger-stopper a quarter turn and press to force diluent into lower chamber.
2. 2. Roll and tilt to effect solution. Do not shake. Use only a clear, colorless solution.
3. 3. Sterilize top of stopper with a suitable germicide.
4. 4. Insert needle through the center of stopper until tip is barely visible. Withdraw dose. No further dilution is required.

It is recommended that vigorous shaking be avoided during reconstitution; roll and tilt to enhance reconstitution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Stability of solutions

Discard any unused reconstituted solution.

AVAILABILITY OF DOSAGE FORMS

KINLYTIC® OPEN-CATH® (urokinase for catheter clearance) is a sterile lyophilized powder supplied in 5,000 IU DIL-U-VIAL* (1 mL when mixed with diluent in upper chamber) and 9,000 IU DIL-U-VIAL* (1.8 mL when mixed with diluent in upper chamber) providing 5,000 IU of urokinase activity per mL.

PHARMACOLOGY

Animal Pharmacology

Urokinase (tissue culture) was administered intravenously to dogs at a dose of 22,000 IU/kg and produced a decrease in plasma plasminogen for a period of 15 to 360 minutes following injection. The prothrombin and thrombin times were prolonged only at the 15-minute measurement, and the slope of the platelet aggregation curve was decreased at this time also. In rabbits, the only significant effects observed following the intravenous administration of urokinase were a decrease in the plasminogen level 15 minutes after a dose of 4,400 IU/kg, and a reduction in the prothrombin time 60 minutes after a dose of 22,000 IU/kg.

Cardiovascular Studies

Urokinase was administered intravenously to anesthetized dogs, monkeys and rabbits (1/sex/dose/species) at doses of 4,400 or 22,000 IU/kg. In dogs and monkeys no effect on arterial blood pressure, heart rate, ECG or respiratory rate were observed. One rabbit following a dose of 4,400 IU/kg exhibited a decrease in mean arterial blood pressure, the others were not affected. In unanesthetized dogs, urokinase administered intravenously at 22,000 IU/kg produced a marginal increase in blood pressure. No consistent, significant changes in heart rate or respiration rate were

observed.

Coronary arterial flow measurements in anesthetized dogs (4/sex/dose) following a 10,000 IU/kg bolus administered intravenously followed by infusion of 10,000 IU/kg per hour for 4 hours causesno change in the left circumflex coronary blood flow, although the rate of change of heart rate was significantly greater than in control animals. The pharmacological significance of this observation is not clear.

TOXICOLOGY

Acute Toxicity Studies

Urokinase (tissue culture source) was administered intravenously as a single dose to mice, rats, rabbits, dogs and monkeys.

No fatalities or behavioral effects were noted in doses of 108,125 IU/kg in mice; 86,500 IU/kg in rats and rabbits; and 4,400, 22,000 and 44,000 IU/kg in monkeys.

Dogs receiving 4,400, 22,000 and 43,250 IU/kg exhibited slight emesis. At 43,250 IU/kg a slight decrease in motor activity was noted.

Chronic Toxicity Studies:

Rats were treated by the intravenous route for 7 days with 105,600 and 528,000 IU/kg/day of urokinase. Body weights, food consumption and behavioral and physical signs of treated animals were similar to those for rats from the control group. No drug-related clinical or anatomic pathologic changes were observed.

Dogs were treated by the intravenous route for 7 days with 105,600 and 528,000 IU/kg/day. At both dosages emesis and occasional excess salivation, with transiently decreased plasma fibrinogen levels and increased prothrombin times, were seen. RBC, hemoglobin and hematocrit values were depressed with normal MCH and MCHC. This was consistent with a picture of mild, chronic hemorrhage and returned to normal following cessation of drug. No pathological changes were found in the lungs or other organs of treated dogs.

Carcinogenicity

Adequate data is not available on the long-term potential for carcinogenicity of KINLYTIC® in animals or humans.

Mutagenicity

In vivo mutagenicity tests including host-mediated assay, cytogenetics, and dominant lethal assay

failed to show a mutagenic potential for KINLYTIC®.

REFERENCES

1. 1.

   Bang NU. Physiology and biochemistry of fibrinolysis in thrombosis and bleeding

   disorders. Bang NU, Beller FK, Deutsch E, Mammen EF, eds. New York Academic Press (New York) 1971;292-327.

2. 2. McNicol GP. The fibrinolytic enzyme system. Postgrad Med J 1973; (Suppl. 5)49:10-12.
3. 3. Hurtubise MR, Bottino JC, Lawson M, McCredie KB. Restoring patency of occluded central venous catheters. Arch Surg 1980;115:212-213.
4. 4. Glynn MFX, Langer B, Jeejeeboy KN. Therapy for thrombotic occlusion of long-term intravenous alimentation catheters. JPEN 1980;4:387-390.
5. 5. Lawson M, Bottino JC, Hurtubise MR, McCredie KB. The use of urokinase to restore the patency of occluded central venous catheters. Am J Intravenous Ther Clin Nutr 1982;9:29-30,32.
6. 6. Monturo CA, Dickerson RN, Mullen JL. Efficacy of thrombolytic therapy for occlusion of long-term catheters. JPEN 1990;14:312-314.
7. 7. Brown LH, W antroba I, Simonson G. Restablishing patency in an occluded central venous access device. Crit Care Nurse 1989;9:114-121.
8. 8. Bjeletich J. Declotting central venous catheters with urokinase in the home by nurse clinicians. N England Critical Care 1987;10:428-430.
9. 9. Kellam B, Fraze D, Kanarek KS. Clot lysis for thrombosed central venous catheters in pediatric patients. J Perinatol 1987;7:242-244.
10. 10. Wachs T. Urokinase administration in pediatric patients with occluded central venous catheters. J Intrav Nurs 1990;13:100-102.
11. 11. Bagnall HA, Gomperts E, Atkinson JB. Continuous infusion of low-dose urokinase in the treatment of central venous catheter thrombosis in infants and children. Pediatrics 1989;83:963-966.
12. 12. Winthrop AL, Wesson DE. Urokinase in the treatment of occluded central venous catheters in children. J Pediatr Surg 1984;19:536-538.
13. 13. Genton E, Claman HN. Urokinase antigenicity in man. Clin Res 1966; 14:435.
14. 14. Genton E, Claman HN. Urokinase: antigen studies in patients following thrombolytic therapy. J Lab Clin Med 1970; 75:619-621.
15. 15. de Haen P. Drugs on the horizon. New York State Med J 1970;70: 177-182