Prescription Drugs

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. Kinlytic™ (urokinase injection) is the low molecular weight form. Kinlytic™ (urokinase injection) 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.1 Thus, reduced urokinase clearance in patients with hepatic impairment might be expected. Intravenous infusion of Kinlytic™ (urokinase injection) 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.2 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, and hemodynamic measurements within 24 hours than did treatment with heparin. Lung perfusion scanning showed no significant treatment-associated difference by day 7.3 Information based on patients treated with fibrinolytics 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.4

Kinlytic™ (urokinase) for Injection DESCRIPTION Kinlytic™ (urokinase for injection) is a thrombolytic agent obtained from human neonatal kidney cells grown in tissue culture. The principal active ingredient of Kinlytic™ 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. Kinlytic™ (urokinase injection) is supplied as a sterile lyophilized white powder containing 250,000 international units urokinase per vial, mannitol (25 mg/vial), Albumin (Human) (250 mg/vial), and sodium chloride (50 mg/vial). Following reconstitution with 5 mL of Sterile Water for Injection, USP, Kinlytic™ (urokinase injection) is a clear, slightly straw-colored solution; each mL contains 50,000 international units of urokinase activity, 0.5% mannitol, 5% Albumin (Human), and 1% sodium chloride (pH range 6.0 to 7.5). Thin translucent filaments may occasionally occur in reconstituted Kinlytic™ vials (see DOSAGE AND ADMINISTRATION). Kinlytic™ (urokinase injection) is for intravenous infusion only. Kinlytic™ (urokinase injection) is produced from human neonatal kidney cells (see WARNINGS). No fetal tissue is used in the production of Kinlytic™ (urokinase injection) . Kidney donations are obtained exclusively in the United States from neonates (birth to 28 days) for whom death has not been attributed to infectious causes and that have exhibited no evidence of an infectious disease based in part, on an examination of the maternal and neonatal donor medical records. The maternal and neonatal donor screening process also identifies specific risk factors for known infectious diseases and includes testing of sera for HBV, HCV, HIV-1, HIV-2, HTLV-I, HTLV-II, CMV, and EBV. Donors with sera testing positive or associated with other risk factors are excluded. During the manufacturing process, cells are tested at multiple stages for the presence of viruses using in vitro and in vivo tests that are capable of detecting a wide range of viruses. Cells are also screened for HPV using a DNA detection-based test and for reovirus using a polymerase chain reaction-based test. The manufacturing process used for this product has been validated in laboratory studies to inactivate and/or remove a diverse panel of spiked model enveloped and nonenveloped viruses, and includes purification steps and a heat treatment step (10 hours at 60°C in 2% sodium chloride). A single vial of Kinlytic™ contains urokinase produced using cells derived from one or two donors.

INDICATIONS Kinlytic™ (urokinase 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 or noninvasive procedures such as lung scanning. DOSAGE AND ADMINISTRATION Kinlytic™ (urokinase injection) IS INTENDED FOR INTRAVENOUS INFUSION ONLY. Kinlytic™ (urokinase injection) treatment should be instituted soon after onset of pulmonary embolism. Delay in instituting therapy may decrease the potential for optimal efficacy (see CLINICAL PHARMACOLOGY). Dosing Administer Kinlytic™ (urokinase injection) with a programmable infusion pump only. Change the infusion rate immediately after completion of the loading dose. The loading dose of 4,400 international units per kilogram of Kinlytic™ (urokinase injection) is given at a rate of 90 mL per hour over a period of 10 minutes. This is followed with a continuous infusion of 4,400 international units per kilogram per hour at a rate of 15 mL for 12 hours. Administration of Kinlytic™ (urokinase injection) may be repeated as necessary. A dosing and preparation chart for patients who weigh 37 to 114 kilograms (81 to 250 pounds) is provided as a guide in the Preparation Section that follows below. If the patient is outside of these weights, calculate with dosing information provided above. Preparation Administer Kinlytic™ (urokinase injection) with a programmable infusion pump only. Change the infusion rate immediately after completion of the loading dose to the maintenance dose rate. The Dose Preparation-Pulmonary Embolism chart is a guidance tool/aid provided for the convenience of the practitioner and may not be complete for every patient. Kinlytic™ (urokinase injection) contains no preservatives. Do not reconstitute until immediately before use. Any unused portion of the reconstituted material should be discarded. Reconstitute Kinlytic™ (urokinase injection) by aseptically adding 5 mL of Sterile Water for Injection, USP, without preservatives, to the vial. DO NOT USE Bacteriostatic Water for Injection, USP. After reconstitution, the drug product will contain 50,000 international units per milliliter. After reconstituting, visually inspect each vial of Kinlytic™ (urokinase injection) for discoloration and for the presence of particulate material. The solution should be pale and straw-colored; highly colored solutions should not be used. Thin translucent filaments may occasionally occur in reconstituted Kinlytic™ (urokinase injection) vials, but do not indicate any decrease in potency of this product. 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, for example, through a 0.45 micron or smaller cellulose membrane filter. No other medication should be added to this solution. Prior to infusing, dilute the reconstituted Kinlytic™ (urokinase injection) with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The following Dose Preparation-Pulmonary Embolism chart may be used as an aid in the preparation of Kinlytic™ (urokinase injection) for administration. For administration directions, see next section. Dose Preparation-Pulmonary Embolism For administration, use a programmable infusion pump only. After ten minutes, change the initial loading dose rate to the maintenance dose rate. Patient Weight [kilograms (pounds)] Total Dosea (Loading and Continuous Infusion) Number of Kinlytic™ Vials Needed for Total Dose Total Volume of Sterile Water for Injection needed for Reconstitution of Kinlytic™ (urokinase injection) Vialsb + Volume of 0.9% Sodium Chloride or 5% Dextrose Injection, USP for Infusion (mL) = Final Volume (mL) for Loading and Continuous Infusion 37-40 (81-90) 2,250,000 9 45 150 195 41-45 (91-100) 2,500,000 10 50 145 195 46-50 (101-110) 2,750,000 11 55 140 195 51-54(111-120) 3,000,000 12 60 135 195 55-59(121-130) 3,250,000 13 65 130 195 60-64 (131-140) 3,500,000 14 70 125 195 65-68(141-150) 3,750,000 15 75 120 195 69-73 (151-160) 4,000,000 16 80 115 195 74-77 (161-170) 4,250,000 17 85 110 195 78-82 (171-180) 4,500,000 18 90 105 195 83-86 (181-190) 4,750,000 19 95 100 195 87-91 (191-200) 5,000,000 20 100 95 195 92-95 (201-210) 5,250,000 21 105 90 195 96-100 (211-220) 5,500,000 22 110 85 195 101-104 (221-230) 5,750,000 23 115 80 195 105-109 (231-240) 6,000,000 24 120 75 195 110-114 (241-250) 6,250,000 25 125 70 195 aLoading Dose + dose administered during 12-hour period. bEach vial is reconstituted with 5 mL of Sterile Water for Injection, USP, without preservatives. (See Preparation.) Administration Kinlytic™ (urokinase injection) is administered using a programmable infusion pump. Change the infusion rate immediately after completion of the loading dose. The loading dose of Kinlytic™ (urokinase injection) admixture (4,400 international units per kilogram) should be delivered at a rate of 90 mL per hour over a period of 10 minutes. This is followed by a continuous infusion of 4,400 international units per kilogram per hour of Kinlytic™ (urokinase injection) at a rate of 15 mL per hour for 12 hours. Since some of the Kinlytic™ (urokinase injection) 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 Kinlytic™ (urokinase injection) is administered. A solution of 0.9% Sodi um Chloride Injection, USP, or 5% Dextrose Injection, USP, approximately equal in amount to the volume of the tubing in the infusion set should be administered via the pump to flush the Kinlytic™ (urokinase injection) admixture from the entire length of the infusion set. The pump should be set to administer the flush solution at the continuous rate of 15 mL per hour. No other drug products/solutions may be administered in the same line with Kinlytic™ (urokinase injection) . Anticoagulation After Terminating Kinlytic™ (urokinase injection) Treatment After infusing Kinlytic™ (urokinase injection) , anticoagulation treatment is recommended to prevent recurrent thrombosis. Do not begin anticoagulation until the aPTT has decreased to less than twice the normal control value. If heparin is used, do not administer a loading dose of heparin. Treatment should be followed by oral anticoagulants. HOW SUPPLIED Kinlytic™ (urokinase injection) is supplied as a sterile lyophilized preparation (NDC 24430-1003-1). Each vial contains 250,000 international units urokinase activity, 25 mg mannitol, 250 mg Albumin (Human), and 50 mg sodium chloride. Refrigerate Kinlytic™ (urokinase injection) powder at 2° to 8°C (36° to 46°F) (See USP). REFERENCES 1. Sato S. et al. Elevated Urokinase-Type Plasminogen Activator Plasma Levels Are Associated With Deterioration of Liver Function But Not With Hepatocellular Carcinoma. J Gastroenterology, 1994; 29:745-750. 2. Bell WR. Thrombolytic Therapy: A Comparison Between Urokinase and Streptokinase. Sem Thromb Hemost. 1975; 2:1-13. 3. Sasahara AA, Hyers TM, Cole CM, et al. The Urokinase Pulmonary Embolism Trial. Circulation. 1973; 47 (suppl. 2):1-108. 4. Daniels LB, Parker JA, Patel SR, Grodstein F, Goldhaber SZ. Relation of Duration of Symptoms With Response to Thrombolytic Therapy in Pulmonary Embolism. Am J Cardiol. 1997; 80:184-188. 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. ImaRx Therapeutics, Inc. Tucson, Arizona 85718, USA. July 2008. FDA revision date: 07/18/08

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

SIDE EFFECTS The most serious adverse reactions reported with Kinlytic™ (urokinase injection) administration include fatal hemorrhage and anaphylaxis (see WARNINGS). Bleeding Bleeding is the most frequent adverse reaction associated with Kinlytic™ and can be fatal (see WARNINGS). In controlled clinical studies using a 12-hour infusion of urokinase for the treatment of pulmonary embolism (UPET and USPET),3,5,6 bleeding resulting in at least a 5% decrease in hematocrit was reported in 52 of 141 urokinase-treated patients. Significant bleeding events requiring transfusion of greater than 2 units of blood were observed during the 14-day study period in 3 of 141 urokinasetreated patients in these studies. Multiple bleeding events may have occurred in an individual patient. Most bleeding occurred at sites of external incisions and vascular puncture, with lesser frequency in gastrointestinal, genitourinary, intracranial, retroperitoneal, and intramuscular sites. Sources of Information on Adverse Reactions There are limited well-controlled clinical studies performed using urokinase. The adverse reactions described in the following sections reflect both the clinical use of Kinlytic™ (urokinase injection) in the general population and limited controlled study data. Because post-marketing reports of adverse reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure. Allergic Reactions Rare cases of fatal anaphylaxis have been reported (see WARNINGS). In controlled clinical trials, allergic reaction was reported in 1 of 141 patients ( < 1%). The following allergic-type reactions have been observed in clinical trials and/or post-marketing experience: bronchospasm, orolingual edema, urticaria, skin rash, and pruritus (see WARNINGS). Infusion reaction symptoms include hypoxia, cyanosis, dyspnea, tachycardia, hypotension, hypertension, acidosis, fever and/or chills/rigors, back pain, vomiting, and nausea (see WARNINGS). Other Adverse Reactions Other adverse events occurring in patients receiving Kinlytic™ (urokinase injection) therapy in clinical studies, regardless of causality, include myocardial infarction, recurrent pulmonary embolism, hemiplegia, stroke, decreased hematocrit, substernal pain, thrombocytopenia, and diaphoresis. Additional adverse reactions reported from post-marketing experience include cardiac arrest, vascular embolization (cerebral and distal) including cholesterol emboli (see WARNINGS), cerebral vascular accident, pulmonary edema, reperfusion ventricular arrhythmias and chest pain. A cause and effect relationship has not been established. Immunogenicity The immunogenicity of Kinlytic™ (urokinase injection) has not been studied. DRUG INTERACTIONS Anticoagulants and agents that alter platelet function (such as aspirin, other non-steroidal antiinflammatory agents, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of serious bleeding. Administration of Kinlytic™ (urokinase injection) prior to, during, or after thrombolytic agents may increase the risk of serious bleeding. Because concomitant use of Kinlytic™ (urokinase injection) with agents that alter coagulation, inhibit platelet function, or are thrombolytic may further increase the potential for bleeding complications, careful monitoring for bleeding is recommended. The interaction of Kinlytic™ (urokinase injection) with other drugs has not been studied and is not known.

WARNINGS Bleeding The risk of serious bleeding is increased with use of Kinlytic™ (urokinase injection) . Fatalities due to hemorrhage, including intracranial and retroperitoneal, have been reported in association with urokinase therapy. Concurrent administration of Kinlytic™ (urokinase injection) with other thrombolytic agents, anticoagulants, or agents inhibiting platelet function may further increase the risk of serious bleeding. Kinlytic™ (urokinase injection) therapy requires careful attention to all potential bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites, and other needle puncture sites). Intramuscular injections and nonessential handling of the patient must be avoided during treatment with Kinlytic™ (urokinase injection) . 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