Urokinase Benesis

Urokinase Benesis™ (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.

Urokinase Benesis™ (urokinase injection) IS INTENDED FOR INTRAVENOUS INFUSION ONLY.

Urokinase Benesis™ (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 Urokinase Benesis™ (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 Urokinase Benesis™ (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 Urokinase Benesis™ (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 Urokinase Benesis™ (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.
• Urokinase Benesis™ (urokinase injection) contains no preservatives. Do not reconstitute until immediately before use. Any unused portion of the reconstituted material should be discarded.
• Reconstitute Urokinase Benesis™ (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 Urokinase Benesis™ (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 Urokinase Benesis™ (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 Urokinase Benesis™ (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 Urokinase Benesis™ (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.

Administration

• Urokinase Benesis™ (urokinase injection) is administered using a programmable infusion pump. Change the infusion rate immediately after completion of the loading dose.
• The loading dose of Urokinase Benesis™ (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 Urokinase Benesis™ (urokinase injection) at a rate of 15 mL per hour for 12 hours.
• Since some of the Urokinase Benesis™ (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 Urokinase Benesis™ (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 Urokinase Benesis™ (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 Urokinase Benesis™ (urokinase injection).

Anticoagulation After Terminating Urokinase Benesis™ (urokinase injection) Treatment

After infusing Urokinase Benesis™ (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.

The use of Urokinase Benesis™ (urokinase injection) is contraindicated in patients with a history of hypersensitivity to the product (see WARNINGS and ADVERSE REACTIONS).

Because thrombolytic therapy increases the risk of bleeding, Urokinase Benesis™ (urokinase injection) is contraindicated in the situations listed below (see WARNINGS).

• Active internal bleeding
• Recent (e.g., within two months) cerebrovascular accident
• 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

WARNINGS

Bleeding

The risk of serious bleeding is increased with use of Urokinase Benesis™ (urokinase injection). Fatalities due to hemorrhage, including intracranial and retroperitoneal, have been reported in association with urokinase therapy.

Concurrent administration of Urokinase Benesis™ (urokinase injection) with other thrombolytic agents, anticoagulants, or agents inhibiting platelet function may further increase the risk of serious bleeding.

Urokinase Benesis™ (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 Urokinase Benesis™ (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
• 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

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 Urokinase Benesis™ (urokinase injection) 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 and urticaria (see ADVERSE REACTIONS: Allergic Reactions). There have also been reports of other infusion reactions which have included one or more of the following: fever and/or chills/rigors, hypoxia, cyanosis, dyspnea, tachycardia, hypotension, hypertension, acidosis, back pain, vomiting, and nausea. Reactions generally occurred within one hour of beginning Urokinase Benesis™ (urokinase injection) 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 livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction and rhabdomyolysis.

Product Source and Formulation with Albumin

Urokinase Benesis™ (urokinase injection) is made from human neonatal kidney cells grown in tissue culture. Products made from human source material may contain infectious agents, such as viruses, that can cause disease. The risk that Urokinase Benesis™ (urokinase injection) will transmit an infectious agent has been reduced by screening donors for prior exposure to certain viruses, by testing donors for the presence of certain current virus infections, by testing for certain viruses during manufacturing, and by inactivating and/or removing certain viruses during manufacturing (see DESCRIPTION). Despite these measures, Urokinase Benesis™ (urokinase injection) may carry a risk of transmitting infectious agents, including those that cause Creutzfeldt-Jakob disease (CJD) or other diseases not yet known or identified; thus, the risk of transmission of infectious agents cannot be totally eliminated. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is considered extremely remote.

This product is formulated in 5% albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, albumin carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to ImaRx Therapeutics, Inc. [1-866-634-6279].

PRECAUTIONS

General

Urokinase Benesis™ (urokinase injection) should be used in hospitals where the recommended diagnostic and monitoring techniques are available.

The clinical response and vital signs should be observed frequently during and following Urokinase Benesis™ (urokinase injection) infusion. Blood pressure should not be taken in the lower extremities to avoid dislodgement of possible deep vein thrombi.

Laboratory Tests

Before beginning thrombolytic therapy, obtain a hematocrit, platelet count, and an activated partial thromboplastin time (aPTT). If heparin has been given, it should be discontinued and the aPTT should be less than twice the normal control value before thrombolytic therapy is started.

Following intravenous infusion of Urokinase Benesis™ (urokinase injection) , before (re)instituting anticoagulants, the aPTT should be less than twice the normal control value.

Results of coagulation tests and measures of fibrinolytic activity do not reliably predict either efficacy or risk of bleeding for patients receiving Urokinase Benesis™ (urokinase injection).

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 Benesis™ (urokinase injection). 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 Benesis™ (urokinase injection) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Urokinase Benesis™ (urokinase injection) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Urokinase Benesis™ (urokinase injection) should be used with caution in elderly patients.

The most serious adverse reactions reported with Urokinase Benesis™ (urokinase injection) administration include fatal hemorrhage and anaphylaxis (see WARNINGS).

Bleeding

Bleeding is the most frequent adverse reaction associated with Urokinase Benesis™ 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 Urokinase Benesis™ (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 Urokinase Benesis™ (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 Urokinase Benesis™ (urokinase injection) has not been studied.

No information provided.