Trasylol (Polypeptide Proteinase Inhibitor)

TRASYLOL®

Bayer Aprotinin

Polypeptide Proteinase Inhibitor

Hemostatic Agent

Action and Clinical Uses:

Aprotinin is a potent and effective proteinase inhibitor obtained by extraction from bovine lung tissue. It inhibits a wide variety of proteinases (estero-proteinases) including trypsin, chymotrypsin, cathepsin, plasmin and kallikrein from plasma, tissue and urine. Aprotinin is rapidly excreted from the body. In humans, a biphasic elimination pattern with an initial half-life of 0.7 hour and a terminal half-life of 7 hours is observed.

Hemorrhages which are caused by a primary or secondary hyperfibrinolysis, due to an increased activation of plasmin or plasmin activator, or by a lack of the natural inhibitors of these enzymes, can be reduced or arrested by aprotinin.

Indications And Clinical Uses:

Hyperfibrinolysis: The treatment of patients suffering from conditions due to excessive fibrinolysis. These conditions occur in surgery, including open heart surgery, prostatic surgery and pathological obstetrical bleeding conditions, such as in abruptio placentae.

Contra-Indications:

During the course of clinical investigations, as well as during its wide use for several years abroad, no contraindications other than hypersensitivity to aprotinin have emerged.:

Aprotinin is contraindicated in individuals who have shown hypersensitivity to aprotinin.

Warnings in Clinical States:

Aprotinin is a polypeptide and thus may act as an antigen. Although adverse reactions due to hypersensitivity have been observed infrequently, this possibility should always be kept in mind.

Hypersensitive reactions, when they occur, will generally be seen at the onset of treatment. In such instances, administration of aprotinin should be discontinued. Animal experiments have shown that aprotinin at very high concentrations has a histamine releasing effect. In patients with a history of hypersensitivity or in cases of known or suspected reexposure to aprotinin, the following prophylactic measures are recommended: 1 mL (10 000 KIU) of aprotinin should be administered with an observation time of at least 10 minutes before the main dose of aprotinin is given. An H 1-antagonist (e.g., diphenhydramine) and an H 2-antagonist (e.g., cimetidine) may be administered 15 minutes before aprotinin. Even after the uneventful administration of the initial 1 mL dose, the therapeutic dose may cause an anaphylactic reaction. If this happens, the infusion of aprotinin should immediately be stopped, and the standard emergency treatment for anaphylaxis should be applied.

In open heart surgery, an i.v. test using 1 mL (10 000 KIU) of aprotinin given at a rate of 5 mL/min at least 10 minutes prior to the remainder of the dose may be helpful in detecting hypersensitivity in some cases. When aprotinin is used in hemorrhagic conditions in which a severe depletion of fibrinogen has occurred, fibrinogen may be given together with aprotinin.

An increase in renal failure and mortality compared to age matched historical controls has been reported for aprotinin-treated patients undergoing cardiopulmonary bypass with deep hypothemic circulatory arrest during operation of the thoracic aorta. Caution should be exercised and a careful risk/benefit assessment made before aprotinin is used in this setting. Specifically, adequate anticoagulation with heparin must be assured. (Also see Precautions, Drug Interactions for information regarding anticoagulation in heparinized blood).

Pregnancy: No evidence of teratogenic or embryotoxic effects has been seen in animals. Experience in human pregnancy is limited and inadequate to assess safety. Use of aprotinin in the first 3 months of pregnancy should only occur after a careful risk/benefit assessment is made.

Lactation: No studies are available on the passage of aprotinin into the mother’s milk. However, since aprotinin is not absorbed after oral administration, if the milk did contain any of the drug it would have no effect on the baby.

Precautions:

Children: Experience with the use of aprotinin in hyperfibrinolytic hemorrhages in children is limited. In most cases, the dose used was approximately half of the recommended adult dose.

Drug Interactions:

Aprotinin has a dose-dependent inhibitory effect on the action of thrombolytic agents (i.e., streptokinase, tPA and urokinase).

An in vitro method for determining the degree of anticoagulation in heparinized blood is confounded in the presence of aprotinin, when celite is used as the contact activator resulting in a much longer activated clotting time (ACT). The ACT is less influenced when kaolin is used as the contact activating agent.

Therefore, prior to open heart surgery (OHS), the standard loading dose of heparin should be given, and during OHS additional heparin should be administered either at fixed intervals or on the basis of heparin levels measured by a method that is not affected by aprotinin, such as protamine titration. Likewise, protamine reversal of heparin should not be based on Activated Clotting Time (ACT) values measured using the Hemochron System but should be determined by the amount of heparin administered. It is recommended to keep the ACT greater than 750 seconds during extracorporeal circulation in patients receiving aprotinin.

An increased incidence of peri-operative myocardial infarction has been observed in 2 clinical trials with aprotinin (see Adverse Effects).

Adverse Reactions:

Aprotinin is well tolerated at the recommended dosages. However, allergic reactions such as flushing, tachycardia, itching, rash and urticaria have been reported, as well as dyspnea, sweating, palpitations and nausea. Administration should be stopped at the onset of such symptoms.

Hypersensitivity and anaphylactic reactions are possible when aprotinin is administered. In case of reexposure the incidence of allergic/anaphylactic reactions – without any prophylactic premedication – may reach the 5% level. A retrospective review showed that the incidence of a hypersensitivity/anaphylactic reaction following reexposure is increased when the reexposure occurs within 6 months of the initial administration (5.0% for reexposure within 6 months and 0.9% for reexposure greater than 6 months). Even when a second administration has been tolerated, subsequent aprotinin therapy may result in severe anaphylaxis. This risk is higher in patients receiving aprotinin several times.

In single cases, anaphylactoid reactions have been observed during first-time administration.

The symptoms of anaphylactic/anaphylactoid reactions range from skin eruptions, itching, dyspnea, nausea, drop in blood pressure, tachycardia or bradycardia and airway obstruction to severe hypotension and anaphylactic shock with circulatory failure; this may develop into the complete picture of life-threatening-shock reaction leading to death in severe cases.

If hypersensitivity reactions occur during injection or infusion, administration should be stopped immediately. Standard emergency treatment may be required, e.g., epinephrine, corticosteroids and volume infusion.

Transient increases of serum creatinine have been observed in clinical studies. During postmarketing surveillance single cases of reversible kidney failure have been reported.

In 3 clinical studies with repeated cardiopulmonary bypass surgery it has been observed that there was an increased incidence of perioperative, fatal/nonfatal myocardial infarction in the aprotinin groups compared to the placebo-treated controls.

Dosage And Administration:

Owing to the slight risk of allergic reactions, a 1 mL (10 000 KIU) initial dose should always be administered especially in patients with documented previous exposure to aprotinin and in those patients for whom a previous experience is uncertain, at least 10 minutes prior to the remainder of the dose. After the uneventful administration of the initial 1 mL dose, the therapeutic dose may be given.

Aprotinin must be given only to patients in the supine position and must be given slowly (maximum 5 mL/minute) as an i.v. injection or a short infusion, due to the possibility of a hypotensive response.

Hemorrhage Due to Hyperfibrinolysis: Initial Dosage: 200 000 to 500 000 KIU of which 200 000 KIU should be given by i.v. injection (at a rate not to exceed 5 mL/min); the rest, if necessary, by slow infusion. Administration should be continued up to 1 000 000 KIU/day until the hemorrhage has been arrested. Before infusion, aprotinin may be diluted with 5% glucose or physiologic saline solution. The duration of treatment should not be longer than 5 days.

Clinical experience so far suggests that patients with decreased renal function do not require special dose adjustment.

Stability and Storage Recommendations: Aprotinin is stable when stored in sealed vials at room temperature. Store below 30°C. Avoid freezing. If a precipitate or particulate matter is present, or if the contents are cloudy, the drug should not be used. Once a vial has been opened, it should be used immediately.

Parenteral Products: Direct I.V. Injection: No dilution is required. Should be given by slow i.v. injection (maximum rate 5 mL/min). Once a vial is opened, it should be used immediately.

Intermittent I.V. Infusions: Aprotinin may be diluted with 5% glucose or physiologic saline solution. It should be administered by slow infusion (at a rate not to exceed 50 000 KIU/min). Diluted product should be used immediately.

Continuous I.V. infusions: Aprotinin may be diluted with 5% glucose or physiologic saline solution. It should be administered by slow infusion (at a rate not to exceed 50 000 KIU/min). Diluted product should be used immediately.

Aprotinin is compatible with glucose 20% solution, hydroxyethyl starch solution and Ringer’s lactate solution.

Aprotinin has been shown to be physically incompatible with corticosteroids, heparin, nutrient solutions containing amino acids or fat emulsions, and tetracyclines.

Administration of aprotinin in mixed infusions (particularly with beta-lactam antibiotics), should be avoided.

Precautions: Although aprotinin has been found to prolong the Activated Clotting Time (ACT) as measured using the Hemochron system, it should not be considered a heparin-sparing agent. When aprotinin is administered during open heart surgery, the ACT measured using the Hemochron system should not be used to determine either the dose of heparin or the dose of protamine for heparin reversal.

Repeated withdrawals should not be made from the 50 mL vial.

Solubility: The concentrate is infinitely miscible with water and dilute salt or buffer solutions. It dissolves without precipitation in methanol (max 70%, v/v), ethanol (max 70%, v/v) and acetone (max 50%, v/v).

Availability And Storage:

Each mL of clear almost colorless aqueous, isotonic solution contains: aprotinin 10 000 KIU (Kallikrein Inhibitory Units). Nonmedicinal ingredients: sodium chloride and water for injection. pH of the concentrate is adjusted to 5 to 7 during manufacture. Preservative-free. Single dose vials of 50, 100 and 200 mL. Store at room temperature.

TRASYLOL® Bayer Aprotinin Polypeptide Proteinase Inhibitor-Hemostatic Agent

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