INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
TRASYLOL®

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

TRASYLOL^®
Sterile solution for IV injection and infusion

COMPOSITION:
TRASYLOL (aprotinin) is a highly purified and concentrated form of a naturally occurring enzyme inhibitor prepared from bovine lung tissue. Each vial of 50 mL contains 70 mg aprotinin (= 500 000 Kallikrein Inactivator Units, KIU = 277,8 European Pharmacopoeia Units, E.P. units) with the vial of 100 mL containing 140 mg aprotinin (= 1 000 000 Kallikrein Inactivator Units, KIU = 555,6 European Pharmacopoeia Units, E.P. units) in sterile 0,9% sodium chloride solution.

PHARMACOLOGICAL CLASSIFICATION:
A.32 Enzyme Inhibitors

PHARMACOLOGICAL ACTION:
TRASYLOL is a proteinase inhibitor. By forming reversible stoichiometric enzyme inhibitor-complexes, aprotinin acts as an inhibitor of human trypsin, plasmin, plasma kallikrein and tissue kallikrein. Aprotinin binds not only to free enzyme molecules but also to enzyme already bound to a third partner when the active centre of the enzyme is still accessible. In this way aprotinin inhibits both free plasmin and the plasmin-streptokinase complex formed as an intermediate under thrombolytic therapy with streptokinase.

INDICATIONS:
TRASYLOL is indicated for the treatment of adult patients at high risk of major blood loss during and following open heart surgery with extracorporeal circulation. These include:

	Patients requiring re-operation through a previous median sternotomy.
	Patients with infective endocarditis.

CONTRA-INDICATIONS:
Known hypersensitivity to TRASYLOL. Experience in children, pregnancy and lactation is limited and inadequate to assess safety and efficacy. Pancreatitis.

WARNING:
The addition of TRASYLOL to heparinised blood will prolong the activated clotting time (ACT). Thus, the ACT should not be taken as a reliable indicator of the need to administer additional heparin during a prolonged period of cardiopulmonary bypass. Furthermore, a prolonged ACT in the presence of TRASYLOL does not necessarily signify excess heparin requiring additional protamine. It is therefore not necessary to adjust the usual heparin/protamine regimen during treatment with TRASYLOL.

DOSAGE AND DIRECTIONS FOR USE:
Open Heart Surgery
Adults
The recommended regimen involves a loading dose, maintenance dose, and a pump prime dose, administered as follows:

i)	Loading Dose The loading dose of 200 mL (2 million KIU) should be administered intravenously after induction of anaesthesia and prior to sternotomy. The initial 1 mL (10 000 KIU) should be administered slowly as a test dose over several minutes 10 minutes prior to the remainder of the dose, to assess the risk of allergic or pseudo-allergic reactions. The remainder of the loading dose should then be given as a slow intravenous infusion or injection over a period of 15-20 minutes.
ii)	Maintenance dose The loading dose should be followed by the administration of a continuous infusion of 50 mL (500 000 KIU) per hour until the end of the operation except in patients with infective endocarditis where it may be continued into the early post-operative period.
iii)	Pump prime dose An additional 200 mL (2 million KIU) should be added to the priming volume of the extracorporeal circuit. In patients with infective endocarditis 300 mL (3 million KIU) should be added to the pump prime.

Elderly
No dosage adjustment in the elderly is necessary.
In general, the administration of aprotinin will not exceed 6 hours of infusion time or 7 million KIU during surgery.
TRASYLOL must be given only to patients in the supine position and must be given slowly (maximum 5-10 mL/min) as an intravenous injection or a short infusion.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Hypersensitivity or pseudo-allergic reactions can occur, not only after repeated courses of treatment but also with first administration. Prophylactic measures are described under DOSAGE AND DIRECTIONS FOR USE.
The symptoms of anaphylactic or anaphylactoid reactions may extend from itching, rash, sweating, flush, urticaria, skin eruptions, pallor or cyanosis, dyspnoea, nausea, drop in blood pressure, tachycardia or bradycardia and airway obstruction to severe hypotension and anaphylactic shock with, in rare cases, fatal outcome. If a hypersensitivity reaction occurs during the injection or infusion, administration should be stopped immediately and the appropriate therapeutic measures instituted e.g. adrenaline, antihistamines and intravenous corticosteroids. Intravenous fluids, bronchodilators and respiratory support may also be needed. Post-operative renal dysfunction has been reported. 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 hypothermic circulatory arrest during operation of the thoracic aorta. TRASYLOL should therefore be used with extreme caution under these circumstances. Adequate anticoagulation with heparin must be assured. Increases of serum creatinine have been observed in clinical studies. During post-marketing surveillance cases of kidney failure have been reported. In two clinical studies with repeated cardiopulmonary bypass surgery it has been observed that there was an increased incidence of perioperative, fatal/non-fatal myocardial infarction in the aprotinin groups compared to the placebo treated controls. In a multi-centre study in patients undergoing primary coronary artery bypass graft surgery there was an increased risk of graft closure for TRASYLOL treated patients compared to patients who received placebo. No differences between the treatment groups were observed for the incidence of myocardial infarctions or of deaths in this study. Local thrombophlebitic reactions may occur after TRASYLOL injections or infusions.
Interactions:
In principle, TRASYLOL must be regarded as being incompatible with other drugs.
TRASYLOL has a dose-dependent inhibitory effect on the action of thrombolytic agents, e.g. streptokinase, urokinase, alteplase (r-tPA).
TRASYLOL has been shown to be incompatible with corticosteroids, heparin, nutrient solutions containing amino acids or fat emulsions and tetracyclines. Administration of TRASYLOL in mixed infusions (particularly with beta-lactam antibiotics) should be avoided. TRASYLOL is compatible with electrolyte and sugar solutions such as Ringer lactate solution, hydroxyethyl starch solution and glucose 20% solution .

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Treatment is symptomatic and supportive. There is no special antidote or other action to be taken.

IDENTIFICATION:
Clear, colourless, foaming solution.

PRESENTATION:
TRASYLOL is supplied as 50 mL and 100 mL vials.

STORAGE INSTRUCTIONS:
Any unused solution should be discarded immediately. TRASYLOL vials are stable at room temperature (below 25°C). If the contents of the vial are cloudy, the product must not be used. Do not use the contents of the vials after the expiry date shown on the label. Keep out of reach of children. Store below 25°C. Protect from freezing.

REGISTRATION NUMBER:
H/32/2912

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Bayer (Pty) Ltd
Wrench Road        Isando        1600
Reg. No. 68/11192/07

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
July 1998

^® = Registered Trade Mark of Bayer AG, Germany

Trasylol/O/7/SA4        C9178/0199

Updated on this site: February 2003
Source: Pharmaceutical Industry
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