SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

TRASYLOL

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 50 ml vial contains aprotinin solution corresponding to 500,000 Kallikrein Inactivator Units, KIU (= 277.8 European Pharmacopoeia Units, Ph.Eur. units) aprotinin in 0.9 % w/v sodium chloride solution.

Each 100 ml vial contains aprotinin solution corresponding to 1,000,000 Kallikrein Inactivator Units, KIU (= 555.6 European Pharmacopoeia Units, Ph.Eur. units) aprotinin in 0.9 % w/v sodium chloride solution.

Each 200 ml vial contains aprotinin solution corresponding to 2,000,000 Kallikrein Inactivator Units, KIU (= 1111.2 European Pharmacopoeia Units, Ph.Eur. units) aprotinin in 0.9 % w/v sodium chloride solution.

For a full list of excipients see section 6.1.

3    PHARMACEUTICAL FORM

Solution for infusion

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Trasylol is indicated for prophylactic use to reduce blood loss and blood transfusion in adult patients who are at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery (i.e. coronary artery bypass graft surgery that is not combined with other cardiovascular surgery).

Trasylol should only be used after careful consideration of the benefits and risks, and the consideration that alternative treatments are available (see section 4.4 and 5.1).

4.2 Posology and method of administration

Posology

An appropriate aprotinin-specific IgG antibody test may be considered before administration of Trasylol (see section 4.3).

Adult:

Owing to the risk of allergic/anaphylactic reactions, a 1 ml (10,000 KIU) test dose should be administered to all patients at least 10 minutes prior to the remainder of the dose. After the uneventful administration of the 1 ml test dose, the therapeutic dose may be given. A Hi-antagonist and a H₂-antagonist may be administered 15 minutes prior to the test dose of Trasylol. In any case standard emergency treatments for anaphylactic and allergic reactions should be readily available (see section 4.4).

A loading dose of 1 - 2 million KIU is administered as a slow intravenous injection or infusion over 20 - 30 minutes after induction of anaesthesia and prior to sternotomy. A further 1 - 2 million KIU should be added to the pump prime of the heart-lung machine. To avoid physical incompatibility of Trasylol and heparin when adding to the pump prime solution, each agent must be added during recirculation of the pump prime to assure adequate dilution prior to admixture with the other component.

The initial bolus infusion is followed by the administration of a continuous infusion of 250,000 - 500,000 KIU per hour until the end of the operation.

In general, the total amount of aprotinin administered per treatment course should not exceed 7 million KIU.

Paediatric population

The safety and efficacy in children below 18 years of age have not been established.

Renal impairment

Available clinical experience suggests that patients with decreased renal function do not require special dose adjustment.

Hepatic impairment

No data are available on dosage recommendations for patients with hepatic dysfunction.

Elderly

Reported clinical experience has not identified differences in responses in elderly patients.

Method of administration

Trasylol should be infused using a central venous catheter. The same lumen should not be used for the administration of any other medicinal product. When using a multi-lumen central catheter a separate catheter is not required.

Trasylol must be given only to patients in the supine position and must be given slowly (maximum 5 - 10ml/min) as an intravenous injection or a short infusion.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients listed in section 6.1.

Patients with a positive aprotinin-specific IgG antibody test are at an increased risk of anaphylactic reaction when treated with Trasylol. Therefore, administration of Trasylol is contraindicated in these patients.

In case no aprotinin specific IgG antibody test is possible prior to treatment, administration of Trasylol to patients with a suspected previous exposure including in fibrin sealant products during the last 12 months is contraindicated.

4.4 Special warnings and precautions for use

Trasylol should not be used when CABG surgery is combined with another cardiovascular surgery because the benefit risk balance of Trasylol in other cardiovascular procedures has not been established.

Laboratory monitoring ofanticoagulation during cardiopulmonary bypass

Trasylol is not a heparin-sparing agent and it is important that adequate anticoagulation with heparin be maintained during Trasylol-therapy. Elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (Celite ACT) are expected in Trasylol-treated patients during surgery, and in the hours after surgery. Therefore, the partial thromboplastin time (PTT) should not be used to maintain adequate anticoagulation with heparin. In patients undergoing cardiopulmonary bypass with Trasylol therapy, one of three methods is recommended to maintain adequate anticoagulation: Activated Clotting Time (ACT), Fixed Heparin Dosing, or Heparin Titration (see below). If activated clotting time (ACT) is used to maintain adequate anticoagulation, a minimal celite-ACT of 750 seconds or kaolin-ACT of 480 seconds, independent of the effects of haemodilution and hypothermia, is recommended in the presence of aprotinin.

Additional note on use with extracorporeal circulation

In patients undergoing cardiopulmonary bypass with Trasylol therapy, one of the following methods is recommended to maintain adequate anticoagulation:

•    Activated Clotting Time (ACT)

An ACT is not a standardised coagulation test, and different formulations of the assay are affected differently by the presence of aprotinin. The test is further influenced by variable dilution effects and the temperature experienced during cardiopulmonary bypass. It has been observed that kaolin-based ACTs are not increased to the same degree by aprotinin as are diatomaceous earth-based (celite) ACTs. While protocols vary, a minimal celite-ACT of 750 seconds or kaolin-ACT of 480 seconds, independent of the effects of haemodilution and hypothermia, is recommended in the presence of aprotinin. Consult the manufacturer of the ACT test regarding the interpretation of the assay in the presence of Trasylol.

•    Fixed Heparin Dosing

A standard loading dose of heparin, administered prior to cannulation of the heart, plus the quantity of heparin added to the prime volume of the cardiopulmonary bypass circuit, should total at least 350 IU/kg. Additional heparin should be administered in a fixed-dose regimen based on patient weight and duration of cardiopulmonary bypass.

•    Determination of Heparin Levels

Protamine titration, a method that is not affected by aprotinin, can be used to measure heparin levels. A heparin dose response, assessed by protamine titration, should be performed prior to administration of aprotinin to determine the heparin loading dose. Additional heparin should be administered on the basis of heparin levels measured by protamine titration. Heparin levels during bypass should not be allowed to drop below 2.7 U/ml (2.0 mg/kg) or below the level indicated by heparin dose-response testing performed prior to administration of aprotinin.

In Trasylol treated patients the neutralisation of heparin by protamine after discontinuation of cardiopulmonary bypass should either be based on a fixed ratio to the amount of heparin applied or be controlled by a protamine titration method.

Important: Trasylol is not a heparin-sparing agent.

Graft Conservation

Blood drawn from the Trasylol central infusion line should not be used for graft preservation.

Re-exposure to aprotinin

Administration of Trasylol, especially to patients who have received aprotinin (including aprotinin containing fibrin sealants) in the past requires a careful risk/benefit assessment because an allergic reaction may occur (see sections 4.3 and 4.8). Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also single case reports of anaphylaxis occurring upon reexposure after more than 12 months.

Standard emergency treatment for allergic/anaphylactic reactions should be readily available during treatment with Trasylol.

Assessment of potential for allergic reactions

All patients treated with Trasylol should first receive a test dose to assess the potential for allergic reactions (see section 4.2). The test dose of Trasylol should only be administered when facilities and equipment for handling acute anaphylactic reactions are available on-site.

Renal impairment

Results from recent observational studies indicate that renal dysfunction could be triggered by Trasylol, particularly in patients with pre-existing renal dysfunction. An analysis of all pooled placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) has found elevations of serum creatinine values >0.5mg/dL above baseline in patients with Trasylol therapy (see section 5.1). Careful consideration of the balance of risks and benefits is therefore advised before administration of Trasylol to patients with pre-existing impaired renal function or those with risk factors (such as concomitant treatment with aminoglycosides).

An increase in renal failure and mortality compared to age-matched historical controls has been reported for Trasylol-treated patients undergoing cardiopulmonary bypass with deep hypothermic circulatory arrest during operation of the thoracic aorta. Adequate anticoagulation with heparin must be assured (see also above).

Mortality

Information on mortality from randomized clinical trials is provided in section 5.1.

An association between Trasylol use and increased mortality has been reported in some non-randomized observational studies (eg, Mangano 2007, Schneeweiss 2008, Olenchock 2008, Shaw 2008) while other non-randomized studies have not reported such an association (eg, Karkouti 2006, Mangano 2006, Coleman 2007, Pagano 2008, Ngaage 2008, Karkouti, 2009). In these studies, Trasylol was usually administered to patients who had more risk factors for increased mortality before surgery than patients in the other treatment groups.

Most of the studies did not adequately account for these baseline differences in risk factors and the influence of these risk factors on the results is not known. Therefore interpretation of these observational studies is limited and an association between Trasylol use and increased mortality can neither be established nor refuted. Thus, Trasylol should only be used as authorized in isolated CABG surgery, after careful consideration of the potential risks and benefits.

A publication by Fergusson et al 2008 analyzed data from a randomized controlled trial, Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART), and reported a higher mortality rate in aprotinin-treated patients compared to those treated with tranexamic acid or aminocaproic acid. However, due to several methodological deficiencies no firm conclusion on cardiovascular risks can be made on the BART study results.

4.5 Interaction with other medicinal products and other forms of interaction

Trasylol has a dose-dependent inhibitory effect on the action of thrombolytic agents, e.g. streptokinase, urokinase, alteplase (r-tPA).

Renal dysfunction could be triggered by Trasylol, particularly in patients with preexisting renal dysfunction. Aminoglycosides are a risk factor for renal dysfunction.

4.6    Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Animal studies did not provide any evidence of teratogenic or other embryotoxic effects of Trasylol.

Trasylol should be used throughout pregnancy only if the potential benefit justifies the potential risk. In case of severe adverse drug reactions (like anaphylactic reaction, heart arrest, etc.) and their consecutive therapeutic measures, damage to the foetus has to be taken into account for a risk/benefit evaluation.

Breastfeeding

It is unknown whether aprotinin is excreted in human milk. However, since aprotinin is not bioavailable after oral administration, any drug contained in the milk is not expected to have a systemic effect on the breast-feed child.

Fertility

There are no adequate and well-controlled studies addressing fertility in men or women.

4.7    Effects on ability to drive and use machines

Not relevant

4.8    Undesirable effects

Summary of the safety profile

The safety of Trasylol has been evaluated in more than forty five phase II and phase III studies including more than 3800 patients exposed to Trasylol. In total, about 11% of Trasylol-treated patients experienced adverse reactions. The most serious adverse reaction was myocardial infarction. The adverse reactions should be interpreted within the surgical setting.

Tabulated summary of adverse reactions

Adverse drug reactions (ADRs) based on all placebo-controlled clinical studies with Trasylol sorted by CIOMS III categories of frequency (Trasylol n=3817 and placebo n=2682; status: April 2005) are listed in the table below:

Frequencies are defined as:

Common: > 1/100 to < 1/10 Uncommon: > 1/1,000 to < 1/100 Rare: > 1/10,000 to < 1/1,000 Very rare: < 1/10,000

Not known: cannot be estimated from the available data

MedDRA Standard System organ class	Common	Uncommon	Rare	Very Rare
Immune system disorders			Allergic reaction Anaphylactic / anaphylactoid reaction	Anaphylactic shock (potentially life threatening)
Blood and lymphatic system disorders				Disseminated intravascular coagulation Coagulopathy
Cardiac disorders		Myocardial ischaemia Coronary occlusion/ thrombosis Myocardial infarction Pericardial effusion
Vascular disorders		Thrombosis	Arterial thrombosis (and its organ specific manifestations that might occur in vital organs such as kidney, lung or brain)	Pulmonary embolism
Renal and urinary disorders		Oliguria, acute renal failure, renal tubular necrosis
General disorders or administration site conditions				Injection and infusion site reactions Infusion site (thrombo-) phlebitis
• ADRs c	erived from post-marketing reports are printed in bold italic

Description of selected adverse reactions

Allergic/anaphylactic reactions are rare in patients with no prior exposure to

aprotinin. In case of re-exposure the incidence of allergic/anaphylactic reactions may reach the five percent level. A retrospective review showed that the incidence of an allergic/anaphylactic reaction following re-exposure is increased when the reexposure occurs within 6 months of the initial administration (5.0% for re-exposure within 6 months and 0.9% for re-exposures greater than 6 months). A retrospective review suggests that the incidence of severe anaphylactic reactions to aprotinin may further increase when patients are re-exposed more than twice within 6 months. Even when a second exposure to aprotinin has been tolerated without symptoms, a subsequent administration may result in severe allergic reactions or anaphylactic shock with, in very rare cases, fatal outcome.

The symptoms of allergic/anaphylactic reactions may include:

Respiratory system:    asthma (bronchospasm)

Cardiovascular system: hypotension

Skin and appendages: pruritus, rash, urticaria

Digestive system:    nausea

If allergic reactions occur during injection or infusion, administration should be stopped immediately. Standard emergency treatment may be required, i.e. adrenaline/epinephrine, volume substitution and corticosteroids.

Cardiovascular system

In the pooled analysis of all placebo-controlled clinical studies, the incidence of investigator-reported myocardial infarction (MI) in Trasylol treated patients was 5.8% compared to 4.8% in placebo treated patients, with difference of 0.98% between the groups (Trasylol n=3817 and placebo n=2682; status: April 2005).

A trend of increased incidence of MI in association with Trasylol was observed in some studies, while other studies showed a lower incidence compared to placebo.

Mortality

For the risk of mortality associated with the use of Trasylol see section 4.4.

4.9 Overdose

There is no specific antidote.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antihemorrhagics, proteinase inhibitors, ATC code: B02AB01

Aprotinin is a broad spectrum protease inhibitor which has antifibrinolytic properties. By forming reversible stoichiometric enzyme-inhibitor complexes, aprotinin acts as an inhibitor of human trypsin, plasmin, plasma kallikrein and tissue kallikrein, thus inhibiting fibrinolysis.

It also inhibits the contact phase activation of coagulation which both initiates coagulation and promotes fibrinolysis.

Data from a global pool of placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) surgery showed that the incidence of serum creatinine elevations >0.5mg/dL above pre-treatment levels was statistically higher at 9.0% (185/2047) in the full-dose Trasylol group compared with 6.6% (129/1957) in the placebo group, with an odds ratio of 1.41 (1.12 - 1.79). In the majority of instances, post-operative renal dysfunction was not severe and reversible. The incidence of serum creatinine elevations >2.0 mg/dL above baseline was similar (1.1% vs 0.8%) in both the full-dose aprotinin and placebo group, with an odds ratio of 1.16 (0.73 -1.85) (see section 4.4).

The in-hospital mortality in a pool of randomized, clinical trials is summarized in the table below:

In-hospital Mortality in a pool of Randomized Clinical Trials (Population: All Global CABG Patients Valid for Safety)
Population	Full-Dose Aprotinin		Placebo		Odds Ratio (95% CI)
	n/N	%	n/N	%
All CABG	65/2249	2.9	55/2164	2.5	1.09 (0.78, 1.52)
Primary CABG	36/1819	2.0	39/1785	2.2	0.92 (0.62, 1.38)
Repeat CABG	22/276	8.0	13/255	5.1	1.47 (0.75, 2.87)

5.2 Pharmacokinetic properties

After intravenous injection, rapid distribution of aprotinin occurs into the total extracellular space, leading to an initial decrease in plasma aprotinin concentration with a half-life of 0.3 - 0.7 hours. At later time points (i.e. beyond 5 hours post-dose) there is a terminal elimination phase with a half-life of about 5 - 10 hours.

The placenta is probably not absolutely impermeable to aprotinin, but permeation appears to take a very slow course.

Metabolism, elimination and excretion

The aprotinin molecule is metabolised to shorter peptides or amino acids by lysosomal activity in the kidney. In man, urinary excretion of active aprotinin accounts for less than 5% of the dose. After receiving injections of ¹³¹I-aprotinin healthy volunteers excreted within 48 hours 25 - 40% of the labelled substance as metabolites in the urine. These metabolites lacked enzyme-inhibitory activity.

No pharmacokinetic studies are available in patients with terminal renal insufficiency. Studies in patients with renal impairment revealed no clinically significant pharmacokinetic alterations or obvious side effects. A special dose adjustment is not warranted.

5.3 Preclinical safety data

Acute toxicity

In rats, guinea-pigs, rabbits and dogs, high doses (>150,000 KIU/kg) injected quickly caused a blood pressure reduction of varying magnitude, which rapidly subsided.

Reproduction toxicity

In rat intravenous studies, daily doses of up to 80,000 KIU/kg produced no maternal toxicity, embryotoxicity, or fetotoxicity. Daily doses of up to 100,000 KIU/kg did not interfere with the growth and development of the young and doses of 200,000 KIU/kg/day were not teratogenic. In rabbits, daily intravenous doses of 100,000 KIU/kg produced no evidence of maternal toxicity, embryotoxicity, fetotoxicity, or teratogenicity.

Mutagenic Potential

Trasylol gave a negative mutagenic response in the Salmonella/microsome and B.subtilis DNA damage system.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

0.9% w/v sodium chloride solution

6.2    Incompatibilities

Trasylol has been shown to be incompatible with corticosteroids, heparin and 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.

6.3    Shelf life

36 months

Any unused solution should be discarded immediately. Do not use the contents of the vials after the expiry date shown on the label.

6.4    Special precautions for storage

Do not store above 25°C

6.5    Nature and contents of container

Type II glass infusion bottles, colourless: vials of 500,000 KIU/50 ml vials of 1,000,000 KIU/100 ml vials of 2,000,000 KIU/200 ml Sealed with chlorobutyl stoppers.

6.6 Special precautions for disposal

Parenteral drug products should be inspected visually for particulate matter and colour change prior to administration. Any residual solution should not be kept for later use.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Bayer plc Bayer House Strawberry Hill Newbury, Berkshire RG14 1JA

Trading as Bayer plc, Bayer Schering Pharma

8    MARKETING AUTHORISATION NUMBER(S)

PL 00010/5900R

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/07/1990 /    14/11/1995

10 DATE OF REVISION OF THE TEXT

08/05/2014