Aprotinin

Results from recent observational studies indicate that renal dysfunction could be triggered by aprotinin, 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 >0.5 mg/dL above baseline in patients with aprotinin therapy. Careful consideration of the balance of risks and benefits is therefore advised before administration of aprotinin 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 aprotinin-treated patients undergoing cardiopulmonary bypass with deep hypothermic circulatory arrest during operation of the thoracic aorta. Adequate anticoagulation with heparin must be assured.

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

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 aprotinin.

Aprotinin 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.

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.

Not relevant.

Summary of the safety profile

The safety of aprotinin has been evaluated in more than forty five phase II and phase III studies including more than 3800 patients exposed to aprotinin. In total, about 11% of aprotinin-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 aprotinin sorted by CIOMS III categories of frequency (aprotinin 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.

Immune system disorders

Rare: Allergic reaction Anaphylactic/anaphylactoid reaction

Very Rare: Anaphylactic shock (potentially life threatening)

Blood and lymphatic system disorders

Very Rare: Disseminated intravascular coagulation, Coagulopathy

Cardiac disorders

Uncommon: Myocardial ischaemia, Coronary occlusion/thrombosis, Myocardial infarction, Pericardial effusion

Vascular disorders

Uncommon: Thrombosis

Rare: Arterial thrombosis (and its organ specific manifestations that might occur in vital organs such as kidney, lung or brain)

Very Rare: Pulmonary embolism

Renal and urinary disorders

Uncommon: Oliguria, acute renal failure, renal tubular necrosis

General disorders or administration site conditions

Very Rare: Injection and infusion site reactions, Infusion site (thrombo-) phlebitis

ADRs derived 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 re-exposure 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 aprotinin treated patients was 5.8% compared to 4.8% in placebo treated patients, with difference of 0.98% between the groups (aprotinin n=3817 and placebo n=2682; status: April 2005).

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