Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Nordic Group B.V., Siriusdreef 22, 2132 WT Hoofddorp, the Netherlands
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 aprotinin. Therefore, administration of aprotinin is contraindicated in these patients.
In case no aprotinin specific IgG antibody test is possible prior to treatment, administration of aprotinin to patients with a suspected previous exposure including in fibrin sealant products during the last 12 months is contraindicated.
Aprotinin should not be used when CABG surgery is combined with another cardiovascular surgery because the benefit risk balance of aprotinin in other cardiovascular procedures has not been established.
Aprotinin is not a heparin-sparing agent and it is important that adequate anticoagulation with heparin be maintained during aprotinin-therapy. Elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (Celite ACT) are expected in aprotinin-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 aprotinin 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.
In patients undergoing cardiopulmonary bypass with aprotinin therapy, one of the following methods is recommended to maintain adequate anticoagulation:
An ACT is not a standardized 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 aprotinin.
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.
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 aprotinin 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: aprotinin is not a heparin-sparing agent.
Blood drawn from the aprotinin central infusion line should not be used for graft preservation.
Administration of aprotinin, 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 re-exposure after more than 12 months.
Standard emergency treatment for allergic/anaphylactic reactions should be readily available during treatment with aprotinin.
All patients treated with aprotinin should first receive a test dose to assess the potential for allergic reactions (see section 4.2). The test dose of aprotinin should only be administered when facilities and equipment for handling acute anaphylactic reactions are available on-site.
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 (see section 5.1). 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 (see also above).
Information on mortality from randomized clinical trials is provided in section 5.1.
An association between aprotinin 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, aprotinin 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 aprotinin use and increased mortality can neither be established nor refuted. Thus, aprotinin 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.
Aprotinin 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 aprotinin, particularly in patients with pre-existing renal dysfunction. Aminoglycosides are a risk factor for renal dysfunction.
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.
There are no adequate and well-controlled studies addressing fertility in men or women.
Not relevant.
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.
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
Rare: Allergic reaction Anaphylactic/anaphylactoid reaction
Very Rare: Anaphylactic shock (potentially life threatening)
Very Rare: Disseminated intravascular coagulation, Coagulopathy
Uncommon: Myocardial ischaemia, Coronary occlusion/thrombosis, Myocardial infarction, Pericardial effusion
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
Uncommon: Oliguria, acute renal failure, renal tubular necrosis
Very Rare: Injection and infusion site reactions, Infusion site (thrombo-) phlebitis
ADRs derived from post-marketing reports are printed in bold italic
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.
Mortality:
For the risk of mortality associated with the use of aprotinin see section 4.4.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Aprotinin is incompatible with antibiotics such as tetracyclines which react with proteins, corticosteroids, heparin and nutrient solutions containing amino acids or fat emulsions. The addition of aprotinin to mixed infusions (particularly with beta-lactam antibiotics) should be avoided. Electrolyte and sugar solutions are compatible with aprotinin.
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