Chester Clinic

 

Nordicpharma.co.uk

NAME OF THE MEDICINAL PRODUCT: Aprotinin 10,000 KIU/ML Injection BP. PRESENTATION:
Each 50ml 1 vial of 50 mL contains aprotinin concentrated solution, corresponding to 500,000
KIU (Kallikrein Inhibitor Units) in sterile 0.9% sodium chloride solution. INDICATIONS: Aprotinin
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). Aprotinin should only be used after careful consideration of the
benefits and risks, and the consideration that alternative treatments are available. POSOLOGY
AND METHOD OF ADMINISTRATION: Posology: An appropriate aprotinin-specific IgG antibody
test may be considered before administration of aprotinin. 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 H1-antagonist and a
H2-antagonist may be administered 15 minutes prior to the test dose of aprotinin. 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 aprotinin 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. Refer to Summary of Product
Characteristics for use in other specific patient populations. Aprotinin 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. Aprotinin 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.
CONTRAINDICATIONS: Hypersensitivity to the active substance or any of the excipients.
Patients with a positive aprotinin specific IgG antibody test. If no such 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. SPECIAL
WARNINGS AND PRECAUTIONS FOR USE: 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. Laboratory
monitoring of anticoagulation during cardiopulmonary bypass: 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. Important: aprotinin is not a heparin-sparing agent. Graft Conservation:
Blood drawn from the aprotinin central infusion line should not be used for graft preservation.
Re-exposure to aprotinin: 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. Standard emergency
treatment for allergic/anaphylactic reactions should be readily available during treatment with
aprotinin. Renal impairment: 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. Mortality: An
association between aprotinin use and increased mortality has been reported in some non-
randomized observational while other non-randomized studies have not reported such an
association. 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 analysed 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. UNDESIRABLE
EFFECTS: Refer to the Summary of Product Characteristics for full details of the safety of the
product. 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. Uncommon: Myocardial ischaemia,
coronary occlusion/thrombosis, myocardial infarction, pericardial effusion, thrombosis,
Oliguria, acute renal failure, renal tubular necrosis. Rare: Allergic reaction,
anaphylactic/anaphylactoid reaction, Arterial thrombosis (and its organ specific manifestations
that might occur in vital organs such as kidney, lung or brain). Very rare: Anaphylactic shock
(potentially life threatening), disseminated intravascular coagulation, coagulopathy,
pulmonary embolism, injection and infusion site reactions, infusion site (thrombo-) phlebitis.
BASIC NHS COST: £60.00 for 1 vial. LEGAL CLASSIFICATION: POM. MA NUMBER: PL
05827/0015. MA HOLDER: Nordic Pharma Ltd, Abbey House, 1650 Arlington Business Park,
Theale, Reading, Berkshire RG7 4SA. DATE OF PREPARATION: February 2016.

Adverse events should be reported. Reporting forms and information can be found Adverse events should also be reported to Nordic Pharma on 0800 121 8924

Source: http://www.nordicpharma.co.uk/pi/aprotinin_pi_201602.pdf