Summary of product characteristics: quixil

Quixil®
1. Name of the Medicinal Product
2. Qualitative and Quantitative Composition
1ml of solution
2ml of solution
5ml of solution
Component 1 (BAC)
Component 2 (Thrombin)
* Total quantity of protein is 60 - 80 mg/ml 3. Pharmaceutical
4. Clinical
Particulars
4.1. Therapeutic
indications
Quixil is used as supportive treatment in surgery where standard surgical techniques are insufficient, for improvement of haemostasis. Efficacy has been demonstrated in liver surgery and orthopaedic surgery (see 5.1). Posology and method of administration
The use of Quixil is restricted to experienced surgeons 4.2.1. Posology
The volume of Quixil to be applied and the frequency of application should always be oriented towards the underlying clinical needs of the patient. The dose to be applied is governed by variables including, but not limited to, the type of surgical intervention, the size of the area and the mode of intended application and the number of applications. Application of the product must be individualised by the treating physician. In clinical trials, dosages have typically ranged from 5 to 10 ml of the combined product. For some procedures (e.g. liver traumata, or the sealing of large burned surfaces) larger volumes may be required. The initial volume of the product to be applied at a chosen anatomic site or target surface area should be sufficient to entirely cover the intended application area. The application can be repeated, if necessary. Quixil should be dripped or sprayed onto the tissue in short bursts (0.1 - 0.2 ml) to produce a thin, even layer. The maximum recommended dosage of combined product is 20 ml for adults, 10ml for children and 5ml for infants. In orthopaedic surgery, there are insufficient data available to recommend the use of Quixil in patients of less than 18 years of age. Method and Route of Administration
Prepare the solutions as described in Section 6.6. Before application, the surface of the wound should be as dry as possible. See 6.6 for more detailed instructions. 4.3. Contra-indications
• Quixil must not be applied intravascularly. • Hypersensitivity to the active substances or any of the excipients • Products containing tranexamic acid should not be used in neurosurgery or surgical procedures where contact with cerebro-spinal fluid or dura mater can occur (e.g. otologic, rhinologic, ophthalmic and vertebral surgery) due to the risk of cerebral neurological toxicity (such as oedema and seizure). Special warnings and precautions for use
! For epilesional use only. Do not apply intravascularly. ! Adequate data are not available to support the use of this product in tissue glueing, application through an endoscope for treatment of bleeding or in gastrointestinal anastomoses. ! Life threatening thromboembolic complications may occur if the product is unintentionally applied intravascularly. ! Before administration of Quixil, care is to be taken that parts of the body outside he desired application area are sufficiently protected (covered) to prevent tissue adhesion at undesired sites. ! As with any protein product, allergic type hypersensitivity reactions are possible. Signs of hypersensitivity reactions include hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, the administration has to be discontinued immediately. ! In case of shock, standard medical treatment for shock should be ! Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infections agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. The measures taken are considered effective for enveloped viruses such as HIV, HCV and HBV. The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoeisis (e.g. haemolytic anaemia). It is strongly recommended that every time that Quixil is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product. 4.5. Interaction with other medicaments and other forms of interaction
No formal interaction studies have been performed. Similar to comparable products or thrombin solutions, the product may be denatured after exposure to solutions containing alcohol, iodine or heavy metals (e.g. antiseptic solutions). Such substances should be removed to the greatest possible extent before applying the product 4.6. Pregnancy and lactation
The safety of fibrin sealants/haemostatics for use in human pregnancy or during breast-feeding has not been established in controlled clinical trials. Experimental animal studies are insufficient to assess the safety with respect to reproduction, development of the embryo or foetus, the course of gestation and peri- and post-natal development. Therefore, the product should be administered to pregnant and lactating women only if clearly needed. 4.7. Effects on ability to drive and use machines
4.8. Undesirable
Hypersensitive or allergic reactions (which may include angioedema, burning and stinging at the application site, bronchospasm, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) may occur in rare cases in patients treated with fibrin sealants/haemostatics. In isolated cases, these reactions have progressed to severe anaphylaxis. Such reactions may especially be seen if the preparation is applied repeatedly, or administered to patients known to be hypersensitive to constituents of the product. Antibodies against components of fibrin sealant/haemostatic products may occur rarely. Inadvertent intravascular injection could lead to thromboembolic event and DIC, and there is also a risk of anaphylactic reaction (see 4.4). For safety with respect to transmissible agents, see 4.4. 4.9. Overdose
5. Pharmacological
Properties
5.1. Pharmacodynamic
properties
Pharmacotherapeutic group: local haemostatics, ATC code: B02BC The fibrin adhesion system initiates the last phase of physiological blood coagulation. Conversion of fibrinogen into fibrin occurs by the splitting of fibrinogen into fibrin monomers and fibrinopeptides. The fibrin monomers aggregate and form a fibrin clot. Factor XIIIa, which is activated form Factor XIII by thrombin, crosslinks fibrin. Calcium ions are required for both the conversion of fibrinogen and the crosslinkage of fibrin. As wound healing progresses, increased fibrinolytic activity is induced by plasmin and decomposition of fibrin to fibrin degradation products is initiated. Proteolytic degradation of fibrin is inhibited by tranexamic acid. Clinical studies demonstrating haemostasis and sealing were conducted in liver surgery (liver resection and liver transplantation) and orthopaedic surgery (total hip replacement and total knee replacement surgery). In addition a Phase II study has been performed in vascular surgery (carotid endarterectomy). Study designs and patient numbers are summarised in the following table: Surgical Procedure
Study Design and Phase
Number of Patients
Phase III; Single-blind, randomised, standard- treatment active controlled, parallel-group, Phase II; Open label, active controlled, non- Phase II; Open, non comparative, prospective Phase III; Single-blind, randomised, controlled, Phase III; Single-blind randomised controlled Phase III; Single blind, randomised, parallel group, standard treatment control multicentre Phase II; Open pilot study comparing three regimens of administration of Quixil in THR Phase II; Single blind, prospective, randomized, The clinical trials in liver surgery included eight paediatric patients of which five were less than 2 years old. In one study involving 59 patients undergoing total knee replacement surgery, Quixil was shown to be haemostatically effective in patients treated with Low Molecular Weight Heparin prior to surgery. 5.2. Pharmacokinetic
properties
Quixil is intended for epilesional use only. Intravascular administration is contraindicated. As a consequence, intravascular pharmacokinetic studies were not performed in man. Studies have been conducted in rabbits to evaluate the absorption and elimination of thrombin and tranexamic acid (a synthetic antifibrinolytic agent used as a stabiliser in BAC) when applied to the cut surface of the liver resulting from partial hepatectomy. Using 125I-thrombin it was shown that a slow absorption of biologically inactive peptides resulting from the breakdown of thrombin occurred, reaching a Cmax in the plasma after 6-8 hours. At the Cmax, the plasma concentration represented only 1-2% of the applied dose. A study using 3H-tranexamic acid showed it to be very quickly absorbed; the Tmax was in most cases between 0.2 and 2 hours. Ten hours after treatment the elimination from the plasma was complete. The plasma levels of tranexamic acid resulting from absorption from Quixil may produce a systemic antifibrinolytic effect. However, the drug is rapidly excreted. Fibrin sealants/haemostatics are metabolised in the same way as endogenous fibrin, by fibrinolysis and phagocytosis. 5.3. Pre-clinical safety data
Quixil has been classified as non-irritant in the Primary Cutaneous Irritation Test and slightly irritant in the Ocular Irritation test. Neither BAC nor thrombin solution induces mutagenic effects in the Ames test. After local application, absorption of thrombin into the plasma is slow and consists principally of thrombin degradation products which are eliminated. No toxicological effects due to the solvent detergent reagents (TnBP and Triton X-100) used in the virus inactivation procedure are expected since the residual levels are less than 5µg/ml. Studies in rabbits have shown that one of the constituents of Quixil, tranexamic acid, exerts neurotoxicity (oedematous lesions with spongiosis) when applied directly to the CSF or dura mater. There were no doses with no observed effect level. 6. Pharmaceutical
particulars
6.1. List of Excipients
BAC:
Arginine Hydrochloride
Glycine
Sodium Chloride
Sodium Citrate
Calcium Chloride
Water for Injections
Thrombin Solution:
Human Albumin
Mannitol
Sodium Acetate
Water for Injections
6.2. Incompatibilities
This medicinal product must not be mixed with other medicinal products and should always be applied with the device supplied. 6.3. Shelf
6.4. Special precautions for storage
Store at ≤ -18°C. Keep the vials in the outer carton in order to protect from light. Do not refreeze. After thawing, unopened vials can be stored at 2 - 8°C and protected from light, for up to 30 days. When BAC and Thrombin have been drawn up into the administration device they must be used immediately. 6.5. Nature and contents of the container
The Quixil kit consists of a package containing two separate vials (glass type I) with rubber stoppers (type I), each containing 1ml, 2ml or 5ml of solution (BAC and Thrombin respectively), and an application device package. The CE-marked application device package contains a sterile, single-use, disposable two-syringe device arranged in clear PVC tray, which is sealed with Tyvek peel paper. The sealed tray is contained in a sealed pouch constructed of paper/polyethylene and supplied in a cardboard carton. 6.6 Instructions for use, handling and disposal
! Thawing:
The vials should be thawed in one of the following ways: 2-8°C (refrigerator): vials thaw within 1 day, or
20-25°C (room temperature): vials thaw within 1 hour, or
37ºC (e.g. water bath, using aseptic technique, or by warming vials in the
hand): vials thaw within 10 minutes and should not be left at 37°C for more
than 90 minutes.
! Preparation (see Figure 1).
The application device package contains a specially designed device for applying the product and a tube with 0.2 µm bacteriological filter which is used to supply pressurised gas to the device to aerosolise Quixil when applied by spraying. The application devices are sterile as long as the package is unopened and undamaged, and must only be used once. No needles are involved in the preparation of Quixil for administration. Draw the contents of the two vials into the administration device, following the instructions in Figure 1. Both syringes should be filled with equal volumes, and should not contain air bubbles. ! Application by dripping
Keeping the tip of the applicator as close to the tissue surface as possible, but without touching the tissue during application, apply individual drops to the area to be treated. The drops should be allowed to separate from each other and from the tip of the applicator. If the applicator tip becomes blocked, the catheter tip can be cut back in 0.5 cm increments. ! Spray Application
Quixil can be sprayed using pressurized CO2 or compressed air. Connect the short tube on the application device to the male luer-lock end of the long gas tube. Connect the female luer lock of the gas tube (with the bacteriostatic filter) to a pressure regulator capable of delivering 2 to 3 bars pressure. The pressure regulator should be used in accordance with the manufacturer’s instructions. A pressure of 2.0 to 2.5 bars (measured by gas flow) should be used for spraying. The distance between the nozzle and the tissue surface should ideally be 10 to 15cm. The product should then be sprayed onto the surface of the tissue in short bursts (0.1-0.2ml) to form a thin, even layer. Quixil forms a clear film over the area of application. Any unused product or waste material should be disposed of in accordance with local requirements. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. 7. Marketing Authorisation Holder
OMRIX biopharmaceuticals S.A. 200 Chaussée de Waterloo 1640 Rhode-St-Genèse Belgium 8. Marketing Authorisation Number
9. Date of First Authorisation
10. Date of Revision of the Text
Figure 1. Instructions for use of the administration device.
Holding the syringe barrels with one hand, loosen the syringe pistons by sliding them back and forth. 1. Insert the two vials (BAC and Thrombin) into 2. Holding the vial cup, press the top of the vial the two sterile vial cups. The vial cups must be into the vial connector which is attached to the applicator (as shown). Repeat with the second vial. 3. Holding the syring barrels with one hand, 4. While holding the syringe barrels with one aspirate both syringes slowly (vials facing up). If hand, gently turn the vial connector anti- needed, inject back into vial and aspirate again to connector/vail/vial cup combination disconnects automatically. 5 If spraying is required, connect the tubing to the pressure regulator. The applicator is now ready for use.

Source: http://www.omrix.com/prescribing/pdf/SPC_Quixil_UK.pdf