Beriplast P Combi-Set

Combi-Set I: Human fibrinogen, coagulation factor XIII (human), aprotinin (bovine).
Combi-Set II: Human thrombin, CaCl₂.

Combi-Set I: For preparing the fibrinogen solution, consisting of vials 1 and 2 linked together via a transfer device.
Vial 1 Fibrinogen Concentrate: 1 mL: total dried substance 174 mg; fibrinogen (human plasma protein fraction) 90 mg; coagulation factor XIII (human plasma protein fraction) 60 IU.
3 mL: total dried substance 522 mg; fibrinogen (human plasma protein fraction) 270 mg; coagulation factor XIII (human plasma protein fraction) 180 IU.
Vial 2 Aprotinin Solution: 1 mL: volume 1.0 ml; bovine lung aprotinin 1000 KIU* corresponding to 0.56 PEU**.
3 mL: volume 3.0 ml; bovine lung aprotinin 3000 KIU* corresponding to 1.67 PEU**.
* KIU = Kallikrein Inactivator Unit.
** PEU = Ph. Eur. Unit (1 PEU ≙ 1800 KIU).
Combi-Set II: For preparing the thrombin solution, consisting of vials 3 and 4 linked together via a transfer device.
Vial 3 Thrombin: 1 mL: total dried substance 7.6 mg with a human plasma protein fraction thrombin activity 500 IU.
3 mL: total dried substance 22.8 mg with a human plasma protein fraction thrombin activity 1500 IU.
Vial 4 Calcium Chloride Solution: 1 mL: volume 1.0 ml; calcium chloride dihydrate 5.9 mg.
3 mL: volume 3.0 ml; calcium chloride dihydrate 17.7 mg.
Excipients/Inactive Ingredients: Vial 1: human albumin, L-arginine hydrochloride, L-isoleucine, sodium chloride, sodium citrate dihydrate, sodium L-glutamate monohydrate.
Vial 2: sodium chloride, water for injections.
Vial 3: sodium chloride, sodium citrate dihydrate.
Vial 4: water for injections.

Pharmacotherapeutic group: Local hemostatics. ATC code: B02BC.

Supportive treatment where standard surgical techniques are insufficient: for improvement of haemostasis (including endoscopic treatment of bleeding gastroduodenal ulcer); as a tissue glue to promote adhesion/sealing or as suture support.

The use of Beriplast is restricted to experienced physicians and/or surgeons.
Posology: The volume of Beriplast 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, the individual dosages have typically ranged from 0.5 to 4 ml. For some procedures (e.g. liver traumata, or the sealing of large burned surfaces) larger volumes (10 ml or more) 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.
Paediatric population: The safety and efficacy of Beriplast in children and adolescents has not yet been established in controlled clinical studies.
Method of administration: For epilesional use.

No case of overdose has been reported.

Beriplast must not be applied intravascularly.
Arterial and strong venous bleeding.
Hypersensitivity to the active substances or to any of the excipients listed in Description.

For epilesional use only. Do not apply intravascularly.
Life threatening thromboembolic complications may occur if the preparation is unintentionally applied intravascularly.
Before administration of Beriplast care is to be taken that parts of the body outside the 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.
Beriplast contains bovine protein (aprotinin). Even in case of strict local application, there is a risk of anaphylactic reactions, linked to the presence of bovine aprotinin. The risk seems higher in case of previous exposure, even if it was well tolerated. Therefore any use of aprotinin or aprotinin-containing products should be documented in the patients' records.
In case of shock, standard medical treatment for shock should be implemented.
Special note on local injection: Administration of Beriplast in the endoscopic treatment of gastrointestinal bleedings can cause tissue damage, which can lead to formation of intramural haematoma. Abdominal pain, nausea, or vomiting within 1 to 3 days after such endoscopic treatment can constitute symptoms of intramural haematoma. In patients with intramural haematoma of the duodenal wall, pancreatitis has been reported in single literature cases. Therefore, differential diagnosis for pancreatitis should be carefully evaluated.
Virus safety: 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 infections 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 infective 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 human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis A virus (HAV). The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19.
Parvovirus B19 infection may be serious for pregnant women (fetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).
It is strongly recommended that every time that Beriplast 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.

Pregnancy and Breastfeeding: The safety of fibrin sealants/haemostatics for use in human pregnancy or breastfeeding 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 postnatal development.
Only limited experience regarding the administration of Beriplast in pregnant women is available. Therefore, the product should be administered to pregnant and lactating women only if clearly indicated.
Fertility: No fertility data are available.

Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects have been observed rarely (may affect up to 1 in 1,000 people): A sudden allergic reaction (such as swelling in the face, mouth, genitals, rarely in the upper airways, burning and stinging where the solution was applied, bronchospasm, chills, flushing, skin rash over the whole body, headache, hives, fall in blood pressure, tiredness, nausea, restlessness, faster heartbeat, tightness of the chest, tingling, vomiting, wheezing).
In isolated cases these side effects may progress to severe allergic reaction (anaphylaxis). Such reactions may especially be seen, if the preparation is applied repeatedly, or administered to patients known to be hypersensitive to aprotinin (see Precautions) or other constituents of the product.
Antibodies against components of fibrin sealant/haemostatic products.
Administration in the endoscopic treatment of gastrointestinal bleeding can cause tissue damage, which can lead to formation of intramural haematoma (see Precautions).
Inadvertent intravascular injection could lead to alterations of coagulation e.g. clotting of vessels or excessive coagulation resulting in severe bleeding, and there is also a risk of anaphylactic reaction (see Precautions).
Reporting of side effects: If any side effects occur, talk to the doctor, nurse or pharmacist. This includes any possible side effects not listed previously. By reporting side effects, more information on the safety of this medicine can be provided.

No formal interaction studies have been performed. Similar to comparable products or thrombin solutions, the product may be denatured after exposure with 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.

Preparation and withdrawal of the solutions: Before reconstitution bring all Beriplast components to room temperature (not exceeding +25°C).
Take the cardboard stand (containing Combi-Sets I and II) out of the outer carton and place in a vertical position.
Do not open the sterile blister packaging and leave the Combi-Sets I and II in the cardboard stand.
Reconstitute each set separately.
Apply strong pressure to the top of the upright Combi-Sets in order to transfer the solvents from the solvent vial (2 resp. 4) into the vial with the powder (1 resp. 3).
The solvent is drawn in by vacuum via the transfer device.
Afterwards leave to stand at room temperature. The process of reconstitution is complete after five to ten minutes at the latest. A clear to slightly opalescent solution is obtained. Air-bubbles may make the viscous solution appear turbid but such turbidity does not interfere with the efficacy or usability of the product.
Note the date and time of reconstitution in the empty space on the cardboard stand (space on right side).
Ensure that Combi-Sets I and II are stored in an upright position once reconstituted.
Prior to use tear open the sterile blister packaging and remove Combi-Set I and II under sterile conditions. Disconnect the empty vials (2 resp. 4) plus transfer devices.
Incline vial 1 (fibrinogen solution/blue marking) and draw up the contents into the blue marked syringe. Completely draw up the contents of vial 3 (thrombin solution/red marking) into the red marked syringe.
The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Reconstituted solutions should be inspected visually for particulate matters and discoloration prior to administration.
Use the reconstituted solutions immediately after withdrawal into the syringes.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Application: The reconstituted solutions (of vial 1 and 3) are to be administered locally to the tissue (sequentially or in combination). Unlike other haemostatic agents that must be removed once haemostasis is achieved, Beriplast remains in place after application and is degraded by the normal physiological process of clot lysis.
Prior to applying Beriplast the surface area of the wound needs to be dried by standard techniques (e.g. intermittent application of compresses, swabs, use of suction devices).
The product should only be reconstituted and administered according to the instructions and with the devices as provided with this product.
Separate application of fibrinogen solution and thrombin solution: a) Apply the fibrinogen solution to the tissue site requiring adhesion and immediately overlay with the thrombin-containing solution.
b) The tissues requiring adhesion should be fixed in place for several minutes until provisional adhesion is achieved.
Joint application with Pantaject application kit: For joint application of fibrinogen solution and thrombin solution, the application kit can be used.
Handling of the application kit for Beriplast: Remove the needles from the syringes filled with the fibrinogen solution (blue marking) and thrombin solution (red marking).
(A) Insert the Y-piece in the conical recess of the syringe holder.
(B) Firmly connect to the Y-piece the syringes filled with the fibrinogen solution (1/blue marking) and thrombin solution (2/red marking).
(C) Snap both syringes into the syringe holder.
(D) Connect the grip plate to the syringe plungers to prevent jamming of the syringe plungers and to ensure smooth forward movement.
(E) Finally firmly screw on the spray tip or the application cannula (both equipped with a Luer-Lock connector).
For covering large wound surfaces the fibrin sealant can be sprayed using the enclosed spray-tips, or used in combination with fleece consisting of e.g. polyglycolic acid or collagen.
Before use in the wound region the system must be checked for blockages. Never push the syringe plungers against a resistance. Any interruption in the application, even of short duration, results in blockage of both either the spray tip or application cannula. In such cases the spray tip or application cannula is unsuitable for further use and must be replaced. For this purpose the 1 ml and 3 ml Beriplast packages contain two and three spray tips, respectively, and four blunt application cannulas.
By applying an even pressure to the grip plate - like for an injection - the fibrin sealant is sprayed from the spray tip as a fine, even aerosol. The best distance is about 10 cm. A fine film of fibrin sealant forms on the tissue to be coated.
Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Description.

Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the container in the outer carton in order to protect from light.
Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (up to max. +25°C). However, from a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately.

Haemostatics

B02BB01 - fibrinogen, human ; Belongs to the class of fibrinogen. Used in the treatment of hemorrhage.

P₁S₁S₃