Evarrest - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

EVARREST Sealant Matrix

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Component 1:

Human Fibrinogen      8.1 mg/cm2

Component 2

Human Thrombin      40 IU/cm2

Excipient(s) with known effect :

Contains up to 3.0 mmol (68.8 mg) sodium per sealant matrix.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Sealant Matrix

EVARREST is a white-to-yellow bio-absorbable combination product made from a flexible composite Matrix, coated with Human Fibrinogen and Human Thrombin. The active side of the sealant matrix is powdery, and the non-active side has an embossed wave pattern.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Supportive treatment in adult surgery where standard surgical techniques are insufficient (see section 5.1):

• – for improvement of haemostasis.

4.2 Posology and method of administration

The use of EVARREST is restricted to experienced surgeons.

Posology

The amount of EVARREST 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.

The quantity of EVARREST to be applied depends upon the area and location of the bleeding area to be treated. EVARREST should be applied so it extends approximately 1 to 2 cm beyond the margins of the target bleeding area. It can be cut to the size and shape required to fit the size of the bleeding area.

Bleeding areas larger than those which can be covered by a single unit of EVARREST have not been investigated in clinical studies. EVARREST should only be used in a single layer, with an overlap of approximately 1 to 2 cm onto non-bleeding tissue or an adjacent EVARREST sealant matrix.

Multiple bleeding sites may be treated simultaneously. In total, no more than the equivalent of two 10.2 cm x 10.2 cm units or four 5.1 cm x 10.2 cm units should remain in the body as there is only limited long-term experience with larger quantities. The use of more than four 10.2 cm x 10.2 cm units or eight 5.1 cm x 10.2 cm units, or the use in patients that have been previously exposed to EVARREST, has not been studied.

If haemostasis is not reached with one application of EVARREST, re-treatment may be administered.

Paediatric population

The safety and efficacy of EVARREST in children from birth to 18 years has not yet been established. No data are available.

Method of administration

For epilesional use only.

For instructions on preparation of the medicinal product before administration, see section 6.6. The product should only be administered according to the instructions recommended for this product (see section 6.6).

Contraindications

EVARREST must not be applied intravascularly.

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Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

EVARREST must not be used to treat severe bleeding from large defects in large arteries or veins where the injured vascular wall requires repair with maintenance of vessel patency and which would result in persistent exposure of EVARREST to blood flow and/or pressure during

healing and absorption of

duct.

EVARREST must not be used in closed spaces (e.g., in, around, or in proximity to foramina in bone or areas of bony confine) since swelling may cause nerve or blood vessel compression.

t not be used in the presence of active infection or in contaminated areas of the body because infection may occur.

4.4 Special warnings and precautions for use

For epilesional use only. Do not apply intravascularly

Life-threatening thromboembolic complications may occur if the preparation is unintentionally applied intravascularly.

As with any protein containing 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 product should be removed immediately and other hemostatic agent or methods should be used.

In case of shock, standard medical treatment for shock should be implemented.

EVARREST should not be used in place of sutures or other forms of mechanical ligation for the treatment of major arterial bleeding.

Applications for which adequate data are not available

Adequate data are not available to support the use of this product in neurosurgery or application through a flexible endoscope for treatment of bleeding, in vascular surgery, or in gastrointestinal anastomoses.

As with any implantable product, foreign body reactions may occur.

EVARREST should only be used in a single layer, with an overlap of approximately 1 to 2 cm onto non-bleeding tissue, to assist with adherence to the wound site. The size of EVARREST should be limited to what is necessary for haemostasis.

EVARREST contains up to 3.0 mmol (68.8 mg) sodium per sealant matrix. To be taken into consideration by patients on a controlled sodium diet.

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 infectious 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 virus 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 (foetal infection) and for individuals with immunodeficiency or abnormal erythropoiesis (e.g., haemolytic anaemia).

It is strongly recommended that every time EV RREST is administered to a patient, the name and batch number of the product are recorded r to maintain a link between the patient and the batch of the product.

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4.5 Interaction with other medicinal products and other forms of interactionNo interaction studies have brformed.

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 Fertility, 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

Not relevant.

4.8 Undesirable effects

Summary of the safety profile

Hypersensitivity 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/haemos­tatic products. 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.

Thromboembolic complications may occur if the preparation is unintentionally applied intravascularly (see section 4.4).

For safety with respect to transmissible agents, see section 4.4.

Adverse Reactions

The safety data for EVARREST reflect the types of post-operative complication generally related to the surgical settings in which the trials were conducted and the underlying disease of the patients. In clinical trials, the most frequently reported adverse reactions were haemorrhage and increased fibrinogen, and the most serious adverse reactions were aspiration, pulmonary embolism, and haemorrhage.

EVARREST was used to treat soft tissue bleeding during retroperitoneal, intra-abdominal, pelvic, or thoracic surgery, suture hole bleeding during cardiovascular surgery, and parenchymal bleeding during hepatic or renal surgery across all clinical trials involving 381 subjects treated with EVARREST and 272 control subjects. Of the enrolled subjects, 4.7% of EVARREST treated subjects (18 subjects out of 381) and 2.6% of control subjects (7 subjects out of 272) experienced one or more adverse reactions.

A post-marketing safety study enrolling 150 subjects was conducted using EVARREST. It was a prospective, randomised, controlled single-centre study observing the clinical utility of EVARREST against Standard of Care (SoC) in soft tissue bleeding during intra-abdominal, retroperitoneal, pelvic and non-cardiac thoracic surgery. Standard of Care was manual compression (MC) with or without a topical absorbable haemostat (TAH) or any other adjunctive haemostasis technique that was deemed by the surgeon to be his/her standard of care.

Study subjects were followed post-operatively through discharge and at Day 30 (+/-14 days) post discharge. The incidence of thromboembolic events, the incidence of post-operative bleeding events specifically related to the target bleeding site and the incidence of increased blood fibrinogen levels were assessed and recorded up to the 30 days follow-up period.

One (1/75) adverse reaction of deep vein thrombosis was reported in the EVARREST group.

Immunogenicity was evaluated in soft tissue clinical studies by testing blood samples collected at baseline, 4 to 6 weeks, and 8 to 10 weeks post-surgery for antibodies to human thrombin and fibrinogen by enzyme-linked immunosorbent assays. Three subjects out of 145 (~2%) in the group treated with EVARREST showed an increase in the titre of anti-thrombin antibodies after treatment. Two subjects out of 145 (~1%) in the group treated with EVARREST showed a transient increase in fibrinogen antibody titres, with titre levels back at background levels at the 8 to 10 week time point.

Tabulated list of adverse reactions

Data from eight clinical trials with EVARREST have been pooled into an integrated dataset and the frequencies of occurrence described in the table below originate from this integrated dataset. In the integrated analyses, 381 patients were treated with EVARREST and 272 patients were treated with control treatment.

All adverse reactions reported during the clinical trials occurred at a frequency of less than 1% (uncommon). Most adverse reactions were reported as single events: intra-abdominal haemorrhage, abdominal distension, anaemia, thoracic cavity drainage, pleural effusion, abdominal abscess, ascites, deep vein thrombosis, localized intra-abdominal fluid collection, operative haemorrhage, ischaemic bowel and pulmonary embolism, except blood fibrinogen increased (3 events, 0.8%), anastomotic haemorrhage (3 events, 0.8%), and post procedural haemorrhage (2 events, 0.5%)

The following categories are used to rank the adverse reactions by frequency of occurrence: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); and very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1Summary of Adverse Reactions to EVARREST

MedDRA System Organ Class	Preferred Term	Frequency
Vascular disorders	Deep vein thrombosis	Uncommon
Respiratory, thoracic and mediastinal disorders	Aspiration Pleural effusion Pulmonary embolism	Uncommon Uncommon Uncommon
Gastrointestinal disorders	Abdominal distension Ascites Haemorrhage • Gastrointestinal haemorrhage Qp • Intra-abdominal haemorrhage Localised intra-abdominal fluidcolrection Peripancreatic fluid collection^	^ncommon “Uncommon Uncommon Uncommon Uncommon
Investigations	Blood fibrinogen increased^	Uncommon
Injury, poisoning and procedural complications	Post-procedural haemorrhage Operative Haemorrhage “ Anastomotic Haemorrhage	Uncommon Uncommon Uncommon

Description of selected adverse reactions

Pulmonary embolism

Blood clots, including those clots that may travel in blood vessels to other parts of the body, particularly the lungs (pulmonary embolus) may occur after any major surgery. In clinical trials of EVARREST no difference has been observed between EVARREST and control groups with regard to the incidence of thrombotic events, currently suggesting no increased risk with EVARREST use. Due to the nature of surgical procedures and the physiological response to surgical trauma all surgical subjects are at risk for occurrence of thromboembolism.

Deep vein thrombosis

The overall incidence of deep vein thrombosis observed during clinical trials was consistent with published data and does not suggest an increased risk for thrombotic events in EVARREST-treated subjects, although from the available data, this risk cannot be completely ruled out.

Anti-thrombin antibodies

Three subjects out of 145 (~2%) in a clinical trial group treated with EVARREST showed an increase in the titre of anti-thrombin antibodies after treatment. None of the patients in any treatment group had a significant change in antibody titre to thrombin or fibrinogen.

Reporting of suspected adverse reactions

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 national reporting system listed in Appendix V.

4.9 Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antihaemorrhagics, local haemostatics, ATC code: B02BC30

Mechanism of Action

EVARREST contains Human Fibrinogen and Human Thrombin as a dried coating on the surface of an absorbable composite Matrix. In contact with physiological fluids, e.g., blood, lymph, or physiological saline, the components of the coating are activated, and the reaction of fibrinogen and thrombin initiates the last phase of physiological blood coagulation. Fibrinogen is converted into fibrin monomers which spontaneously polymerise to form a fibrin clot that holds the Matrix firmly to the wound surface. The fibrin is then cross-linked by endogenous Factor XIII, creating a firm, mechanically stable fibrin network with good adhesive properties.

The composite Matrix is composed of polyglactin 910 and oxidized regenerated cellulose, a commonly used haemostat. The Matrix provides physical support and a large surface area for the biological components, imparts inherent mechanical integrity to the prodd supports clot formation. The clot formation of EVARREST is integrated with the       ; it forms a mechanical

barrier to bleeding and reinforces the wound site. Natural healing owhile the fibrin degrades and the product is absorbed by the body; absorption is considered to take approximately 8 weeks, as demonstrated in rodent and swine animal models.

Clinical efficacy and safety

Clinical studies demonstrating haemostasis in mild or moderate soft tissue bleeding were conducted in a total of 141 subjects (111 treated with EVA

retroperitoneal, pelvic, and (non-cardiac) thoracic surgery. A further trial in 91 patients undergoing abdominal, retroperitoneal, pelvic, and (ncardiac) thoracic surgery (59 treated with EVARREST and 32 with control) demonstrated haeasis in severe soft tissue bleeding. Two clinical studies in 206 patients undergoing hepatic sur (110 treated with EVARREST and 96 with control) demonstrated haemostatic efficacy in persistent parenchymal bleeding.

A prospective randomised controlled clinical study was conducted enrolling 156 subjects (76 EVARREST, 80 haemostatic fleece) demonstrating the safety and haemostatic effectiveness of EVARREST as an adjunct to controlling bleeding during cardiovascular surgery.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with EVARREST in one or more subsets of the paediatric population for the treatment of haemorrhage resulting from a surgical procedure (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

EVARREST 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 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 to 2% of the applied dose.

Fibrin sealants/haemos­tatics are metabolised in the same way as endogenous fibrin, by fibrinolysis and phagocytosis.

After the biologic components have been absorbed, the Matrix components (polyglactin 910 and oxidized regenerated cellulose) absorb completely. In animal studies EVARREST was absorbed by 56 days when used at the anticipated clinical dose.

5.3 Preclinical safety data

The haemostatic efficacy of EVARREST was demonstrated in a number of animal models assessing time to haemostasis and post-treatment blood loss, among other endpoints.

Non-clinical data on the Matrix component reveal no special hazard for humans based on studies of cytotoxicity, sensitization, intracutaneous reactivity, acute systemic toxicity, material-mediated pyrogenicity, subchronic toxicity, genotoxicity, implantation, and hemocompatibility.

A 90-day study in rats to evaluate subchronic systemic toxicity and immunogenicity of EVARREST after subcutaneous implantation found no signs of toxic effects and no evidence of increased immunogenicity relative to fibrin sealant products.

PHARMACEUTICAL PARTICULARS

List of excipients

Composite Matrix (Polyglactin 910 and oxidised regenerat

Arginine hydrochloride

Glycine

Sodium chloride

Sodium citrate

Calcium chloride

Human albumin

Mannitol

Sodium acetate

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

2 years.

Once the foil sachet is opened, EVARREST can remain in the sterile field to be available for use throughout the procedure.

6.4 Special precautions for storage

Do not store above 25°C. Do not freeze.

6.5 Nature and contents of container

10.2 cm x 10.2 cm sealant matrix in a tray (polyester). The tray is in a sachet (polyester laminated aluminium foil) with a seal. Pack size of 1, 10.2 cm x 10.2 cm sealant matrix.

• 5.1 cm x 10.2 cm sealant matrix in a tray (polyester). The tray is in a sachet (polyester laminated aluminum foil) with a seal. Pack size of 2, 5.1 cm x 10.2 cm sealant matrices.

6.6 Special precautions for disposal and other handling

The instructions for use are also described in the in the healthcare professional’s pac­kage leaflet part.

• • EVARREST comes ready to use in sterile packages and must be handled using sterile technique in aseptic conditions. Discard damaged packages.
• • To open the product, remove the foil sachet from the carton, carefully peel open the foil sachet avoiding contact with the inside of the foil or the white sterile tray containing EVARREST.
• • Remove the white sterile tray from the pouch and place onto the sterile field.
• • Hold the tray securely in the palm of the hand, ensuring that the side with the holes is facing

upwards, and use the tabs on the side of the tray to remove the top of the tray with the other hand.

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• • The lower portion of the tray contains EVARREST with the active side facing downwards. The active side is powdery in appearance. The non-active side has an embossed wave pattern.

Keep EVARREST dry after opening. The product can remain in the sterile field to be available for use throughout the procedure. EVARREST does not stick to gloves, forceps, or surgical instruments.

EVARREST is to be applied with approximately

ST to the size and shape as necessary to fit and

maintain contact with the bleeding area with an overlap of approximately 1 to 2 cm. Keep the powdery white-to-yellow colour active side of EVARREST facing down while in the tray.

• 2. Remove excess blood or fluid from the site of application if required to improve visibility. The bleeding source should be clearly identified, and it must be ensured that EVARREST is applied directly onto the bleeding source by covering it completely. EVARREST can be used in an actively bleeding field.

• 3. Apply the active side of EVARREST to the bleeding area, allowing full contact with the tissue. The product is activated upon contact with fluid, and adheres and conforms to tissue.

  
  

• 4. Apply an appropriately sized piece of EVARREST to adequately cover the entire bleeding area, with an overlap of approximately 1 to 2 cm onto non-bleeding tissue, to assist with adherence to the wound site.

5a) Hold dry or moist surgical gauze or laparotomy pads over EVARREST to achieve full contact with the bleeding surface.

5b) To ensure haemostasis, immediately apply manual compression over the entire surface of EVARREST (including the area of overlap) sufficient to stem all bleeding. Maintain compression for approximately 3 minutes, to control the bleeding.

• 6. Gently remove surgical gauze or laparotomy pads from the application site, without disrupting or dislodging EVARREST or the clot. Inspect EVARREST to verify that haemostasis has been achieved and to ensure that there is no crimping over the bleeding area. If not satisfied with the placement, remove EVARREST and use a new EVARREST sealant matrix. EVARREST will remain in place and adhere to the tissue, and is absorbable.

• 7. The application site should be monitored intraoperatively to verify that haemostasis is maintained.

Re-Treatment

• • Re-treatment may be required if there are folds, creases, or crimps in the EVARREST sealant matrix. If not satisfied with the placement of EVARREST, remove the used EVARREST sealant matrix and repeat the application procedure above with a new EVARREST sealant matrix.
• • If bleeding is due to insufficient coverage of the bleeding area, additional EVARREST sealant matrices may be applied. Apply in a single layer; ensure that the edges overlap (by approximately 1 to 2 cm) with the existing EVARREST sealant matrix.
• • If bleeding is due to incomplete adherence to the tissue (where bleeding persists from under the dressing), remove EVARREST sealant matrix and use a new EVARREST sealant matrix.
• • If bleeding still occurs during or after the specified duration of compression, remove the used EVARREST sealant matrix and inspect the bleeding site. If no other primary haemostatic measures (i.e., standard surgical techniques) appear to be required, repeat the application procedure above with a new EVARREST sealant matrix.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements

7. MARKETING AUTHORISATION HOLDER

Omrix Biopharmaceuticals N.V.

Leonardo Da Vincilaan 15

1831 Diegem

Belgium

Telephone: +32 2 746 30 00

Telefax: + 32 2 746 30 01

• 8. MARKETING AUTHORISATION

  BER(S)

  
  

EU/1/13/868/001

EU/1/13/868/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION