- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1.NAME OF THE MEDICINAL PRODUCT
EVARREST Sealant Matrix
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
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.
EVARREST is a
Supportive treatment in adult surgery where standard surgical techniques are insufficient (see section 5.1):
-for improvement of haemostasis.
4.2Posology and method of administration
The use of EVARREST is restricted to experienced surgeons.
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
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
If haemostasis is not reached with one application of EVARREST,
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).
●EVARREST must not be applied intravascularly.
●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 the product.
●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.
●EVARREST must not be used in the presence of active infection or in contaminated areas of the body because infection may occur.
4.4Special warnings and precautions for use
For epilesional use only. Do not apply intravascularly
As with any protein containing product,
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
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
It is strongly recommended that every time EVARREST 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.
4.5Interaction with other medicinal products and other forms of interaction
No 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.
4.6Fertility, pregnancy and lactation
The safety of fibrin sealants/haemostatics for use in human pregnancy or during
Therefore, the product should be administered to pregnant and lactating women only if clearly needed.
4.7Effects on ability to drive and use machines
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.
The safety data for EVARREST reflect the types of
EVARREST was used to treat soft tissue bleeding during retroperitoneal,
Study subjects were followed
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
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:
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
Deep vein thrombosis
Respiratory, thoracic and
Peripancreatic fluid collection
Blood fibrinogen increased
Injury, poisoning and procedural
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
- Evicel - Omrix Biopharmaceuticals N. V.
Prescription drugs listed. Manufacturer: "Omrix Biopharmaceuticals N. V."
Three subjects out of 145 (~2%) in a clinical trial group treated with EVARREST showed an increase in the titre of
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.
No case of overdose has been reported.
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
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 product and supports clot formation. The clot formation of EVARREST is integrated with the Matrix; it forms a mechanical barrier to bleeding and reinforces the wound site. Natural healing occurs while 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 EVARREST and 30 with control) undergoing abdominal, retroperitoneal, pelvic, and
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.
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).
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
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.
5.3Preclinical safety data
The haemostatic efficacy of EVARREST was demonstrated in a number of animal models assessing time to haemostasis and
6.1List of excipients
Composite Matrix (Polyglactin 910 and oxidised regenerated cellulose) 20 mg/cm2 Arginine hydrochloride
Glycine Sodium chloride Sodium citrate
Calcium chloride Human albumin Mannitol Sodium acetate
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Once the foil sachet is opened, EVARREST can remain in the sterile field to be available for use throughout the procedure.
6.4Special precautions for storage
Do not store above 25°C. Do not freeze.
6.5Nature 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.
6.6Special 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.
●The lower portion of the tray contains EVARREST with the active side facing downwards. The active side is powdery in appearance. The
●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.
Application of EVARREST
EVARREST is to be applied with approximately 3 minutes of firm manual compression.
1.Using sterile scissors, carefully cut EVARREST 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
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
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.
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.
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
Telephone: +32 2 746 30 00
Telefax: + 32 2 746 30 01
8.MARKETING AUTHORISATION NUMBER(S)
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 29 September 2013
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.