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Raplixa (human fibrinogen / human thrombin) – Summary of product characteristics - B02BC30

Updated on site: 09-Oct-2017

Medication nameRaplixa
ATC CodeB02BC30
Substancehuman fibrinogen / human thrombin
ManufacturerMallinckrodt Specialty Pharmaceuticals Ireland Ltd

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

Raplixa sealant powder

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gram of powder contains 79 mg human fibrinogen and 726 IU human thrombin.

Raplixa is supplied in three different presentations 0.5 grams (39.5 mg human fibrinogen and 363 IU human thrombin), 1 gram (79 mg human fibrinogen and 726 IU human thrombin) and 2 grams (158 mg human fibrinogen and 1452 IU human thrombin).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Sealant powder

Dry white powder.

4. CLINICAL PARTICULARS

4.1Therapeutic indications

Supportive treatment where standard surgical techniques are insufficient for improvement of haemostasis. Raplixa must be used in combination with an approved gelatin sponge (see section 5.1).

Raplixa is indicated in adults over 18 years of age.

4.2Posology and method of administration

The use of Raplixa is restricted to experienced surgeons.

Gelatin sponges must be used in combination with Raplixa. Gelatin sponges are CE marked and separately supplied and packed (see instructions for use for the specific gelatin sponge selected for use).

Posology

The amount of Raplixa to be applied and the frequency of application should always be oriented towards the underlying clinical needs for the patient. The dose to be applied is governed by variables including, but not limited to, the type of surgery, the size of the bleeding surface area, the severity of bleeding, the mode of application selected by the surgeon, and the number of applications.

Application of the product must be individualised by the treating surgeon. In clinical trials a thin layer of Raplixa produced doses that typically ranged from 0.3 to 2 g. For some procedures eg. liver resection, larger amounts may be required. The initial amount 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 with a thin layer

of Raplixa which is then covered by an absorbable gelatin sponge (saline-wetted). The application can be repeated, if necessary.

The required dose of Raplixa, can vary based on the size of the area to be treated. In clinical trials, smaller bleeding sites (< 10 cm²) used 0.5 g to 1 g on average. Larger bleeding sites used 1 to 2 grams

(10-100 cm²). It is known from in vitro testing that 1 g can cover 100 cm² using the RaplixaSpray device. Maximum amount of Raplixa recommended is 3 gram.

The required dose of Raplixa based on the size of the bleeding surface area to be treated is shown in the table below:

Table 1:

Required Dose of Raplixa

 

Maximum Surface Area

Maximum Surface Area

Raplixa Package Size

Direct Application from Vial

Application Using RaplixaSpray

 

 

25 cm²

50 cm²

0.5 g

 

50 cm²

100 cm²

1.0 g

Paediatric Population

The safety and efficacy of Raplixa in children and adolescents under the age of 18 years have not been established. No data are available, Raplixa is therefore not recommended for use in children and adolescents.

Elderly

Dose adjustment not required.

Method and route of administration For epilesional use only.

For instructions on use of the medicinal product before administration, see section 6.6.

One of the following methods of application of Raplixa may be used based on the type of surgery, location and size and severity of the bleeding:

Direct application followed by gelatin sponge

Powder is applied directly from the vial onto the bleeding surface and then applied to a CE marked gelatin sponge cut to the appropriate size and apply manual pressure with sterile gauze.

Apply first to gelatin sponge

Powder is applied directly from the vial onto a saline-wetted CE marked gelatin sponge and then applied to the bleeding site. When using a moistened gelatin sponge, a thin layer of Raplixa should be applied to the sponge immediately prior to application to the bleeding site.

Spray application using RaplixaSpray device followed by gelatin sponge

The vial and RaplixaSpray device are taken out of their respective pouches maintaining sterility. Connect the RaplixaSpray device to the RaplixaReg pressure regulator and thereby to the medical CO2 gas supply (CO2 is recommended; Raplixa may be also used with medical grade air) set to a pressure setting of

1.5 bar (22 psi).

The vial should be held upright, shaken gently and the aluminium cap and rubber stopper should be removed.

The vial with powder is attached to the RaplixaSpray device by inverting the device over the upright vial and pushing the vial into place.

The RaplixaSpray device is used to spray the powder on to the bleeding site and then the gelatin sponge is applied (see Instructions For Use for RaplixaSpray device and gelatin sponge).

Application must be within 2 hours after connecting the vial to the device.

The RaplixaSpray device comes with the rigid nozzle attached. This may be removed and the flexible nozzle can be attached depending on the intended use and surgeon preference.

To avoid the risk of potentially life-threatening air embolism Raplixa is recommended to be sprayed using pressurised CO2. Raplixa may also be used with medical air (see sections 4.4 and 6.6).

4.3Contraindications

Known hypersensitivity to the Raplixa active substances or to any of the excipients listed in section 6.1. Raplixa must not be applied intravascularly.

Spray application of Raplixa must not be used in endoscopic or laparoscopic procedures. Raplixa must not be used as a glue for the fixation of patches.

Raplixa must not be used as a glue for intestines (gastrointestinal anastomoses). Do not use Raplixa for treatment of severe arterial bleeding.

4.4Special warnings and precautions for use

Use and Application

For epilesional use only. Do not apply intravascularly. Follow specific instructions for use of the absorbable gelatin sponge.

Do not use Raplixa (and gelatin sponge) in contaminated areas of the body, or in the presence of active infection.

Intravascular application

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

Air or gas emboli

Life threatening air or gas embolism has occurred with the use of spray devices employing a pressure regulator to administer fibrin sealant/haemostatic products. This event appears to be related to the use of spray devices at higher than recommended pressures and/or in close proximity to the tissue surface. The risk appears to be higher when fibrin sealants are sprayed with air, as compared to CO2 and therefore cannot be excluded with Raplixa. Before administration of Raplixa 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. Spray application of Raplixa should only be used if it is possible to accurately judge the spray distance. Spray distance from tissue and pressure should be within the ranges recommended by the manufacturer (see table in section 6.6 for pressure and distance).

When spraying Raplixa, changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored because of the possibility of occurrence of air or gas embolism.

When using accessory nozzles with this product, the instructions for use of the nozzles should be followed.

Hypersensitivity reactions

As with any protein product, allergic type hypersensitivity reactions are possible. Signs of hypersensitivity reactions may include hives, generalized urticarial, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur, the administration should be discontinued immediately.

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

Transmissible infectious agents

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 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 human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV).

The measures may be of limited value against non- enveloped viruses such as HAV and parvovirus B19. Parvovirus B19 may be serious for pregnant women (fetal infection) and of individuals with immunodeficiency or increased erythropoiesis (e.g. Haemolytic anaemia).

Other

Raplixa has been studied in patients undergoing spinal surgery, vascular surgery, soft tissue surgery and hepatic resection. There is limited experience of use of Raplixa in vascular surgery when applied with the RaplixaSpray device.

Data are not available to support the use of this product in tissue gluing, neurosurgery, application through a flexible endoscope for treatment of bleeding or in gastrointestinal anastomoses.

It is strongly recommended that every time Raplixa 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 formal interaction studies have been performed.

Raplixa may be denatured after exposure to solutions containing alcohol, iodine or heavy metals (e.g. antiseptic solutions). Such substances should be removed as much as possible before applying the product.

4.6Fertility, pregnancy and lactation

Pregnancy and Breast-feeding

Animal reproduction studies have not been conducted with Raplixa. The safety of Raplixa for use in human pregnancy or during breast-feeding has not been established in controlled clinical trials.

The product should not be administered to pregnant and breast-feeding women.

Fertility

Fertility studies have not been conducted.

4.7Effects on ability to drive and use machines

Not relevant.

4.8Undesirable 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 isolated cases in patients treated with fibrin sealants / haemostatics: 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 disseminated intravascular coagulation (DIC), and there is also a risk of anaphylactic reaction (see section 4.4).

Life threatening air or gas embolism has occurred with the use of spray devices employing pressure regulators to administer the fibrin sealant. This event appears to be related to the use of the spray device at higher than recommended pressures and/or in close proximity to the tissue surface. The risk appears to be higher when fibrin sealants are sprayed with air, as compared to CO2 and therefore cannot be excluded with Raplixa.

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

Tabulated list of adverse reactions

System organ class

Common (≥1/100 to <1/10)

General disorders and administrative site conditions

Insomnia

 

Pruritus

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.

Ireland

HPRA Pharmacovigilance Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie

e-mail: medsafety@hpra.ie

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9Overdose

In the event of overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment and supportive measures instituted.

5. PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: local haemostatics, other haemostatics

ATC code: B02BC30

Mechanism of Action

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 from 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.

Clinical studies with Raplixa demonstrating haemostasis were conducted in patients undergoing spinal (n=146), vascular (n=137), liver (n=158) and soft tissue surgery (n=125).

Clinical studies in the EU were done with the CE marked Spongostan gelatin sponge. Bleeding at target sites was mild or moderate. Conventional surgical techniques such as suture, ligature and cautery were ineffective or impractical. The combination of Raplixa and a gelatin sponge reduced the median time to haemostasis at target sites by up to 2 minutes compared to a gelatin sponge alone.

The European Medicines Agency has deferred the obligation to submit the results of studies with Raplixa in one or more subsets of the paediatric population in the treatment of haemorrhage resulting from surgical procedure as per Paediatric Investigational Plan (PIP) decision, for the granted indication (see section 4.2 for information on paediatric use).

5.2Pharmacokinetic properties

Raplixa is intended for epilesional use only. Intravascular administration is contraindicated. As a consequence, intravascular pharmacokinetic studies were not performed in man.

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

5.3Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

6. PHARMACEUTICAL PARTICULARS

6.1List of excipients

Trehalose

Calcium chloride

Albumin

Sodium chloride

Sodium citrate

L-arginine-hydrochloride

6.2Incompatibilities

In absence of compatibility studies, Raplixa must not be mixed with other medicinal products.

6.3Shelf life

3 years

In use shelf life: Once the vial is opened Raplixa should be applied within 2 hours.

6.4Special precautions for storage

Store between + 2 °C to + 25 °C.

Keep the vial in the outer packaging in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5Nature and contents of container

0.5 g, 1 g, 2 g of powder per vial (Type I glass) with a rubber stopper and aluminium/ plastic tear-off.

Presentation

Pack of 1 vial.

Not all pack sizes may be marketed.

6.6Instructions for use and handling and special precautions for disposal

Raplixa is a pre-mixed, ready to use blend of thrombin and fibrinogen supplied as a ready to use dry- powder fibrin sealant in a glass vial containing 0.5 g, 1 g or 2 g of Raplixa that is applied onto the surgical bleeding site directly from the vial or using the RaplixaSpray device. The Raplixa should be stored at controlled, ambient room temperature. The outer aluminium foil sachet may be opened in a non-sterile operating area. The vial must be opened in a sterile field.

There are three methods of application: direct application of Raplixa to the bleeding tissue followed by application of the gelatin sponge or application of Raplixa first to a gelatin sponge and application of the sponge to the bleeding tissue; or application of the Raplixa powder by using the RaplixaSpray device followed by the application of the gelatin sponge.

Prior to applying Raplixa 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 administered according to the instructions and with the devices recommended for this product.

The initial amount 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 with a thin layer of Raplixa which is then covered by an absorbable gelatin sponge (saline-wetted). The application can be repeated, if necessary.

When using the RaplixaSpray device

Take the vial and device out of their respective pouches maintaining sterility. Connect the RaplixaSpray device to the RaplixaReg air pressure regulator or CO2 pressure regulator and thereby to the medical air or CO2 gas supply set to a pressure setting of 1.5 bar (22 psi). Hold the vial upright, shake gently and remove the aluminium cap and rubber stopper.

Connect the vial to the device by inverting the device over the upright vial and pushing the vial into place. Raplixa should not be sprayed at a distance closer than that recommended by the spray device manufacturer and in no case closer than 5 cm from the tissue surface.

The pressure should be within the range recommended by ProFibrix. Spray application of Raplixa should only be done using the provided spray application accessories and the pressure should not exceed 1.5 bars (22 psi).

Application must be within 2 hours after connecting the vial to the device. The RaplixaSpray device comes with the rigid nozzle attached, which can be easily removed and the flexible nozzle attached depending on the intended use and surgeon preference.

To avoid the risk of potentially life-threatening air embolism, it is recommended that Raplixa should be sprayed using pressurised CO2. Raplixa may also be used with medical air. See section 4.4.

When spraying Raplixa, changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored because of the possibility of occurrence of air or gas embolism.

Surgery

Spray set to

Applicator

Pressure

Recommended

Recommended

 

be used

tips to be used

regulator to

distance from

spray pressure

 

 

 

be used

target tissue

 

Open surgery

1 or 2

RaplixaReg

5 cm

1.5 Bar (22 psi)

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

7. MARKETING AUTHORISATION HOLDER

Mallinckrodt Pharmaceuticals Ireland Ltd

College Business & Technology Park

Cruiserath

Blanchardstown

Dublin 15

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/985/001

EU/1/14/985/002

EU/1/14/985/003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 March 2015

10. DATE OF REVISION OF TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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