This information is intended for use by health professionals

 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

FibCLOT 1.5 g. Powder and solvent for solution for injection/infusion.

2. Qualitative and quantitative composition

Human Fibrinogen

Each vial of FibCLOT contains nominally 1.5 g of human fibrinogen.

After reconstitution with 100 mL of solvent (water for injections), FibCLOT contains nominally 15 mg/mL of human fibrinogen.

The potency is determined according to the European Pharmacopoeia monograph for human fibrinogen.

Produced from the plasma of human donors.

Excipients with known effect: the product contains a maximum of 69 mg of sodium/vial.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder and solvent for solution for injection/infusion.

White or pale yellow powder in a vial.

4. Clinical particulars
4.1 Therapeutic indications

Treatment and perioperative prophylaxis of bleeding in patients with congenital hypo- or afibrinogenaemia with bleeding tendency.

4.2 Posology and method of administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of coagulation disorders.

Posology

The dosage and duration of the substitution therapy depend on the severity of the disorder, location and extent of bleeding and the patient's clinical condition.

The (functional) fibrinogen level should be determined in order to calculate individual dosage and the amount and frequency of administration should be determined on an individual patient basis by regular measurement of plasma fibrinogen level and continuous monitoring of the clinical condition of the patient and other replacement therapies used.

Normal plasma fibrinogen level is in the range of 1.5 - 4.5 g/L. In congenital hypo- or afibrinogenaemia, the critical plasma fibrinogen level below which haemorrhages may occur is approximately 0.5 – 1.0 g/L.

In case of major surgical intervention, precise monitoring of replacement therapy by coagulation assays is essential.

Treatment of bleeding and prophylaxis in patients with congenital hypo- or afibrinogenaemia and known bleeding tendency.

To treat nonsurgical bleeding episodes, it is recommended to raise fibrinogen levels to 1 g/L and maintain fibrinogen at this level until haemostasis is controlled and above 0.5 g/L until healing is complete.

To prevent excessive bleeding during surgical procedures, prophylactic treatment is recommended to raise fibrinogen levels to 1 g/L and maintain fibrinogen at this level until haemostasis is controlled and above 0.5 g/L until wound healing is complete.

In case of surgical procedure or treatment of a nonsurgical bleeding, the dose should be calculated as follows:

Dose (g) = (target level (g/L) – baseline level (g/L)) x 0.043 x body weight (kg),

where 0.043 corresponds to 1/recovery ((g/L)/(g/kg)).

In case of an emergency situation when the baseline fibrinogen level is not known, the recommended initial dose is 0.05 g per kg of body weight administered intravenously.

Subsequent posology (doses and frequency of injections) should be adapted based on the patient's clinical status and laboratory results.

Biological half-life of fibrinogen is 3 - 4 days. Thus, in the absence of consumption, repeated treatment with human fibrinogen is not usually required. Given the accumulation that occurs in case of repeated administration for a prophylactic use, the dose and the frequency should be determined according to the therapeutic goals of the physician for a given patient.

Paediatric population

Currently available data are described in section 4.8 and 5.1 but no recommendation on a posology can be made in children.

Method of administration

Intravenous infusion or injection.

FibCLOT should be administered by slow intravenous infusion. Maximum rate of 4 mL/min.

For instructions on reconstitution of the product before administration, see sections 6.2 and 6.6.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Thromboembolism

There is a risk of thrombosis when patients are treated with human fibrinogen particularly with high dose or repeated dosing. Patients given human fibrinogen should be observed closely for signs or symptoms of thrombosis.

In patients with a history of coronary heart disease or myocardial infarction, in patients with liver disease, in peri- or post-operative patients, in neonates, or in patients at risk of thromboembolic events or disseminated intravascular coagulation, the potential benefit of treatment with human plasma fibrinogen should be weighed against the risk of thromboembolic complications. Caution and close monitoring should also be performed.

Allergic or anaphylactic-type reactions

If allergic or anaphylactic-type reactions occur, the injection/infusion should be stopped immediately. In case of anaphylactic shock, standard medical treatment for shock should be implemented.

Transmissible 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 or 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 (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived fibrinogen.

It is strongly recommended that every time that FibCLOT 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.

Immunogenicity

In the case of replacement therapy with coagulation factors in other congenital deficiencies, antibody reactions have been observed, but there is currently no data with fibrinogen.

Sodium Level

The product contains a maximum of 3 mmol (or 69 mg) of sodium/vial. This should be taken into consideration in patients following a strict low sodium diet.

Paediatric population

Same warnings and precaution apply to the paediatric population.

4.5 Interaction with other medicinal products and other forms of interaction

No interactions of human fibrinogen products with other medicinal products are known.

4.6 Fertility, pregnancy and lactation

The safety of human plasma fibrinogen products for use in human pregnancy and during lactation has not been established in controlled clinical trials.

Clinical experience with fibrinogen products in the treatment of obstetric complications suggests that no harmful effects on the course of the pregnancy or health of the foetus or the neonate are to be expected.

4.7 Effects on ability to drive and use machines

FibCLOT has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Tabulated list of adverse reactions

The adverse reactions presented in the table below have been reported in 35 patients with congenital fibrinogen deficiency included in two clinical interventional studies and in one non-interventional post-marketing safety study. During these studies, 36 adverse reactions have been reported in 13/35 (37.1%) patients who received a total of 572 infusions of FibCLOT.

The most significant reactions are described according to the MedDRA classification (System Organ Class and Preferred Term Level). Frequencies have been estimated on a per-infusion basis according to the following conventions: 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); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA Standard System Organ Class

Adverse reactions

Frequency per infusion

(N=572)

Immune system disorders

Allergic/anaphylactic-type reactions (including anaphylactic shock, pallor, vomiting, cough, blood pressure decreased, chills, urticaria)

Uncommon

Nervous system disorders

Headache

Dizziness

Common

Uncommon

Ear and labyrinth disorders

Tinnitus

Uncommon

Vascular disorders

Thromboembolic episodes (including deep vein thrombosis, superficial thrombophlebitis) (see section 4.4)

Uncommon

Respiratory, thoracic and mediastinal disorders

Asthma

Uncommon

Skin and subcutaneous tissue disorders

Rash erythematous

Erythema

Skin irritation

Night sweat

Uncommon

Uncommon

Uncommon

Uncommon

General disorders and administration site conditions

Feeling hot

Uncommon

For safety with respect to transmissible agents, see 4.4.

The overall safety profile does not differ in patients treated with FibCLOT in other clinical situations requiring fibrinogen therapy.

Paediatric population:

Among the 35 patients included in the congenital fibrinogen deficiency safety analysis, 14 were less than 18 years, including 10 less than 12 years and 3 under the age of 6.

The overall safety profile does not differ between adults and paediatric patients.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

In order to avoid overdosage, regular monitoring of the plasma level of fibrinogen therapy is indicated (see 4.2).

In case of overdosage, the risk of development of thromboembolic complications is enhanced.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antihaemorrhagics, human fibrinogen, ATC code: B02BB01

Human fibrinogen (coagulation factor I), in the presence of thrombin, activated coagulation factor XIII (FXIIIa) and calcium ions, is converted into a stable and elastic three-dimensional fibrin haemostatic clot.

The administration of human fibrinogen provides an increase in plasma fibrinogen level and can temporarily correct the coagulation defect of patients with fibrinogen deficiency.

In a clinical pharmacology study (dose 0.06 g/kg of FibCLOT), normalisation of global coagulation tests (e.g. activated partial thromboplastin time [aPTT] and prothrombin time [PT]) was achieved at fibrinogen levels at or above 0.5 g/L and lasted for at least 3 days.

Across all studies in congenital fibrinogen deficiency, FibCLOT was administered for:

• 100 nonsurgical bleeding episodes in 18 patients (including 17 major episodes in 9 patients),

• 38 surgical procedures in 15 patients (including 10 major procedures in 7 patients).

The majority (92.8%) of the events (128/138) were managed with a single dose of about 3 g FibCLOT, corresponding to a median dose per infusion of 0.050 g/kg.

In a post marketing study, 9 patients have been treated for long term prophylaxis for at least 12 months with a median dose of 0.059 g/kg once a week.

Paediatric population

FibCLOT was administered in clinical studies in 14 patients under the age of 18 years. The median dose per infusion was 0.059 g/kg for the treatment of 26 nonsurgical bleeding episodes or prevention of excessive bleeding during 14 surgical procedures.

The European Medicines Agency has deferred the obligation to submit the results of study with FibCLOT in patients less than 12 years of age as per Paediatric Investigation Plan (PIP) decision (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

In plasma, the biological half-life of fibrinogen is 3-4 days.

The product is administered intravenously and is immediately available in the plasma at concentration corresponding to the dosage administered.

In a clinical pharmacology study, 14 patients were evaluated over 14 days. After infusion of a dose of 0.06 g/kg of FibCLOT, the maximal fibrinogen concentration was reached within 1 hour and was followed by a slow decrease reaching the critical plasma fibrinogen level of 0.5 g/L in about 3 to 4 days.

Pharmacokinetic parameters

FibCLOT single dose IV infusion

(Geometric mean (geometric CV%))

Cmax (g/L)

1.4

(24.4)

t1/2 (h)

69.3

(21.8)

AUC0-∞ (g.h/L)

114

(23.4)

MRT (h)

95.6

(20.7)

Cl (mL/h/kg)

0.53

(22.0)

Vss (mL/kg)

50.7

(16.7)

IR ((g/L)/(g/kg))

23.5

(23.2)

R (%)

93.6

(20.9)

Cmax = maximum concentration (activity)

t1/2 = terminal elimination half-life

AUC = area under the curve

MRT = mean residence time

Cl = clearance

Vss = volume of distribution at steady state

IR = incremental recovery

R = in vivo recovery

CV = coefficient of variation

Paediatric population

No pharmacokinetic data are available in paediatric patients <12 years of age.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity as well as thrombogenicity.

Given the nature of the product carcinogenicity studies were not conducted. Animal reproduction studies have not been performed since fibrinogen is a normal constituent of the human body.

6. Pharmaceutical particulars
6.1 List of excipients

Powder:

Arginine hydrochloride

Isoleucine

Lysine hydrochloride

Glycine

Sodium citrate dihydrate

Solvent:

Water for injections.

6.2 Incompatibilities

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

A standard infusion set is recommended for intravenous application of the reconstituted solution at room temperature.

6.3 Shelf life

3 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 25 °C. From a microbiological point of view the product should be used immediately.

6.4 Special precautions for storage

Do not store above 25°C.

Do not freeze.

Store in the original outer package in order to protect from light and moisture.

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

6.5 Nature and contents of container

One pack contains:

- Powder (1.5 g human fibrinogen) in a colourless type I glass vial sealed with a siliconised bromobutyl stopper, an aluminium cap and a plastic disc.

- Solvent (100 mL water for injections) in a type II glass vial sealed with a bromobutyl stopper, an aluminium cap and a plastic disc.

- Transfer system equipped with a sterile filtering air vent.

6.6 Special precautions for disposal and other handling

Reconstitution:

Use current guidelines for aseptic procedure.

If necessary, increase the temperature of the two vials (powder and solvent) to ambient temperature.

Remove the protective cap from the solvent vial and from the powder vial.

Disinfect the surface of each stopper.

Remove the translucent protective sheath from the transfer system and completely insert the exposed piercing spike through the centre of the stopper of the solvent vial while simultaneously twisting the piercing spike.

Remove the second grey protective sheath from the other end of the transfer system.

Turn the solvent vial and quickly push the free end of the piercing spike into the center of the stopper of the powder vial to allow the solvent to transfer into the powder.

Ensure that the spike always remains immersed in the solvent to avoid releasing the vacuum prematurely.

During transfer, direct the jet of solvent over the entire surface of the powder and along the wall of the vial by a rotational horizontal movement. Ensure that all of the solvent is transferred.

The vacuum is automatically released at the end of the transfer procedure by sterile air through the venting part of the transfer system.

Remove the empty vial (solvent) with the transfer system.

Gently swirl for a few minutes with a rotating movement to avoid the formation of foam until the powder has completely dissolved.

The reconstituted product should be examined visually prior to administration in order to ensure that it does not contain particulate matter. The reconstituted solution should be almost colourless, slightly opalescent. Do not use solutions which are cloudy or contain deposits.

Administration:

FibCLOT should only be administered intravenously, as a single dose, immediately after reconstitution, at no more than 4 mL/min.

If the reconstituted solution is not administered immediately, storage shall not exceed 24 hours at room temperature (maximum 25°C).

It is recommended to use an infusion set with a non-sterilising 15 µm filter.

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

7. Marketing authorisation holder

Laboratoire Français du Fractionnement et des Biotechnologies

3 Avenue des Tropiques

ZA de Courtaboeuf

91940 Les Ulis

FRANCE

Tel: + 33 (0)1 69 82 70 10

Fax: + 33 (0)1 69 82 19 03

8. Marketing authorisation number(s)

PL 17469/0006

9. Date of first authorisation/renewal of the authorisation

05/04/2016

10. Date of revision of the text

05/04/2016