Fibryga

Human fibrinogen.

Each bottle of FIBRYGA contains 1 g human fibrinogen. After reconstitution with 50 mL water for injections FIBRYGA contains approximately 20 mg/mL human fibrinogen.
The content of clottable protein is determined according to the European Pharmacopoeia for human fibrinogen.
Produced from the plasma of human donors.
Excipients with known effect: sodium up to 132 mg (5.8 mmol) per bottle.
Excipients/Inactive Ingredients: Powder: L-arginine hydrochloride, Glycine, Sodium chloride, Sodium citrate dihydrate.
Solvent: Water for Injections.

Pharmacotherapeutic group: antihaemorrhagics, fibrinogen. ATC code: B02BB01.
Pharmacology: Pharmacodynamics: 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.
An open-label, prospective, randomized, controlled, two-arm cross-over single-dose pharmacokinetic phase 2 study in 22 patients with congenital fibrinogen deficiency (afibrinogenaemia) (see Pharmacology: Pharmacodynamics under Actions) also evaluated the maximum clot firmness (MCF) as a surrogate marker for haemostatic efficacy (FORMA-01). MCF was determined by thromboelastometry (ROTEM) testing. For each patient, MCF was determined before (baseline) and one hour after the single-dose administration of FIBRYGA. MCF values were significantly higher after administration of FIBRYGA than at baseline (see the table as follows). (See Table 1.)

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A prospective, open label, uncontrolled, multicentre phase 3 study (FORMA-02) was conducted in 25 patients with congenital fibrinogen deficiency (afibrinogenaemia and hypofibrinogenaemia), ranging in age from 12 to 54 years (6 adolescents, 19 adults). This included the treatment of 89 bleeding episodes and 12 surgical procedures. There was significant change from baseline in the MCF as measured by ROTEM and fibrinogen plasma levels. The median dose of FIBRYGA per infusion for the treatment of bleeding episodes was 57.5 mg/kg and the median total dose was 59.4 mg/kg. The median total dose of FIBRYGA per surgery was 85.8 mg/kg. Overall haemostatic efficacy was rated as successful (rating of good or excellent efficacy) for 98.9% of the treated bleeding episodes and for 100% of the surgeries by an independent adjudication committee using an objective scoring system.
Another prospective, open label, uncontrolled, multicentre phase 3 study (FORMA-04) was conducted in 14 children with congenital fibrinogen deficiency (afibrinogenaemia and hypofibrinogenaemia), ranging in age from 1 to 10 years (6 <6 years of age and 8 between 6 and <12 years of age). This included the treatment of 10 bleeding episodes and 3 surgical procedures, as well as single dose pharmacokinetics. There was a significant change from baseline in the MCF as measured by ROTEM and fibrinogen plasma levels. The median dose of FIBRYGA per infusion for treatment of bleeding episodes was 70.2 mg/kg and the median total dose was 73.9 mg/kg. The median total dose of FIBRYGA per surgery was 108 mg/kg. Overall haemostatic efficacy was rated as successful (rating of good or excellent efficacy) for 100 % of the treated bleeding episodes and of the surgeries by an independent adjudication committee using an objective scoring system.
The prospective, randomised, controlled study FORMA-05 investigated the haemostatic efficacy and safety of FIBRYGA by comparison with cryoprecipitate as fibrinogen supplementation sources in patients developing acquired fibrinogen deficiency during cytoreductive surgery for the extensive abdominal malignancy pseudomyxoma peritonei. The study included 43 adult patients in the Per Protocol (PP) analysis set, 21 patients treated with FIBRYGA and 22 patients treated with cryoprecipitate. Intraoperative fibrinogen supplementation was performed pre-emptively (i.e. after 60-90 minutes in surgery, when excessive blood loss was observed, but before 2 litres of blood had been lost) with doses of 4 g of FIBRYGA or of 2 pools of 5 units of cryoprecipitate, repeated as needed. During the 7.8 ± 1.7 hours of surgery, 6.5 ± 3 g of FIBRYGA (89 ± 39 mg/kg bw) and 4.1 ± 2.2 pools of 5 units of cryoprecipitate were used, respectively. A median of 1 unit and 0.5 units RBC were administered intraoperatively to the patients treated with FIBRYGA and cryoprecipitate, respectively, with a median of 0 units RBC during the first 24 hours post-operatively in both groups (see the table as follows). No fresh frozen plasma or platelet concentrates were transfused during the study Haemostatic therapy based on fibrinogen supplementation was rated as successful for 100% of the surgeries in both groups by an independent adjudication committee using an objective scoring system. (See Table 2.)

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Paediatric population: In congenital fibrinogen deficiency, FIBRYGA was administered in two clinical studies (FORMA-02 and FORMA-04) in 20 patients from 1 to <18 years of age, of which 6 adolescents 12 to <18 years of age, 8 children 6 to <12 years of age and 6 children 1 to <6 years of age. Haemostatic efficacy was assessed as successful by an independent adjudication committee for all bleeding episodes treated (10 bleeding episodes in adolescents, 5 in children 6 to <12 years of age and 5 in children 1 to <6 years of age) and prophylaxis was also assessed as successful for the 4 surgeries performed in these patients (1 in adolescents and 3 in children 1 to <6 years of age).
Pharmacokinetics: Human fibrinogen is a normal constituent of human plasma and acts like endogenous fibrinogen. In plasma, the biological half-life of fibrinogen is 3-4 days. FIBRYGA is administered intravenously and is immediately available in a plasma concentration corresponding to the dosage administered.
An open-label, prospective, randomised, controlled, two-arm cross-over phase 2 study in 22 patients with congenital fibrinogen deficiency (afibrinogenaemia), ranging in age from 12 to 53 years (6 adolescents, 16 adults), compared the single-dose pharmacokinetic properties of FIBRYGA with those of another commercially available fibrinogen concentrate in the same patients (FORMA-01).
Each patient received a single intravenous 70 mg/kg dose of FIBRYGA and the comparator product. Blood samples were drawn to determine the fibrinogen activity at baseline and up to 14 days after the infusion. The pharmacokinetic parameters of FIBRYGA in the per protocol (PP) analysis (n=21) are summarised in the table as follows. (See Table 3.)

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The incremental in vivo recovery (IVR) was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was 1.8 mg/dL (range, 1.08-2.62 mg/dL) increase per mg/kg. The median IVR indicates that a dose of 70 mg/kg will increase the patient's fibrinogen plasma concentration by approximately 125 mg/dL.
Pharmacokinetics in specific populations: No statistically relevant difference in fibrinogen activity was observed between male and female study participants.
Paediatric population: Pharmacokinetic data in adolescents from 12 to less than 18 years of age was obtained in the FORMA-02 study. In the PP analysis, a small difference between the half-life for adolescents (n=5) and for adults (n=16) was observed, with 72.8 ± 16.5 hours as compared to 76.9 ± 26.1 hours, respectively. Clearance was almost identical in the two age groups, i.e., 0.68 ± 0.18 mL/hr/kg and 0.66 ± 0.21 mL/hr/kg, respectively.
The pharmacokinetic properties of FIBRYGA were further investigated in the FORMA-04 study in 13 children less than 12 years of age with congenital fibrinogen deficiency (afibrinogenaemia). Each patient received a single intravenous 70 mg/kg dose of FIBRYGA. The pharmacokinetic parameters of FIBRYGA are summarised in the table as follows. The median incremental IVR was 1.4 mg/dL (range, 1.3-2.1 mg/dL) increase per mg/kg. (See Table 4.)

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Lower incremental in vivo recovery (IVR), faster clearance and shorter half-life were observed in children aged 1 to less than 12 years of age, compared to adults and adolescents. As higher doses of FIBRYGA were administered for the treatment of bleeding episodes in children aged 1 to less than 12 years of age, higher doses may be required in this age group.
Toxicology: Preclinical safety data: The safety of FIBRYGA has been demonstrated in several non-clinical safety pharmacology (cardiovascular effects, thrombogenic potential) and toxicology studies (acute toxicity, local tolerance). The non-clinical data reveal no special hazard for humans based on these studies. In the venous stasis test (Wessler test) FIBRYGA proved to be non-thrombogenic at doses up to 400 mg/kg body weight.

Treatment of bleeding episodes and peri-operative prophylaxis in patients with congenital hypo- or afibrinogenaemia with bleeding tendency.
As complementary therapy to management of uncontrolled severe haemorrhage in patients with acquired hypofibrinogenaemia in the course of surgical intervention.

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.
In case of major surgical intervention, precise monitoring of replacement therapy by coagulation assays is essential.
1. Prophylaxis in patients with congenital hypo- or afibrinogenaemia and known bleeding tendency.
Adult and Adolescent (≥12 years old) Population: 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 secured and above 0.5 g/L until wound healing is complete.
In case of surgical procedure or treatment of a bleeding episode, the dose should be calculated as follows: (See Equation 1.)

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Subsequent posology (doses and frequency of injections) should be adapted based on the patient's clinical status and laboratory results.
The 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.
FIBRYGA dose when baseline fibrinogen level is not known: If the patient's fibrinogen level is not known, the recommended dose is 60 mg/kg of body weight.
Paediatric population (<12 years old): In case of surgical procedure or treatment of a bleeding episode, the dose in adolescents should be calculated according to the formula previously described for adults, while the dose in children <12 years of age should be calculated as follows: (See Equation 2.)

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Subsequent posology should be adapted based on the patient's clinical status and laboratory results.
Elderly patients: Clinical studies of FIBRYGA did not include patients aged 65 years and over to provide conclusive evidence as to whether or not they respond differently than younger patients.
2. Treatment of bleeding: Bleeding in patients with congenital hypo- or afibrinogenaemia: Bleeding episodes should be treated according to the formulas previously mentioned for adults/adolescents and children, respectively, to achieve a recommended target fibrinogen plasma level of 1 g/L. This level should be maintained until haemostasis is secured.
Bleeding in patients with acquired fibrinogen deficiency: Adults: Generally 1-2 g is administered initially with subsequent infusions as required. In case of severe haemorrhage e.g. major surgery, larger amounts (4-8 g) of fibrinogen may be required.
Paediatric population (<18 years old): The dosage should be determined according to the body weight and clinical need but is usually 20-30 mg/kg.
Method of administration: Intravenous infusion or injection.
FIBRYGA should be administered slowly intravenously at a recommended maximum rate of 5 mL per minute for patients with congenital hypo- or afibrinogenaemia and at a recommended maximum rate of 10 mL per minute for patients with acquired fibrinogen deficiency.
For instructions on reconstitution of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.

In order to avoid overdose, regular monitoring of the plasma level of fibrinogen during therapy is indicated (see Dosage & Administration).
In case of overdose, the risk of development of thromboembolic complications is enhanced.

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

Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Thromboembolism: There is a risk of thrombosis when patients, with either congenital or acquired deficiency, 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.
Acquired hypofibrinogenaemia is associated with low plasma concentrations of all coagulation factors (not only fibrinogen) and inhibitors and so treatment with blood products containing coagulation factors should be considered. Careful monitoring of the coagulation system is necessary.
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.
Sodium Level: This medicinal product contains up to 132 mg sodium per bottle, equivalent to 6.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration by patients on a controlled sodium diet.
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 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 as HIV, HBV and HCV, and for the non-enveloped 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).
Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived products.
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 concentrate.
Effects on ability to drive and use machines: FIBRYGA has no influence on the ability to drive and use machines.

Pregnancy: The safety of FIBRYGA for use in human pregnancy 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 fetus or the neonate are to be expected.
Animal reproduction studies have not been conducted with FIBRYGA (see Pharmacology: Toxicology: Preclinical safety data under Actions). Since the active substance is of human origin, it is catabolised in the same manner as the patient's own protein. These physiological constituents of the human blood are not expected to induce adverse effects on reproduction or on the fetus.
The benefit of FIBRYGA during pregnancy must be evaluated taking into consideration that clinical experience with fibrinogen concentrates is available but data from controlled clinical trials are missing.
Breastfeeding: It is unknown whether FIBRYGA is excreted in human milk. However, because of the nature of the substance, no effects on the breastfed newborn/infant are anticipated.
Thus, a decision must be made whether FIBRYGA therapy is indicated during breast-feeding taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: There are no data on fertility available.

Summary of the safety profile: There are no robust data on the frequency of adverse reactions from clinical trials with this product.
In clinical studies, the following adverse reactions have been reported: pyrexia, drug eruption, phlebitis and thrombosis.
The following adverse reactions have been reported for FIBRYGA and other fibrinogen concentrates: (See Table 5.)

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For safety in respect to transmissible agents, see Precautions.
Paediatric population: Twenty-six patients, 1 to <18 years of age, were included in the congenital fibrinogen deficiency safety analysis, of which 12 adolescents 12 to <18 years of age, 8 children 6 to <12 years of age and 6 children 1 to <6 years of age.
The overall safety profile does not differ between adults, adolescents and children.
There are no data on use of FIBRYGA in paediatric patients with acquired fibrinogen deficiency.
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.

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

Incompatibilities: This medicinal product must not be mixed with other medicinal products.
Special precautions for disposal and other handling: General Instructions: The reconstituted solution should be almost colourless and slightly opalescent. Do not use solutions that are cloudy or have deposits.
Reconstitution: 1. Warm both the powder (FIBRYGA) and the solvent (WFI) in unopened containers up to room temperature. This temperature should be maintained during reconstitution. If a water bath is used for warming, care must be taken to avoid water coming into contact with the rubber stoppers or the caps of the containers. The temperature of the water bath should not exceed +37°C (98°F).
2. Remove the cap from the powder (FIBRYGA) bottle and the solvent to expose the central portion of the infusion stopper. Clean the rubber stoppers with an alcohol swab and allow the rubber stoppers to dry.
3. Peel away the lid of the outer package of the Octajet transfer device. To maintain sterility, leave the Octajet device in the clear outer packaging.
4. Take the Octajet in its outer package and invert it over the powder (FIBRYGA) bottle. Place device while in the outer package onto the centre of the powder bottle until the clips of the product spike (colourless) are locked. While holding onto the powder bottle, carefully remove the outer package from the Octajet, being careful to not touch the water spike (blue) and leave the Octajet attached firmly to the powder bottle.
5. With the powder (FIBRYGA) bottle held firmly on a level surface, invert the solvent vial and place it at the centre of the water spike. Push the blue plastic spike of the Octajet firmly through the rubber stopper of the solvent vial.
6. Remove the distance ring and press the solvent vial down. Solvent will flow into the powder (FIBRYGA) bottle.
7. When transfer of the solvent is complete, gently swirl the product bottle until the powder is fully dissolved. Do not shake the bottle to avoid foam formation. The powder should be dissolved completely within approximately 5 minutes. It should not take longer than 30 minutes to dissolve the powder. If the powder is not dissolved within 30 minutes the product should be discarded.
8. Turn the blue solvent vial connector (both directions possible) to bring position markers together and remove solvent vial together with the water spike.
9. Attach a syringe to the provided filter and connect the filter to the Octajet Luer Lock on the powder bottle. Withdraw the solution through the filter into the syringe.
10. Detach the filled syringe from the filter and discard the empty bottle.
A standard infusion set is recommended for intravenous application of the reconstituted solution at room temperature.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store above 25°C. Do not freeze. Keep the bottle in the outer carton to protect from light.
Shelf life: 30 months.
The chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hours at room temperature (max. 25°C). From a microbiological point of view the product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions are the responsibility of the user. The reconstituted solution must not be frozen or stored in a refrigerator. Partially used bottles should be discarded.

Haemostatics

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

B