2.1 Dosage

FIBRYGA dosing, duration of dosing, and frequency of administration should be individualized based on the extent of bleeding, laboratory values, and the clinical condition of the patient.

The recommended target fibrinogen plasma level is 100 mg/dL for minor bleeding and 150 mg/dL for major bleeding.

FIBRYGA dose when baseline fibrinogen level is known

Dose should be individually calculated for each patient based on the target plasma fibrinogen level for the type of bleeding, actual measured plasma fibrinogen level and body weight , using the following age-specific formulas (see Pharmacokinetics [ 12.3 ] ):

Adults and adolescents 12 years of age and above:

Children 0 to <12 years of age:

FIBRYGA dose when baseline fibrinogen level is not known

If the patient’s fibrinogen level is not known, the recommended dose is 70 mg/kg of body weight administered intravenously.

Monitor the patient’s fibrinogen level during treatment with FIBRYGA.

Additional infusions of FIBRYGA should be administered if the plasma fibrinogen level is below the accepted lower limit (80 mg/dL for minor bleeding, 130 mg/dL for major bleeding) of the target level until hemostasis is achieved.

2.2 Preparation and Handling

FIBRYGA package contains:

• 1 single-dose bottle of FIBRYGA concentrate
• 1 transfer device (Octajet)
• 1 17-micron particle filter

Reconstitute FIBRYGA with 50 mL of sterile Water for Injection (not provided).

Do not use FIBRYGA beyond the expiration date. FIBRYGA contains no preservatives. Use aseptic technique when preparing and reconstituting FIBRYGA.

The procedures below are provided as general guidelines for preparation and reconstitution of FIBRYGA.

Reconstitute FIBRYGA as follows:

1. Warm both the powder and sterile Water for Injection (sWFI) in their closed bottles to room temperature. This temperature should be maintained during reconstitution. If a water bath is used for warming, prevent water from coming into contact with the rubber stoppers or the caps of the bottles. The temperature of the water bath should not exceed +37°C (98°F).

2. Remove the cap from the FIBRYGA bottle and the sWFI bottle to expose the central portion of the rubber stoppers. 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 package.

4. Take the Octajet in its outer package and invert it over the FIBRYGA bottle. Place the device while in the outer package onto the center of the FIBRYGA bottle until the clips of the product spike (colorless) are locked. While holding onto the FIBRYGA bottle, carefully remove the outer package from the Octajet, being careful not to touch the water spike (blue) and leave the Octajet attached firmly to the FIBRYGA bottle. (Fig. 1)

5. With the FIBRYGA bottle held firmly on a level surface, invert the sWFI bottle and place it at the center of the water spike. Push the blue plastic cannula of the Octajet firmly through the rubber stopper of the sWFI bottle. (Fig. 2)

6. Remove the distance ring (Fig. 3) and press the sWFI bottle down (Fig. 4). sWFI will flow into the FIBRYGA bottle.

7. When transfer of the sWFI is complete, gently swirl the FIBRYGA bottle until the powder is fully dissolved. To avoid foam formation, do not shake the bottle. The powder should be dissolved completely within approximately 5 to 10 minutes.

8. Turn the blue sWFI bottle connector (in either direction) to bring the position markers together and remove the sWFI bottle together with the water spike (Fig. 5). Keep the concentrate bottle upright to avoid leaking.

9. Firmly connect the provided particle filter on the remaining Luer Lock on the FIBRYGA bottle (Fig. 6) and withdraw the solution through the particle filter into a syringe. (Fig. 7, 8)

10. Detach the filled syringe from the particle filter and discard the empty bottle and the filter.

• After reconstitution, the FIBRYGA solution should be almost colorless and slightly opalescent. Inspect the reconstituted FIBRYGA solution in the syringe for visible particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration are observed.

The powder should be reconstituted only directly before injection. After reconstitution, do not refrigerate or freeze the FIBRYGA solution. Use the reconstituted FIBRYGA solution immediately or within 4 hours after reconstitution. Discard any remaining FIBRYGA solution.

2.3 Administration

For intravenous use only after reconstitution.

• Do not administer FIBRYGA in the same tubing or container as other medications.
• Use aseptic technique when administering FIBRYGA.
• Administer FIBRYGA at room temperature by slow intravenous injection at a rate not exceeding 5 mL per minute.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions may occur. If early signs of hypersensitivity reactions (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis) or symptoms of allergic reactions occur, immediately discontinue administration (see Patient Counseling Information [ 17 ]). The treatment required depends on the nature and severity of the reaction.

5.2 Thrombosis

Thrombosis may occur spontaneously in patients with congenital fibrinogen deficiency with or without the use of fibrinogen replacement therapy. Thrombotic events have been reported in patients receiving FIBRYGA. Treatment with human fibrinogen concentrate has been associated with risk of thrombosis at target fibrinogen levels that were less than 150 mg/dL. The risk of thrombosis may be greater when the target fibrinogen plasma level is 150 mg/dL. Weigh the benefits of FIBRYGA administration versus the risks of thrombosis. Patients receiving FIBRYGA should be monitored for signs and symptoms of thrombosis. (see Patient Counseling Information [ 17 ])

5.3 Transmissible Infectious Agents

FIBRYGA is made from human plasma. Products made from human plasma may contain infectious agents (e.g., viruses and the CJD agent that can cause disease). Also, unknown infectious agents may be present in such products (see Patient Counseling Information [ 17 ]). The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by a process demonstrated to inactivate and/or remove certain viruses during manufacturing. (see Description [ 11 ]). Despite these measures, such products may transmit disease. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Octapharma at 1-866-766-4860.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rate in the clinical trials of another drug and may not reflect the rates observed in practice.

Thirty-four subjects received at least one dose of FIBRYGA for the treatment of bleeding episodes and/or for perioperative management, in total, 167 doses were infused in two studies.

One patient had a mild skin reaction (itchiness and redness) after FIBRYGA administration for a bleeding episode and was treated with diphenhydramine and hydrocortisone. Thereafter, the patient received another infusion of FIBRYGA for the treatment of the same bleeding episode and another FIBRYGA infusion for surgical management during the next week. For both of those FIBRYGA infusions the patient was treated with diphenhydramine and hydrocortisone prophylactically and did not experience any drug reactions.

Further adverse reactions included one case each of digital foot ischemia, portal vein thrombosis following splenectomy, and peripheral phlebitis of the upper limbs.

8.1 Pregnancy

Risk Summary

There are no data with FIBRYGA use in pregnant women to determine whether there is a drug-associated risk. Animal reproduction studies have not been conducted with FIBRYGA. It is not known whether FIBRYGA can cause fetal harm when administered to a pregnant woman or can affect fertility. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the presence of FIBRYGA in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FIBRYGA and any potential adverse effects on the breastfed infant from FIBRYGA or from the underlying maternal condition.

8.4 Pediatric Use

There was no difference in the pharmacokinetics of FIBRYGA between adults and adolescents (12-17 years of age).

Lower incremental in vivo recovery (IVR), faster clearance and shorter half-life were observed in children aged 1 to < 12 years, compared to adults and adolescents. As higher doses of FIBRYGA were administered for the treatment of bleeding episodes in children aged 1 to < 12 years, higher doses may be required in this age group. (see Dosage [ 2.1 ])

8.5 Geriatric Use

Clinical studies of FIBRYGA did not include sufficient numbers of subjects age 65 years and over to provide conclusive evidence as to whether or not they respond differently than younger subjects.

12.1 Mechanism of Action

Fibrinogen (Factor I) is a soluble plasma protein that, during the coagulation process, is converted to fibrin, one of the key components of the blood clot. Fibrinogen is a heterohexamer with a molecular weight of 340 kDa and composed of two sets of A alpha , B beta , and gamma polypeptide chains.

Following coagulation activation and thrombin generation, fibrinogen is cleaved by thrombin at specific sites on the A alpha and B beta chains to remove fibrinopeptide A (FPA) and fibrinopeptide B (FPB). The removal of FPA and FPB exposes binding sites on the fibrinogen molecule and leads to the formation of fibrin monomers that subsequently undergo polymerization. The resulting fibrin is stabilized by activated factor XIII. Factor XIIIa acts on fibrin to form cross links between fibrin polymers and renders the fibrin clot more resistant to fibrinolysis. The end product of the coagulation cascade is cross-linked fibrin which stabilizes the primary platelet plug and achieves secondary hemostasis.

12.2 Pharmacodynamics

Administration of FIBRYGA to patients with congenital fibrinogen deficiency supplements the missing coagulation factor or increases low plasma fibrinogen levels. Normal plasma fibrinogen level is in the range of 200-450 mg/dL.

An open-label, prospective, randomized, controlled, two-arm, cross-over study was conducted in 22 subjects with congenital fibrinogen deficiency (afibrinogenemia), ranging in age from 12 to 53 years (6 adolescents, 16 adults). Each subject received a single intravenous 70 mg/kg dose of FIBRYGA and the comparator product. Blood samples were drawn from the patients to measure the fibrinogen activity at baseline and up to 14 days after the infusion. Maximum Clot Firmness (MCF) was measured by thromboelastometry (ROTEM).

For each subject, MCF was determined before (baseline) and one hour after the single dose administration of FIBRYGA. In this cross-over study, the results were compared with another fibrinogen concentrate available on the US market. The results of the study demonstrated that the MCF values were significantly higher after administration of FIBRYGA than at baseline (see Table 2 ). The mean change from pre-infusion to 1 hour post-infusion was 9.7 mm in the primary analysis (9.0 mm for subjects < 18 years old and 9.9 mm for subjects ≥ 18 to < 65 years old).

Table 2: MCF [mm] (ITT population) n=22

MCF = maximum clot firmness; mm = millimeter; ITT = intention-to-treat.

a p-value was <0.0001, 95% CI 8.37, 10.99

12.3 Pharmacokinetics

An open-label, prospective, randomized, controlled, two-arm, cross-over study was conducted in 22 subjects with congenital fibrinogen deficiency (afibrinogenemia), ranging in age from 12 to 53 years (6 adolescents, 16 adults), where each subject received a single intravenous 70 mg/kg dose of FIBRYGA and the comparator product. In addition, a prospective, open-label, uncontrolled, multicenter clinical study was conducted in 14 pediatric subjects with afibrinogenemia, ranging in age from 1 to 10 years. Thirteen subjects each received a single intravenous 70 mg/kg dose of FIBRYGA. In both studies, blood samples were drawn from the subjects to determine the fibrinogen activity at baseline and up to 14 days after the infusion. The pharmacokinetic parameters of FIBRYGA (n=34) are summarized in Table 3 .

In the study of adult and adolescent subjects, the incremental in vivo recovery (IVR) was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was a 1.8 mg/dL (range 1.1-2.6 mg/dL) increase per mg/kg. The median in vivo recovery indicates that a dose of 70 mg/kg will increase patients’ fibrinogen plasma concentration by approximately 125 mg/dL. In pediatric subjects, the incremental in vivo recovery (IVR) was determined from levels obtained up to 3 hours post-infusion. The median incremental IVR was a 1.4 mg/dL (range 1.3-2.1 mg/dL) increase per mg/kg.

Table 3: Pharmacokinetic Parameters for Fibrinogen Activity

C max = maximum plasma concentration; AUC = area under the curve; AUC norm = area under the curve normalized to the dose administered; SD = standard deviation

No difference in fibrinogen activity was observed between males and females. There was no difference in the pharmacokinetics of FIBRYGA between adults and adolescents (12-17 years of age). Lower recovery, shorter half-life and faster clearance were observed in children aged 1 to < 12 years, compared to adults and adolescents. Other parameters, such as Cmax (maximum plasma concentration), AUC (area under the curve) and AUCnorm (area under the curve normalized to the dose administered), were also lower in children. Such differences may be expected for the younger age subgroup owing to physiological differences in body size and composition.