2.1 Dose

For intravenous use after reconstitution only

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

The actual amount of fibrinogen in milligrams per vial of FESILTY is printed on the vial label and carton.

FESILTY dose when baseline fibrinogen level is known

The dose for each patient must be individually calculated taking into consideration age, the location and extent of bleeding, the plasma level of fibrinogen (mg/dL), and the clinical condition of the patient.

Calculate the recommended dose in milligrams fibrinogen per kilogram BW according to the age of the patient:

• Adults and pediatric patients ≥ 6 years of age

• Pediatric patients < 6 years of age

Monitor plasma fibrinogen level and repeat the dose if the plasma fibrinogen level drops below the target level until hemostasis is achieved.

Individualize the frequency and duration of dosing based on the extent of bleeding, plasma fibrinogen level, and the clinical condition of the patient.

FESILTY dose when baseline fibrinogen level is not known

The recommended dose when the baseline fibrinogen is not known is 70 mg/kg BW for patients of all ages.

Monitor plasma fibrinogen level and repeat the dose as needed to maintain the target fibrinogen level.

Individualize the frequency and duration of dosing based on the extent of bleeding, plasma fibrinogen level, and the clinical condition of the patient.

2.2 Preparation and Reconstitution

FESILTY is a white powder. Upon reconstitution with sterile water, the solution is almost colorless and clear to slightly opalescent.

The following procedures are provided as a guide for the preparation and reconstitution of FESILTY.

Preparation

Inspect the carton kit before opening. Discard the kit if the package is damaged or if the seal on the carton shows signs of tampering.

Do not use FESILTY after the expiration date printed on the vial label and carton.

If stored refrigerated, allow the unopened vials of Sterile Water for Injection, USP (vial number 1) and product (FESILTY, vial number 2) to come to room temperature.

Use aseptic technique (clean and sanitized) and a flat surface during reconstitution of FESILTY.

Reconstitution with nextaro® v, 20/20 5 µm transfer system

1. Remove the caps from the water vial and the product vial in order to expose the central portions of the stoppers (Fig. 1). Cleanse each vial stopper with an alcohol swab and allow surface to dry.
2. Completely remove the paper seal of the transfer system blister package (Fig. 2). To maintain sterility, keep the transfer device in the clear blister package. Do not touch the spike.
3. Place the water vial on an even surface. Place the blue part of the transfer system within the blister straight onto the upright water vial (Fig. 3) until it snaps into place. Do not twist the transfer system.
   
4. Remove the clear part of the blister package from the transfer system. Now the white part of the transfer system is visible (Fig. 4).
   
5. Place the product vial on an even surface.
   
6. Turn the combination of transfer system and water vial upside down (Fig. 5). Push the spike of the white end of the transfer system straight down through the product vial stopper (Fig. 6) until it snaps into place. The vacuum present in the product vial causes the water to flow into the product vial (Fig. 7). Wait until water transfer is complete.
   
7. Gently sway the unit consisting of the transfer system, product and water vial, to dissolve the powder. Do not shake the unit, to avoid foaming. The powder should be dissolved completely within approximately 3 minutes. Discard the product if the powder is not fully dissolved within 30 minutes. After reconstitution the solution should be clear or slightly opalescent.
   
8. Afterwards unscrew the blue part of the transfer system together with the empty water vial counterclockwise (Fig. 8). Discard the water vial with the blue part of the transfer system attached. The luer-lock connector is now visible. To maintain sterility do not touch the luer-lock connector.
   
9. The solution is ready for use. Keep the solution at room temperature and use within 4 hours after dissolving. Do not use solutions that are cloudy or contain visible particles.
   
   
   
   
   
10. Screw a sterile syringe (not supplied) onto the luer-lock connector of the product vial with the white part of the transfer system and invert (Fig. 9) to allow you to easily draw the dissolved drug into the syringe. Use constant force during drawing to avoid foaming. A separate filter is not necessary because the transfer system has its own integrated filter.
    
11. Carefully disconnect the vial with the white part of the transfer system from the syringe. A standard infusion set is recommended for intravenous injection of the solution.
    
12. If the dose requires more than one vial of FESILTY, reconstitute each vial using a new nextaro® v, 20/20 transfer system provided in the carton. The nextaro® v, 20/20 transfer system is for single use only.
    

Do not shake.

Do not mix FESILTY with other intravenous medications. Administer by a separate injection/infusion line.

FESILTY is for single use only. It contains no preservatives.

Discard unused portion.

2.3 Administration

Inspect visually for particulate matter and discoloration prior to administration. Do not use if the liquid is cloudy or turbid, discolored, or if it contains visible particulate matter.

Infusion Rates

Infuse FESILTY intravenously using an infusion pump at an infusion rate not to exceed 5 mL/min. The initial infusion rates are provided in Table 1. Selection of the infusion rate remains principally at the discretion of the treating physician considering the exact clinical situation of the patient.

5.1 Hypersensitivity

Hypersensitivity reactions have occurred to FESILTY or its components (arginine hydrochloride, polysorbate 80, sodium citrate dihydrate, trehalose dihydrate). Monitor patients for signs and symptoms of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If symptoms occur, discontinue FESILTY infusion immediately. Manage patients based on clinical practice accordingly.

5.2 Thrombosis

Thrombotic events have occurred in patients receiving FESILTY [see Adverse Reactions (6)]. Thrombosis may occur spontaneously in patients with congenital fibrinogen deficiency with or without the use of fibrinogen replacement therapy. Weigh the benefits of FESILTY administration versus the risks of thrombosis. Monitor patients receiving FESILTY for signs and symptoms of thrombosis.

5.3 Transmissible Infectious Agents

Because FESILTY is made from pooled human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. The risk of infectious agent transmission has been reduced by screening plasma donors and by including virus inactivation as well as virus and prion removal steps in the manufacturing process of FESILTY[see Description (11)].

All infections suspected to have been transmitted by FESILTY should be reported by the physician or other healthcare provider to Grifols at 1-800-520-2807.

6.1 Clinical Trials Experience

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

The safety data described in this section reflects exposure to FESILTY in one clinical study (Study 984). A total of 45 patients with congenital fibrinogen deficiency received at least one dose of FESILTY. A total of 175 bleeding episodes were treated with a mean dose of 3.9 g [see Clinical Studies (14)].

Serious adverse reactions occurred in 4 patients (9%) including portal vein thrombosis (n=1), deep vein thrombosis (n=1), and pain in extremity with clinically suspected thrombosis (n=1). One patient had episode of epilepsy and died due to extradural hematoma four weeks after FESILTY administration.

Table 2 lists the most common adverse reactions that occurred in > 2% patients in Study 984.

8.1 Pregnancy

Risk Summary

No human data are available to indicate the presence or absence of a drug-associated risk. Animal reproduction studies have not been conducted with FESILTY. One patient in clinical trial 984 reported pregnancy 11 months after receiving FESILTY. The patient withdrew from the study and there were no reports of complications during the pregnancy. It is not known whether FESILTY 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 FESILTY in breast milk, the effect on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breast feeding should be considered along with the mother’s clinical need for FESILTY and any potential adverse effects on the breast-fed infant from FESILTY or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of FESILTY have been established in pediatric patients with congenital fibrinogen deficiency. Use of FESILTY in pediatric patients was supported by evidence from one clinical study (Study 984) that enrolled 24 pediatric patients 0 to 16 years of age (6 patients aged 0 to < 6 years, 18 patients aged ≥6 years) with congenital fibrinogen deficiency [see Adverse Reactions (6) and Clinical Studies (14)].

8.5 Geriatric Use

Clinical study of FESILTY in patients with congenital fibrinogen deficiency did not include patients aged 65 years and over to provide evidence as to whether or not they respond differently than younger patients.

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 alpha, beta, and gamma polypeptide chains.

Fibrinogen plays a fundamental role in achieving and maintaining overall hemostasis. Following coagulation activation and thrombin generation, fibrinogen is cleaved by thrombin at specific sites on the alpha and 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 which forms cross links between fibrin polymers and renders the fibrin clot more resistant to fibrinolysis. Additionally, soluble fibrinogen mediates platelet aggregation by binding to the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor on the platelet surface activated following blood vessel injury. This interaction acts as a bridge between platelets, facilitating their aggregation, i.e., formation of primary platelet plug. The end product of the coagulation cascade, cross-linked fibrin, stabilizes and reinforces the primary platelet plug to achieve secondary hemostasis and stop bleeding.

12.2 Pharmacodynamics

In a prospective, open-label, multicenter phase I clinical trial the pharmacodynamic properties for FESILTY were evaluated in 27 patients of all age groups with congenital afibrinogenemia or severe hypofibrinogenemia. The assessment was based on fibrinogen activity (FiAc) levels in plasma after a single intravenous administration of 70 mg/kg BW. Maximum clot firmness (MCF) was measured by thromboelastometry and showed a positive correlation with FiAc levels of FESILTY in patients across the age groups.

12.3 Pharmacokinetics

PK properties of FESILTY were investigated based on FiAc levels in plasma after a single intravenous administration of 70 mg/kg BW in patients with congenital afibrinogenemia or severe hypofibrinogenemia of all age groups.

A population pharmacokinetic model was developed that pooled the data collected in 27 patients aged 1 to 40 years who received 70 mg/kg of FESILTY. A two-compartment model was used for integrated assessments of FiAg and FiAc levels, with body weight included as a covariate to describe the pharmacokinetic data. The analysis demonstrated that the median AUC0-239h of FiAc was lower by 27.6% in patients aged < 6 years, by 13.6% in patients aged 6 to < 12 years, and by 3.4% in patients aged 12 to < 18 years compared to adult patients. The median Cmax was comparable between pediatric and adult patients.