Fibrinogen concentrate is a purified, lyophilized fibrinogen powder manufactured from pooled human plasma. Fibrinogen concentrate is indicated for the treatment of acute bleeding in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. Congenital fibrinogen deficiency is a rare genetic disease with an estimated incidence of 1 to 2 per million in the general population. Without treatment, patients with this condition are at risk for life-threatening bleeding. Prior to the approval of fibrinogen concentrate, correction of fibrinogen deficiencies occurred via administration of cryoprecipitate or fresh frozen plasma (FFP) infusions. Fibrinogen concentrate maintains several advantages over cryoprecipitate and FFP including purification during the production process, dose standardization to target fibrinogen concentrations, and minimization of the infusion volume. Spontaneous thrombosis may occur in patients with congenital fibrinogen deficiency with or without the use of fibrinogen replacement therapy; thromboembolic events have been reported in patients receiving fibrinogen concentrate.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
Intravenous Administration
-The actual potency of fibrinogen concentrate in milligram (mg) is printed on the vial label and carton.
Reconstitution (RiaSTAP)
-Using an appropriate transfer device or syringe, transfer 50 mL of Sterile Water for Injection into the fibrinogen concentrate vial.
-Gently swirl the vial to ensure that the product is completely dissolved. Do not shake.
-After reconstitution, the solution should be colorless and clear to slightly opalescent. Do not use if the product contains particulates or appears cloudy.
-Filter the reconstituted solution with a 17-micron filter into an appropriate syringe before administration.
-Storage: The reconstituted solution is stable for 8 hours when stored at 20 to 25 degrees C (68 to 77 degrees F); administer within this time period. Discard partially used vials.
Reconstitution (Fibryga)
-Warm both the powder and Sterile Water for Injection to room temperature. If a water bath is used for warming, prevent water from coming into contact with the rubber stoppers or caps of the bottles; do not exceed a water temperature of 37 degrees C (98 degrees F).
-Using the Octajet transfer device, transfer 50 mL of Sterile Water for Injection into the fibrinogen concentrate vial.
-Gently swirl the vial to ensure that the product is completely dissolved. Do not shake. The powder should be dissolved within approximately 5 to 10 minutes.
-After reconstitution, the solution should be colorless and clear to slightly opalescent. Do not use if the product contains particulates or is discolored.
-Storage: Administer reconstituted product immediately or within 4 hours. Do not refrigerate or freeze. Discard any unused portion.
Intravenous injection
-Administer via a separate injection site; do not mix with any other intravenous solutions or medical products.
-Administer at room temperature by slow intravenous injection at a rate not exceeding 5 mL/minute.
The most common adverse reactions observed in clinical trials of fibrinogen were nausea, vomiting, and thrombocytosis, all occurring in more than 5% of patients. Headache and fever were observed in more than 1% of patients. Visual impairment, cough, and flushing were each reported as a single event during a retrospective trial (n = 22) of fibrinogen for routine prophylaxis or treatment of bleeding or surgery in patients with congenital fibrinogen deficiency. Chills have been reported with postmarketing use of fibrinogen.
Thrombotic events including myocardial infarction, pulmonary embolism, deep vein thrombosis, and arterial thrombosis have been reported with fibrinogen use. A single case each of venous thrombosis of the limb, digital foot ischemia, portal vein thrombosis after splenectomy, and peripheral phlebitis of the upper limbs have also been reported. Thrombosis may occur spontaneously in patients with congenital fibrinogen deficiency regardless of the use of fibrinogen concentrate. Data are limited to case reports, and the incidence of spontaneous thrombosis in this population is unknown. Thrombus development is theorized to begin with damage to the vascular endothelium by recurrent hemorrhages stimulating the release of thrombin. In the absence of fibrinogen, thrombin is not bound by fibrin clots but rather remains in circulation for a longer duration. The abundance of circulating thrombin causes platelet activation and aggregation to occur, resulting in the formation of a thrombus that is free of fibrin deposits. It is reasonable, based on the mechanism of action, that thrombosis may occur after administration of fibrinogen concentrate. In a study of congenital fibrinogen deficient patients, 1 patient developed a deep vein thrombosis and non-fatal pulmonary embolism during treatment with a fibrinogen substitute. The patient developed this thromboembolism after a surgical procedure despite prophylactic heparin. In a separate study, 3 ischemic cerebrovascular incidents and 1 myocardial infarction were observed. All 4 were postoperative events occurring a median of 7.5 days after fibrinogen concentrate administration, and in all 4 events, the patients experienced perioperative hemorrhages with hypotension requiring transfusion (range, 13 to 36 transfusions). The dose of fibrinogen concentrate received by these 4 patients was 2 to 4 g, and the peak plasma fibrinogen concentration was 139 to 205 mg/dL. Chest pain (unspecified) and chest discomfort were each reported as a single event during a retrospective trial (n = 22) of fibrinogen for routine prophylaxis or treatment of bleeding or surgery in patients with congenital fibrinogen deficiency.
Anaphylactoid reactions are among the most serious adverse reactions reported with fibrinogen use. If early signs of hypersensitivity (e.g., hives, urticaria, chest tightness, wheezing, hypotension, anaphylaxis) occur, discontinue administration immediately and institute appropriate medical treatment. A single patient developed a mild skin irritation (pruritus and erythema) during clinical trials and was treated with diphenhydramine and hydrocortisone. The patient received 2 more infusions and was treated prophylactically with diphenhydramine and hydrocortisone with no further drug reactions. Wheezing (n = 1) and dyspnea (n = 2) were reported during a retrospective trial (n = 22) of fibrinogen for routine prophylaxis or treatment of bleeding or surgery in patients with congenital fibrinogen deficiency. Anaphylaxis, dyspnea, and rash have been reported with postmarketing use of fibrinogen.
RiaSTAP is contraindicated in patients with known anaphylactic or severe systemic reactions to human plasma-derived products. Fibryga is contraindicated in patients with severe immediate hypersensitivity reactions, including anaphylaxis, to Fibryga or its components (sodium citrate dihydrate; glycine; L-arginine hydrochloride). RiaSTAP may be inappropriate for patients with albumin hypersensitivity; each vial contains 400 to 700 mg of human albumin. Hypersensitivity reactions such as hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis may occur.
Weigh the benefits of fibrinogen concentrate in patients with thromboembolic disease against the risk of complications. Life-threatening thromboses have been reported in patients receiving fibrinogen concentrate. The risk of thrombosis may be greater when the target fibrinogen plasma concentration is 150 mg/dL. However, treatment with human fibrinogen concentrate has been associated with risk of thrombosis at target fibrinogen concentrations less than 150 mg/dL. Based on the mechanism of action of fibrinogen concentrate, patients predisposed to thromboembolic events may be at increased risk of clot development after fibrinogen administration. In addition, thromboses may develop in patients with congenital fibrinogen deficiency (afibrinogenemia and hypofibrinogenemia) with or without the use of fibrinogen replacement therapy. Patients with dysfibrinogenemia (presence of abnormal or dysfunctional fibrinogen) are also at risk for clotting complications. Two mechanisms have been proposed for the abnormal thrombus formation in dysfibrinogenemic patients. The first mechanism involves a fibrin binding site mutation causing thrombin to adhere to fibrin with low-affinity. As a result of the weak binding, thrombin is released by the fibrin clot back into circulation and is available for further thrombus formation. The second proposed mechanism involves mutations that impair profibrinolytic function. The impaired fibrinolytic function may be a result of defective plasmin binding to fibrin or of fibrin resistance to the digestive action of plasmin. Fibrinogen concentrate is not indicated for acute bleeding in patients with dysfibrinogenemia.
Fibrinogen concentrate, human is derived from human blood and therefore carries a remote risk for transmission of viral infection and the variant Creutzfeldt-Jakob disease (vCJD) agent. There is a theoretical risk for transmission of the Creutzfeldt-Jakob disease (CJD) agent. The risk of infectious agent transmission has been reduced by screening plasma donors, testing for the presence of current viral infections, and including virus inactivation/removal steps in the manufacturing process. Report all infections thought to be possibly transmitted by fibrinogen to the manufacturer.
There are no studies of fibrinogen concentrate in pregnant women. Animal reproduction studies have not been conducted with fibrinogen concentrate. It is not known whether fibrinogen concentrate can affect reproductive capacity or cause fetal harm when given to a pregnant woman. Use fibrinogen concentrate during pregnancy only if clearly needed.
There is no information regarding the presence of fibrinogen concentrate in breast milk, the effect on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for fibrinogen concentrate and any potential adverse effects on the breast-fed infant from fibrinogen concentrate or the underlying maternal condition.
For the treatment of acute hemorrhage in persons with hypofibrinogenemia, including congenital afibrinogenemia and hypofibrinogenemia or after trauma*:
-for the treatment of acute hemorrhage in persons with congenital fibrinogen deficiency including afibrinogenemia and hypofibrinogenemia when baseline fibrinogen concentration is known:
Intravenous dosage (RiaSTAP):
Adults: Individualize dosage based on the target plasma fibrinogen concentration, actual measured plasma fibrinogen concentration, bleeding type, and body weight utilizing the following formula: Dose (mg) = [Target concentration (mg/dL) - Measured concentration (mg/dL)] / 1.7 (mg/dL per mg/kg body weight) x Weight (kg). A single dose of 70 mg/kg will increase the fibrinogen plasma concentration by approximately 120 mg/dL. Monitor plasma fibrinogen concentration during treatment, and maintain a target fibrinogen concentration of 100 mg/dL until hemostasis is obtained. The desired peak fibrinogen concentration and duration of treatment may vary based on bleeding severity or surgical procedure. In a survey of 34 physicians known to treat patients with fibrinogen deficiency, a post-infusion peak fibrinogen concentration of 150 to 200 mg/dL (duration, 4 to 14 days) was recommended for life-threatening bleeds or major surgeries; a post-infusion peak fibrinogen concentration of 100 mg/dL was targeted for less severe bleeds (duration, 1 to 2 days) or minor surgeries (duration, 1 to 7 days).
Infants, Children, and Adolescents: Individualize dosage based on the target plasma fibrinogen concentration, actual measured plasma fibrinogen concentration, bleeding type, and body weight utilizing the following formula: Dose (mg) = [Target concentration (mg/dL) - Measured concentration (mg/dL)] / 1.7 (mg/dL per mg/kg body weight) x Weight (kg). A single dose of 70 mg/kg will increase the fibrinogen plasma concentration by approximately 120 mg/dL. Monitor plasma fibrinogen concentration during treatment, and maintain a target fibrinogen concentration of 100 mg/dL until hemostasis is obtained. The desired peak fibrinogen concentration and duration of treatment may vary based on bleeding severity or surgical procedure. In a survey of 34 physicians known to treat patients with fibrinogen deficiency, a post-infusion peak fibrinogen concentration of 150 to 200 mg/dL (duration, 4 to 14 days) was recommended for life-threatening bleeds or major surgeries; a post-infusion peak fibrinogen concentration of 100 mg/dL was targeted for less severe bleeds (duration, 1 to 2 days) or minor surgeries (duration, 1 to 7 days).
Intravenous dosage (Fibryga):
Adults: Individualize dosage based on the target plasma fibrinogen concentration, actual measured plasma fibrinogen concentration, bleeding type, and body weight utilizing the following formula: Dose (mg) = [Target concentration (mg/dL) - Measured concentration (mg/dL)] / 1.8 (mg/dL per mg/kg body weight) x Weight (kg). A single dose of 70 mg/kg will increase the fibrinogen plasma concentration by approximately 125 mg/dL. Monitor plasma fibrinogen concentration during treatment, and maintain a target fibrinogen concentration of 100 mg/dL for minor bleeding and 150 mg/dL for major bleeding. Additional infusions should be administered if the plasma fibrinogen concentration is below the accepted lower limit of the target concentration (80 mg/dL for minor bleeding and 130 mg/dL for major bleeding) until hemostasis is achieved.
Children and Adolescents 12 to 17 years: Individualize dosage based on the target plasma fibrinogen concentration, actual measured plasma fibrinogen concentration, bleeding type, and body weight utilizing the following formula: Dose (mg) = [Target concentration (mg/dL) - Measured concentration (mg/dL)] / 1.8 (mg/dL per mg/kg body weight) x Weight (kg). A single dose of 70 mg/kg will increase the fibrinogen plasma concentration by approximately 125 mg/dL. Monitor plasma fibrinogen concentration during treatment, and maintain a target fibrinogen concentration of 100 mg/dL for minor bleeding and 150 mg/dL for major bleeding. Additional infusions should be administered if the plasma fibrinogen concentration is below the accepted lower limit of the target concentration (80 mg/dL for minor bleeding and 130 mg/dL for major bleeding) until hemostasis is achieved.
Children 1 to 11 years: Individualize dosage based on the target plasma fibrinogen concentration, actual measured plasma fibrinogen concentration, bleeding type, and body weight utilizing the following formula: Dose (mg) = [Target concentration (mg/dL) - Measured concentration (mg/dL)] / 1.4 (mg/dL per mg/kg body weight) x Weight (kg). A single dose of 70 mg/kg will increase the fibrinogen plasma concentration by approximately 125 mg/dL. Monitor plasma fibrinogen concentration during treatment, and maintain a target fibrinogen concentration of 100 mg/dL for minor bleeding and 150 mg/dL for major bleeding. Additional infusions should be administered if the plasma fibrinogen concentration is below the accepted lower limit of the target concentration (80 mg/dL for minor bleeding and 130 mg/dL for major bleeding) until hemostasis is achieved.
-for the treatment of acute hemorrhage in persons with congenital fibrinogen deficiency including afibrinogenemia and hypofibrinogenemia when baseline fibrinogen concentration is unknown:
Intravenous dosage (RiaSTAP):
Adults: 70 mg/kg IV. A single dose of 70 mg/kg will increase the fibrinogen plasma concentration by approximately 120 mg/dL. Monitor fibrinogen concentration during treatment, and maintain a target fibrinogen concentration of 100 mg/dL until hemostasis is obtained. The desired peak fibrinogen concentration and duration of treatment may vary based on bleeding severity or surgical procedure. In a survey of 34 physicians known to treat patients with fibrinogen deficiency, a post-infusion peak fibrinogen concentration of 150 to 200 mg/dL (duration, 4 to 14 days) was recommended for life-threatening bleeds or major surgeries; a post-infusion peak fibrinogen concentration of 100 mg/dL was targeted for less severe bleeds (duration, 1 to 2 days) or minor surgeries (duration, 1 to 7 days).
Infants, Children, and Adolescents: 70 mg/kg IV. A single dose of 70 mg/kg will increase the fibrinogen plasma concentration by approximately 120 mg/dL. Monitor fibrinogen concentration during treatment, and maintain a target fibrinogen concentration of 100 mg/dL until hemostasis is obtained. The desired peak fibrinogen concentration and duration of treatment may vary based on bleeding severity or surgical procedure. In a survey of 34 physicians known to treat patients with fibrinogen deficiency, a post-infusion peak fibrinogen concentration of 150 to 200 mg/dL (duration, 4 to 14 days) was recommended for life-threatening bleeds or major surgeries; a post-infusion peak fibrinogen concentration of 100 mg/dL was targeted for less severe bleeds (duration, 1 to 2 days) or minor surgeries (duration, 1 to 7 days).
Intravenous dosage (Fibryga):
Adults: 70 mg/kg IV. A single dose of 70 mg/kg will increase the fibrinogen plasma concentration by approximately 125 mg/dL. Monitor plasma fibrinogen concentration during treatment, and maintain a target fibrinogen concentration of 100 mg/dL for minor bleeding and 150 mg/dL for major bleeding. Additional infusions should be administered if the plasma fibrinogen concentration is below the accepted lower limit of the target level (80 mg/dL for minor bleeding and 130 mg/dL for major bleeding) until hemostasis is achieved.
Children and Adolescents: 70 mg/kg IV. A single dose of 70 mg/kg will increase the fibrinogen plasma concentration by approximately 125 mg/dL. Monitor plasma fibrinogen concentration during treatment, and maintain a target fibrinogen concentration of 100 mg/dL for minor bleeding and 150 mg/dL for major bleeding. Additional infusions should be administered if the plasma fibrinogen concentration is below the accepted lower limit of the target level (80 mg/dL for minor bleeding and 130 mg/dL for major bleeding) until hemostasis is achieved.
-for the treatment of acute hemorrhage in persons with hypofibrinogenemia after trauma*:
Intravenous dosage:
Adults: 3 to 4 g IV as a single dose.
Maximum Dosage Limits:
Specific maximum dosage information is not available. Individualize dosage based on bleeding extent, laboratory parameters, and the patient's clinical status.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Fibrinogen Concentrate, Human products.
The administration of fibrinogen concentrate aids clot formation in patients with congenital fibrinogen deficiency by replacing the low or missing coagulation factor. Fibrinogen (factor I) is the final substrate in a clot forming process known as the coagulation cascade. The ultimate goal of the multi-step coagulation cascade is to convert fibrinogen into an insoluble fibrin clot. This conversion is accomplished through the interaction of fibrinogen with 2 enzymes: thrombin and activated factor XIII. Initially, fibrinogen binds with circulating thrombin, which causes the release of fibrinopeptide A (FPA) and B (FPB). The release of FPA occurs rapidly and results in the formation of a soluble fibrin monomer (fibrin I). FPB is released at a much slower rate and results in the formation of fibrin II, which is capable of polymerization. Next, in the presence of calcium, activated factor XIII causes the aggregated fibrin II polymers to cross-link. The cross-linked fibrin polymers are the end result of the coagulation cascade and provide elasticity and strength to the hemostatic platelet plug.
Fibrinogen is vital to clot strength and elasticity, which can be assessed via maximum clot firmness (MCF). Clot firmness depends on activation of coagulation, fibrinogen concentration of the sample, and cross-linking of the fibrin network. A pharmacokinetic study evaluating MCF was performed in 14 patients who received a single 70 mg/kg dose of fibrinogen concentrate. MCF was determined at baseline and 1 hour after the administration of fibrinogen concentrate. Fibrinogen concentrate was found to be effective in increasing clot firmness in patients with congenital fibrinogen deficiency. The mean change in MCF values was significantly higher after the administration of fibrinogen concentrate (8.9 mm) when compared to baseline (0 mm).
Fibrinogen concentrate is administered intravenously. Reported pharmacokinetic parameters are as follows: Vd = 52.7 to 70.2 mL/kg; half-life 75.9 to 78.7 hours; clearance 0.59 to 0.7 mL/kg/hour; Cmax = 139 to 140 mg/dL; AUC 124.3 mg/mL x hour; mean residence time (MRT) = 92.8 to 106.3 hours; in vitro recovery: 1.7 to 1.8 mg/dL per mg/kg. These parameters were attained after a single 70 mg/kg dose in adults and adolescents. Based on these results, a single 70 mg/kg dose will increase a patient's fibrinogen concentration by approximately 125 mg/dL.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Special Populations
Pediatrics
Lower incremental in vivo recovery (IVR), faster clearance, and shorter half-life were observed in patients 1 to 11 years, compared to adolescents and adults. Additionally, Cmax and AUC were also lower in children.
Children 6 to 11 years
Reported pharmacokinetic parameters are as follows: Vd = 67.2 mL/kg; half-life = 66.1 hours; clearance = 0.7 mL/kg/hour; Cmax = 112.4 mg/dL; AUC = 102.1 mg/mL x hour; IVR = 1.5 mg/dL per mg/kg; MRT = 92.2 hours.
Children 1 to 5 years
Reported pharmacokinetic parameters are as follows: Vd = 68.6 mL/kg; half-life = 56.9 hours; clearance = 0.9 mL/kg/hour; Cmax = 99 mg/dL; AUC = 83.8 mg/mL x hour; IVR = 1.3 mg/dL per mg/kg; MRT = 78.4 hours.