Limitation of Use

RIASTAP is not indicated for dysfibrinogenemia.

2.1 Treatment of Congenital Fibrinogen Deficiency

RIASTAP 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.

2.2 Preparation and Reconstitution

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

Use aseptic technique when preparing and reconstituting RIASTAP.

Reconstitute RIASTAP at room temperature as follows:

1. Remove the cap from the product vial to expose the central portion of the rubber stopper.
2. Clean the surface of the rubber stopper with an antiseptic solution and allow it to dry.
3. Using an appropriate transfer device or syringe, transfer 50 mL of Sterile Water for Injection into the product vial.
4. Gently swirl the product vial to ensure the product is fully dissolved. Do not shake the vial.

After reconstitution, the RIASTAP solution should be colorless and clear to slightly opalescent. Inspect visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates. Discard partially used vials.

RIASTAP is stable for 8 hours after reconstitution when stored at 20-25°C; administer within this time period.

Before administration, filter reconstituted RIASTAP solution with a 17-micron filter (not supplied) into an appropriate syringe.

2.3 Administration

Do not mix RIASTAP with other medicinal products or intravenous solutions. Administer through a separate injection site.

Use aseptic technique when administering RIASTAP.

Administer RIASTAP at room temperature by slow intravenous injection at a rate not exceeding 5 mL per minute.

5.1 Hypersensitivity Reactions

Allergic reactions may occur. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension) 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.1 Thromboembolic events have been reported in patients treated with RIASTAP. Weigh the benefits of RIASTAP administration versus the risk of thrombosis. Monitor patients receiving RIASTAP for signs and symptoms of thrombosis [see Patient Counseling Information (17)].

5.3 Transmissible Infectious Agents

Because RIASTAP is made from human blood, 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. 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 still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products [see Patient Counseling Information (17)]. 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 CSL Behring Pharmacovigilance at 1-866-915-6958.

6.1 Clinical Trials Experience

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

The safety and efficacy of fibrinogen concentrate (human) for routine prophylaxis, treatment of bleeding or surgery in subjects with congenital fibrinogen deficiency was evaluated in a retrospective, multicenter trial with a prospective one-year follow-up period. Twenty-two subjects between 2 to 78 years with a mean age of 34 years were enrolled, with treatment recorded during the retrospective period from an age of less than 1 year. Thirteen of the 22 (59.1%) subjects were female, 21 (95.5%) subjects were white, and 1 (4.5%) subject Asian [see Clinical Studies (14)].

The adverse reactions reported in the retrospective period were visual impairment, chest discomfort, chest pain, cough, wheezing, flushing, and venous thrombosis of the limb [1 event each] and dyspnea [2 events]. No adverse reactions were found in the prospective period.

6.2 Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

The following adverse reactions, identified by system organ class, have shown a possible causal relationship with RIASTAP.

• Allergic-anaphylactic reactions: anaphylaxis, dyspnea, rash
• Cardiovascular: thromboembolic complications such as myocardial infarction, pulmonary embolism, and deep vein thrombosis [see Warnings and Precautions (5.2)]
• General/Body as a Whole: chills, nausea, vomiting

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

RIASTAP studies have included subjects below the age of 16 years. In the pharmacokinetic study [see Clinical Pharmacology (12.3)], 2 children aged 8 and 11 years and 3 adolescents aged 12, 14 and 16 years were studied. Subjects <16 years of age (n = 4) had shorter half-life (69.9 ± 8.5 h) and faster clearance (0.7 ± 0.1 mL/h/kg) compared with adults (half-life: 82.3 ± 20.0 h, clearance: 0.53 ± 0.1 mL/h/kg. The number of subjects <16 years of age in this study limits statistical interpretation.

A multicenter, non-interventional, retrospective cohort study with a prospective observational 12-month follow-up period was conducted to investigate the safety and efficacy of RIASTAP [see Clinical Studies (14)]. In this study, 11 of 22 subjects below 16 years were enrolled. Seven patients were 6 years or younger at first recorded treatment with fibrinogen concentrate (human), starting from an age of <1 year. Fibrinogen concentrate (human) was administered for prophylaxis as well as for treatment of bleeding events and for perioperative use. Ten patients younger than 18 years of age experienced bleeding events; hemostatic efficacy of fibrinogen concentrate (human) was rated as "effective" in all cases. Six patients underwent 7 surgeries and hemostatic efficacy was rated as "effective" in all cases.

8.5 Geriatric Use

The safety and efficacy of RIASTAP in the geriatric population has not been studied. There were an insufficient number of subjects in this age group to determine whether they respond differently from younger subjects.

Viral Clearance

All plasma used in the manufacture of RIASTAP is tested using serological assays for hepatitis B surface antigen and for antibodies to Human Immunodeficiency Virus (HIV)-1/2 and Hepatitis C Virus (HCV). As an additional safety measure, the plasma is tested with Nucleic Acid Testing (NAT) for Hepatitis B Virus (HBV), HCV and HIV-1 and found to be non-reactive (negative). The plasma is also screened for Hepatitis A Virus (HAV) and Human Parvovirus B19 (B19V) by NAT. Only plasma that passed virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU of B19V DNA per mL.

RIASTAP is manufactured from cryoprecipitate into a glycine precipitate, which is then further purified by multiple precipitation/adsorption steps. The manufacturing process has been demonstrated to reduce the risk of virus transmission in an additive manner: cryoprecipitation, heat treatment (+60ºC for 20 hours in an aqueous solution), two subsequent glycine precipitation steps (initial and main glycine precipitation steps), and lyophilization. These steps have been validated independently in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses. The results of virus clearance validation studies for RIASTAP manufacturing process are summarized in Table 1.

12.1 Mechanism of Action

During the coagulation process, thrombin cleaves the Aα and Bβ chains releasing fibrinopeptides A and B (FPA and FPB, respectively).2 FPA is separated rapidly and the remaining molecule is a soluble fibrin monomer (fibrin I). The slower removal of FPB results in formation of fibrin II that is capable of polymerization that occurs by aggregation of fibrin monomers.2 The resulting fibrin is stabilized in the presence of calcium ions and by activated factor XIII, which acts as a transglutaminase. Factor XIIIa-induced cross-linking of fibrin polymers renders the fibrin clot more elastic and more resistant to fibrinolysis.3 Cross-linked fibrin is the end result of the coagulation cascade, and provides tensile strength to a primary hemostatic platelet plug and structure to the vessel wall.

12.2 Pharmacodynamic Action

Administration of RIASTAP to patients with congenital fibrinogen deficiency replaces missing or low levels of coagulation factor. Normal levels are in the range of 200 to 450 mg/dL.4

12.3 Pharmacokinetics

A prospective, open label, uncontrolled, multicenter pharmacokinetic study was conducted in 5 females and 9 males with congenital fibrinogen deficiency (afibrinogenemia), ranging in age from 8 to 61 years (2 children, 3 adolescents, 9 adults). Each subject received a single intravenous dose of 70 mg/kg RIASTAP. Blood samples were collected to determine fibrinogen activity at baseline and up to 14 days after infusion. The pharmacokinetic parameters of RIASTAP are summarized in Table 2.

No statistically relevant difference in fibrinogen activity was observed between males and females. Subjects <16 years of age (n=4) had shorter half-life (69.9 ± 8.54 h) and faster clearance (0.73 ± 0.14 mL/h/kg) compared with subjects ≥16 years of age (half-life of 82.3 ± 20.04 h and clearance of 0.53 ± 0.07 mL/h/kg). The number of subjects <16 years of age in this study limits statistical interpretation.

The incremental in vivo recovery (IVR) was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was 1.7 mg/dL (range 1.30 – 2.73 mg/dL) increase per mg/kg. The median in vivo recovery indicates that a dose of 70 mg/kg will increase fibrinogen plasma concentration in patients by approximately 120 mg/dL.

The pharmacokinetic analysis using fibrinogen antigen data (ELISA) was concordant with the fibrinogen activity (Clauss assay).

h: hours

• When stored at temperatures of 2-8°C (36-46°F), RIASTAP is stable for the period indicated by the expiration date on the carton and vial label (up to 60 months). Do not use RIASTAP beyond the expiration date.
• Keep RIASTAP in its original carton until ready to use.
• Do not freeze. Protect from light.
• Discard partially used vials.

• Allergic Reactions

  Inform patients of the early signs of allergic or hypersensitivity reactions to RIASTAP, including hives, chest tightness, wheezing, hypotension, and anaphylaxis. Advise them to notify their physician immediately if they experience any of these symptoms [see Warnings and Precautions (5.1)].

• Thrombosis

  Inform patients that thrombosis with or without embolization has been reported with the use of RIASTAP. Any symptoms of thrombotic events such as unexplained pleuritic, chest and/or leg pain or edema, hemoptysis, dyspnea, tachypnea or unexplained neurologic symptoms should be reported to their physician immediately [see Warnings and Precautions (5.2)].

• Transmissible Infectious Agents

  Inform patients that RIASTAP is made from human plasma (part of the blood) and 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. Explain that the risk of transmitting an infection agent using RIASTAP has been reduced by screening plasma donors, testing the donated plasma for certain virus infections, and incorporating a process demonstrated to inactivate and/or remove certain viruses during manufacturing. Symptoms of possible virus infection include headache, fever, nausea, vomiting, weakness, malaise, diarrhea, or, in the case of hepatitis, jaundice [see Warnings and Precautions (5.3)].