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fibrinogen injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
RiaSTAP®, Fibrinogen Concentrate (Human) is indicated for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia.
RiaSTAP is not indicated for dysfibrinogenemia.
2 DOSAGE AND ADMINISTRATION
For intravenous use only. Reconstitute prior to use.
Should be administered under the supervision of a physician.
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.
RiaSTAP dose when baseline fibrinogen level is known
Dose should be individually calculated for each patient based on the target plasma fibrinogen level based on the type of bleeding, actual measured plasma fibrinogen level and body weight, using the following formula (see Pharmacokinetics [12.3]):
RiaSTAP dose when baseline fibrinogen level is not known
If the patient's fibrinogen level is not known, the recommended dose is 70 mg per kg of body weight administered intravenously.
Monitoring of patient's fibrinogen level is recommended during treatment with RiaSTAP. A target fibrinogen level of 100 mg/dL should be maintained until hemostasis is obtained.
2.2 Preparation and Reconstitution
The procedures below are provided as general guidelines for preparation and reconstitution of RiaSTAP.
Do not use RiaSTAP beyond the expiration date. RiaSTAP contains no preservative. Use aseptic technique when preparing and reconstituting RiaSTAP.
Reconstitute RiaSTAP at room temperature as follows:
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. Do not freeze RiaSTAP solution. Discard partially used vials.
RiaSTAP is stable for 24 hours after reconstitution when stored at 20-25ºC and should be administered within this time period.
Do not mix RiaSTAP with other medicinal products or intravenous solutions, and should be administered 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.
3 DOSAGE FORMS AND STRENGTHS
RiaSTAP is available as a single-use vial containing 900 mg to 1300 mg lyophilized fibrinogen concentrate powder for reconstitution with 50 mL of Sterile Water for Injection.
The actual fibrinogen potency for each lot is printed on the vial label and carton.
RiaSTAP is contraindicated in individuals who have manifested severe immediate hypersensitivity reactions, including anaphylaxis to RiaSTAP or its components.
5 WARNINGS AND PRECAUTIONS
5.1 Allergic Reactions
Allergic reactions may occur. If symptoms of allergic or early signs of hypersensitivity reactions (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis) occur, immediately discontinue administration (see Patient Counseling Information [17.1]). The treatment required depends on the nature and severity of the reaction.
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. Patients receiving RiaSTAP should be monitored for signs and symptoms of thrombosis. (see Patient Counseling Information [17.2])
5.3 Transmissible Infectious Agents
RiaSTAP is made from human plasma. Products made from human plasma may contain infectious agents (e.g., viruses and theoretically the Creutzfeldt-Jakob disease agent [CJD]) that can cause disease. 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 ). 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 [17.3]). 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 at 1-866-915-6958.
6 ADVERSE REACTIONS
The most serious adverse reactions that have been reported in clinical studies or through postmarketing surveillance following RiaSTAP treatment are allergic-anaphylactic reactions and thromboembolic episodes, including myocardial infarction, pulmonary embolism, deep vein thrombosis, and arterial thrombosis.
The most common adverse reactions that have been reported in clinical studies or through postmarketing surveillance following RiaSTAP treatment are allergic reactions and generalized reactions such as chills, fever, nausea, and vomiting.
6.1 Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in practice.
The most common adverse reactions observed in more than one subject in clinical studies (frequency >1%) were fever and headache.
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.
Adverse reactions reported in patients receiving RiaSTAP for treatment of fibrinogen deficiency include allergic-anaphylactic reactions (including rash, dyspnea, etc.), general reactions such as chills, fever, nausea, vomiting and thromboembolic complications such as myocardial infarction, pulmonary embolism, and deep vein thrombosis.
The following adverse reactions, identified by system organ class, have shown a possible causal relationship with RiaSTAP.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C. Animal reproduction studies have not been conducted with RiaSTAP. It is not known whether RiaSTAP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RiaSTAP should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
RiaSTAP has not been studied in nursing mothers with congenital fibrinogen deficiency.
8.4 Pediatric Use
RiaSTAP studies have included subjects below the age of 16 years. In the pharmacokinetic study (see Pharmacokinetics [12.3]), 2 children (8 and 11 years), 3 adolescents (12, 14 and 16 years), were studied. Subjects less than 16 years of age (n = 4) had shorter half-life (69.9 ± 8.5h) and faster clearance (0.7 ± 0.1 mg/L) compared to adults (half-life: 82.3 ± 20.0h, clearance: 0.53 ± 0.1 mg/L). The number of subjects less than 16 years of age in this study limits statistical interpretation.
RiaSTAP is a heat-treated, lyophilized fibrinogen (coagulation factor I) powder made from pooled human plasma.
Each vial contains 900 to 1300 mg fibrinogen, 400 to 700 mg human albumin, 375 to 660 mg L-arginine hydrochloride, 200 to 350 mg sodium chloride and 50 to 100 mg sodium citrate. Sodium hydroxide and hydrochloric acid may have been used to adjust the pH.
All plasma used in the manufacture of RiaSTAP is tested using FDA-licensed serological assays for hepatitis B surface antigen and antibodies to HIV-1/2 and HCV. Additionally, the plasma is tested with FDA-licensed Nucleic Acid Testing (NAT) for HCV and HIV-1 and found to be non-reactive (negative). For HBV, an investigational NAT procedure is used; however, the significance of a negative result has not been established. In addition, the plasma has been tested by NAT for HAV and B19V. 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, Al(OH)3 adsorption/glycine precipitation/Al(OH)3 adsorption, heat treatment (+60ºC for 20 hours in an aqueous solution), and two subsequent glycine precipitation steps (initial and main glycine precipitation steps). 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. Table 1 shows the virus clearance during the manufacturing process for RiaSTAP, expressed as the mean log10 reduction factor (LRF).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Fibrinogen (factor I) is a soluble plasma glycoprotein with a molecular weight of about 340 kDa. The native molecule is a dimer and consists of three pairs of polypeptide chains (Aα, Bβ and γ). Fibrinogen is a physiological substrate of three enzymes: thrombin, factor XIIIa, and plasmin.
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 the missing, or low coagulation factor. Normal levels are in the range of 200 to 450 mg/dL.4
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 drawn from the patients to determine the fibrinogen activity at baseline and up to 14 days after the infusion. The pharmacokinetic parameters of RiaSTAP are summarized in Table 2.
No statistically relevant difference was observed between males and females for fibrinogen activity. Subjects less than 16 years of age (n=4) had shorter half-life (69.9 ± 8.5) and faster clearance (0.73 ± 0.14) compared to subjects >16 years of age. The number of subjects less than 16 years of age in this study limits statistical interpretations.
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 patients' fibrinogen plasma concentration by approximately 120 mg/dL.
The pharmacokinetic analysis using fibrinogen antigen data (ELISA) was concordant with the fibrinogen activity (Clauss assay).
14 CLINICAL STUDIES
The pharmacokinetic study evaluated the single-dose PK (see Pharmacokinetics [12.3]) and maximum clot firmness (MCF) in subjects with afibrinogenemia. MCF was determined by thromboelastometry (ROTEM) testing. MCF was measured to demonstrate functional activity of replacement fibrinogen when a fixed dose of RiaSTAP was administered. Clot firmness is a functional parameter that depends on: activation of coagulation, fibrinogen content of the sample and polymerization/crosslinking of the fibrin network. Thromboelastometry has been shown to be a functional marker for the assessment of fibrinogen content and for the effects of fibrinogen supplementation on clinical efficacy.5
For each subject, the MCF was determined before (baseline) and one hour after the single dose administration of RiaSTAP. RiaSTAP was found to be effective in increasing clot firmness in patients with congenital fibrinogen deficiency (afibrinogenemia) as measured by thromboelastometry. The study results demonstrated that the MCF values were significantly higher after administration of RiaSTAP than at baseline (see Table 3). The mean change from pre-infusion to 1 hour post-infusion was 8.9 mm in the primary analysis (9.9 mm for subjects < 16 years old and 8.5 mm for subjects ≥ 16 to < 65 years old). The mean change in MCF values closely approximated the levels expected from adding known amounts of fibrinogen to plasma in vitro.6 Hemostatic efficacy in acute bleeding episodes, and its correlation with MCF, are being verified in a postmarketing study.
16 HOW SUPPLIED/STORAGE AND HANDLING
RiaSTAP is supplied in a single-use vial. Each carton contains one vial of RiaSTAP. The components used in the packaging for RiaSTAP are latex-free.
The actual potency of fibrinogen concentrate in milligram (mg) is stated on each RiaSTAP vial label and carton.
The following dosage form is available:
17 PATIENT COUNSELING INFORMATION
17.1 Allergic Reactions
Inform patients of the early signs of allergic or hypersensitivity reactions to RiaSTAP, including hives, chest tightness, wheezing, hypotension, and anaphylaxis (see Warnings and Precautions [5.1]). Advise them to notify their physician immediately if they experience any of these symptoms.
Inform patients that thrombosis with or without embolization may be due to the underlying fibrinogen deficiency and 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]).
17.3 Transmissible Infectious Agents
Inform patients that RiaSTAP is made from human plasma (part of the blood) and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Explain the risk that RiaSTAP may transmit an infectious agent has been reduced by screening the plasma donors, by testing the donated plasma for certain virus infections, and by a process demonstrated to inactivate and/or remove certain viruses during manufacturing (see Warnings and Precautions [5.3]). Symptoms of a possible virus infection include headache, fever, nausea, vomiting, weakness, malaise, diarrhea, or, in the case of hepatitis, jaundice.
PRINCIPAL DISPLAY PANEL - One Single-use Vial Label
PRINCIPAL DISPLAY PANEL - One Single-use Vial Carton
One single-use vial containing
For Intravenous Administration
Revised: 03/2010 CSL Behring GmbH
Reproduced with permission of U.S. National Library of Medicine
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