RiaSTAP

RiaSTAP™ (fibrinogen concentrate human) for Intravenous Use Lyophilized Powder for Reconstitution

DESCRIPTION

RiaSTAP (fibrinogen concentrate human for intravenous use) 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 (fibrinogen concentrate human for intravenous use) 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 signifcance 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 (fibrinogen concentrate human for intravenous use) is manufactured from cryoprecipitate into a glycine precipitate, which is then further purifed 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 (fibrinogen concentrate human for intravenous use) , expressed as the mean log₁₀ reduction factor (LRF).

Table 1: Cumulative (Log₁₀) Virus Inactivation/Reduction in RiaSTAP (fibrinogen concentrate human for intravenous use)

Manufacturing Step	Virus Reduction Factor (log10)
	Enveloped viruses					Non-enveloped viruses
	HIV	BVDV	WNV	HSV-1	PRV	H AV	CPV	B19V*
Cryoprecipitation	n.d.	n.d.	n.d.		1.6†	2.4	2.8	n.d.
Al(OH)3 adsorption/ glycine precipitation/ Al(OH)3 adsorption	(2.8)‡	(1.5)‡	n.d.	(0.9)‡				n.d.
Heat Treatment	≥ 5.7	≥ 9.1	≥ 8.3	≥ 8.1		≥ 4.3	1.6	≥ 4.5*
Glycine precipitation (two subsequent steps)	3.9	2.1	n.d.	1.0		(1.0)‡	(1.6)‡	n.d.
Cumulative virus reduction (log10)	≥ 9.6	≥ 11.2	≥ 8.3	≥ 9 .1	1.6	≥ 6.7	4.4	≥ 4.5
BVDV, bovine viral diarrhea virus, model for HCV WNV,West Nile virus HSV-1, herpes simplex virus type 1 CPV, canine parvovirus, model for B19V *B19V, human parvovirus B19, the virus elimination studies for parvovirus B19 employed a novel experimental infectivity assay utilizing clone of cell line UT7 that contains erythropoietic progeny cells. Virus titer was determined using an mmunofuorescence-based detection method. † PRV as HSV-1 a herpes virus – is reduced by cryoprecipitation by 1.6 log10 ‡ Not included in the calculation of the cumulative virus reduction factor n.d., not done

INDICATIONS

RiaSTAP™ (fibrinogen concentrate (human) for intravenous use) , Fibrinogen Concentrate (Human) is indicated for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia.

RiaSTAP (fibrinogen concentrate (human) for intravenous use) is not indicated for dysfibrinogenemia

DOSAGE AND ADMINISTRATION

For intravenous use only. Reconstitute prior to use.

Should be administered under the supervision of a physician.

Treatment of Congenital Fibrinogen Defciency

RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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 (fibrinogen concentrate (human) for intravenous use) 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):

[Target level (mg/dL) - measured level (mg/dL)]

1.7 (mg/dL per mg/kg body weight)

RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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 (fibrinogen concentrate (human) for intravenous use) . A target  fibrinogen level of 100 mg/dL should be maintained until hemostasis is obtained.

Preparation and Reconstitution

The procedures below are provided as general guidelines for preparation and reconstitution of RiaSTAP (fibrinogen concentrate (human) for intravenous use) .

Do not use RiaSTAP (fibrinogen concentrate (human) for intravenous use) beyond the expiration date. RiaSTAP (fibrinogen concentrate (human) for intravenous use) contains no preservative. Use aseptic technique when preparing and reconstituting RiaSTAP (fibrinogen concentrate (human) for intravenous use) .

Reconstitute RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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 (fibrinogen concentrate (human) for intravenous use) 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 (fibrinogen concentrate (human) for intravenous use) solution. Discard partially used vials.

RiaSTAP (fibrinogen concentrate (human) for intravenous use) is stable for 24 hours after reconstitution when stored at 20-25ºC and should be administered within this time period.

Administration

Do not mix RiaSTAP (fibrinogen concentrate (human) for intravenous use) with other medicinal products or intravenous solutions, and should be administered through a separate injection site.

Use aseptic technique when administering RiaSTAP (fibrinogen concentrate (human) for intravenous use)

Administer RiaSTAP (fibrinogen concentrate (human) for intravenous use) at room temperature by slow intravenous injection at a rate not exceeding 5 mL per minute.

HOW SUPPLIED

Dosage Forms And Strengths

RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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 (fibrinogen concentrate (human) for intravenous use) is supplied in a single-use vial. Each carton contains one vial of RiaSTAP (fibrinogen concentrate (human) for intravenous use) . The components used in the packaging for RiaSTAP (fibrinogen concentrate (human) for intravenous use) are latex-free.

The actual potency of fibrinogen concentrate in milligram (mg) is stated on each RiaSTAP (fibrinogen concentrate (human) for intravenous use) vial label and carton.

The following dosage form is available:

NDC Number	RiaSTAP Vial
63833-8915-1	Approximately 1 g (900 – 1300 mg)

When stored at temperatures of 2-25°C (36-77°F), RiaSTAP (fibrinogen concentrate (human) for intravenous use) is stable for the period idicated by the expiration date on the carton and vial label (up to 30 months). Keep RiaSTAP (fibrinogen concentrate (human) for intravenous use) in its original carton until ready to use. Do not freeze. Protect from light.

Manufactured by: CSL Behring GmbH. 35041 Marburg Germany. Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

SIDE EFFECTS

The most serious adverse reactions that have been reported in clinical studies or through postmarketing surveillance following RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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 (fibrinogen concentrate (human) for intravenous use) treatment are allergic reactions and generalized reactions such as chills, fever, nausea, and vomiting.

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.

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 (fibrinogen concentrate (human) for intravenous use) 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 (fibrinogen concentrate (human) for intravenous use) .

• Allergic-anaphylactic reactions: anaphylaxis, dyspnea, rash
• Cardiovascular: thromboembolism, pulmonary embolism (see WARNINGS AND PRECAUTIONS, Thrombosis)
• General/Body as a Whole: chills, fever, nausea, vomiting

DRUG INTERACTIONS

No information provided.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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). The treatment required depends on the nature and severity of the reaction.

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 (fibrinogen concentrate (human) for intravenous use) . Weigh the benefits of RiaSTAP (fibrinogen concentrate (human) for intravenous use) administration versus the risk of thrombosis. Patients receiving RiaSTAP should be monitored for signs and symptoms of thrombosis. (see Patient Counseling Information)

Transmissible Infectious Agents

RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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). 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.

Use In Specific Populations

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with RiaSTAP (fibrinogen concentrate (human) for intravenous use) It is not known whether RiaSTAP (fibrinogen concentrate (human) for intravenous use) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RiaSTAP (fibrinogen concentrate (human) for intravenous use) should be used during pregnancy only if clearly needed.

Labor and Delivery

RiaSTAP (fibrinogen concentrate (human) for intravenous use) has not been studied for use during labor and delivery

Nursing Mothers

RiaSTAP (fibrinogen concentrate (human) for intravenous use) has not been studied in nursing mothers with congenital fibrinogen deficiency

Pediatric Use

RiaSTAP (fibrinogen concentrate (human) for intravenous use) studies have included subjects below the age of 16 years. In the pharmacokinetic study (see Pharmacokinetics), 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.

Geriatric Use

The safety and efficacy of RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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.

REFERENCES

1. Peyvandi F, Haertal S, KnaubS, etal. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost 2006; 4:1634-7.

OVERDOSE

No information provided.

CONTRAINDICATIONS

RiaSTAP (fibrinogen concentrate (human) for intravenous use) is contraindicated in individuals who have manifested severe immediate hypersensitivity reactions, including anaphylaxis to RiaSTAP (fibrinogen concentrate (human) for intravenous use) or its components.

CLINICAL PHARMACOLOGY

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  fbrin 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.

Pharmacodynamic Action

Administration of RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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

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 (fibrinogen concentrate (human) for intravenous use) . 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 (fibrinogen concentrate (human) for intravenous use) 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) ncrease per mg/kg. The median in vivo recovery indicates that a dose of 70 mg/kg will ncrease 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).

Table 2: Pharmacokinetic Parameters (n=14) for Fibrinogen Activity

Parameters	Mean ± SD (range)
Half-life [hours]	78.7 ± 18.13 (55.73-117.26)
Cmax [mg/dL]	140 ± 27 (100-210)
AUC for dose of 70 mg/kg [mg*hr/mL]	124.3 ± 24.16 (81.73-156.40)
Clearance [mL/h/kg]	0.59 ± 0.13 (0.45-0.86)
Mean residence time [hours]	92.8 ± 20.11 (66.14-126.44)
Volume of distribution at steady state [mL/kg]	52.7 ± 7.48 (36.22-67.67)

Clinical Studies

The pharmacokinetic study evaluated the single-dose PK (see Pharmacokinetics) 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  fxed dose of RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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 effcacy.⁵

For each subject, the MCF was determined before (baseline) and one hour after the single dose administration of RiaSTAP (fibrinogen concentrate (human) for intravenous use) . RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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 signifcantly higher after administration of RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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 vitro⁶. Hemostatic effcacy in acute bleeding episodes, and its correlation with MCF, are being verifed in a postmarketing study.

Table 3: MCF [mm] (ITT population)

Time point	n	Mean ± SD	Median (range)
Pre-infusion	13	0 ± 0	0 (0-0)
1 hour post-infusion	13	10.3 ± 2.7	10.0 (6.5-16.5)
Mean change (primary analysis)a	15b	8.9 ± 4.4	9.5 (0-16.5)
MCF = maximum clot  frmness; mm = millimeter; ITT = intention-to-treat a p-value was < 0.0001. b The mean change was set to 0 for 2 subjects with missing MCF data.

REFERENCES

1. Peyvandi F, Haertal S, KnaubS, etal. Incidence of bleeding symptoms in 100 patients with nherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost 2006; 4:1634-7.

2. Kreuz W, Meili E, Peter-Salonen K, et al. Pharmacokinetic properties of a pasteurized fibrinogen concentrate. Transfusion and Apheresis Science 2005;32:239-46.

3. Colman R, Clowes A, George J, et al. Overview of Hemostasis. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice (5th ed.). Colman R, Clowes A, George J, Goldhaber S, MarderVJ (eds.). LippincottWilliams & Wilkins, Philadelphia 2006:11-14.

4. KreuzW, Meili E, Peter-Salonen K, et al. Effcacy and tolerability of a pasteurized human fibrinogen concentrate in patients with congenital fibrinogen deficiency. Transfusion and Apheresis Science 2005;32:247-253.

5. Fries D, Innerhofer P, Reif C, et al. The Effect of Fibrinogen Substitution on Reversal of Dilutional Coagulopathy: An In Vitro Model. Anesth Analg 2006; 102:347-351.

6. Kalina U, Stöhr HA, Bickhard H, et. al. Rotational thromboelastographyfor monitoring of fibrinogen concentrate therapy in fibrinogen deficiency. Blood Coagulation and Fibrinolysis. 2008; 19:777-783.

PATIENT INFORMATION

Allergic Reactions

Inform patients of the early signs of allergic or hypersensitivity reactions to RiaSTAP (fibrinogen concentrate (human) for intravenous use) , including hives, chest tightness, wheezing, hypotension, and anaphylaxis (see WARNINGS AND PRECAUTIONS). Advise them to notify their physician immediately if they experience any of these symptoms.

Thrombosis

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 (fibrinogen concentrate (human) for intravenous use) . 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).

Transmissible Infectious Agents

Inform patients that RiaSTAP (fibrinogen concentrate (human) for intravenous use) 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 (fibrinogen concentrate (human) for intravenous use) 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). Symptoms of a possible virus infection include headache, fever, nausea, vomiting, weakness, malaise, diarrhea, or, in the case of hepatitis, jaundice.