Immune Globulin Intravenous (Human) - Flebogamma DIF
Status: approved; marketed
Organizations involved:
Instituto Grifols, S.A. – Manuf.; R&D; Tech.; Intl. mark.
Grifols Biological Inc. – USA mark.
Probitas Pharma – Parent
Cross ref: See the Immune Globulin Products entry (#743) and the entries for other IGIV products.
Description: Immune Globulin Intravenous (Human) or Flebogamma DIF is a 5% aqueous formulation of pasteurized highly purified immunoglobulin (IgG) derived from Plasma (Human). The purification process includes cold ethanol fractionation, 8% polyethylene glycol (PEG) precipitation, and ion exchange chromatography. Besides ethanol fractionation, the two main processing steps for viral inactivation/removal are the pasteurization heat treatment (at 60˚C for 10 hours) and PEG precipitation. Flebogamma is a highly purified (≥99% IgG) unmodified, human IgG that contains the antibody specificities found in the donor population. IgG subclasses are fully represented with the following approximate percents of total IgG: IgG1 is 70.3%, IgG2, 24.7%, IgG3, 3.1%, and IgG4, 1.9%. The IgA content is <0.05 mg/mL; and IgM is present in trace amounts. Flebogamma is one of two liquid formulations (not lyophi-lized) IGIV formulations marketed in the U.S.
Flebogamma 5% is packaged in 10 mL (5. g), 50 mL (2.5 g), 100 mL (50 g), and 200 mL (100 g) fill size vials. Flebogamma 5% contains 50 mg/mL IgG, 50 mg/mL D-sorbitol, and ≤ 6 mg/mL polyethylene glycol (PEG), with no antimicrobial preservatives. The pH of the solution ranges from 5-6 and the osmolarity from 240-350 mOsm/L. The dating period is 24 months from the date of manufacture when stored at 2-25°C (36-77˚F; includes room temperature), with the date of manufacture is the date of final sterile filtration of the formulated drug product.
Nomenclature: Immune Globulin (IGIV)/Flebogamma [BIO]; Flebogamma [TR]; Immune Globulin Intravenous (Human) [FDA]; IGIV [SY]; gamma globulin, intravenous [SY]; intravenous immune globulin (IVIG) [SY]; NDC 61953-0003-1, NDC 61953-0003-2, NDC 61953-0003-3, NDC 61953-0003-4 [NDC]
Companies.: Flebogamma was developed and is manufactured by Instituto Grifols, CBER/FDA est. no. 1181, at facilities in Barcelona, Spain. It is marketed in the U.S. by Grifols Biological Inc.. Both Instituto Grifols and Grifols Biological Inc. are subsidiaries of Probitas Pharma S.A.
The company has about 1 million Liters annual plasma processing capacity, and is expanding with construction of a new facility (including for its next-genera-tion IGIV), and facilities to store over 1 million units at -30˚C. Biomat USA, a subsidiary of Probitas, has 43 plasmapheresis centers in the U.S., which supply plasma to Instituto Grifols.
Manufacturing: Pasteurization (at 60˚C for 10 hours) provides the following log10 reductions in viral titers: HIV-1, >5.9; infectious bovine rhinotracheitis (IBR; model for hepatitis B virus and herpesviruses), 5.8; pseudorabies virus (model for hepatitis B virus and herpesviruses), ≥4.3; bovine viral diarrhea virus (BVDV; model for hepatitis C virus), ≥5.1; Sindbis virus (model for hepatitis C virus), ≥6.6; encephalo-myocarditis virus (EMC), 5.0; and porcine parvovirus (model for parvovirus B19), 2.3. PEG (8%) precipitation provides the followings reductions in viral titers: HIV-1, 3.7; IBR, 4.3; pseudorabies virus, 4.2; BVDV, ≥5.3; Sindbis virus, 4.2; EMC, 3.8; and porcine parvovirus, 3.9. Cumulative (entire processing) reductions in viral titer are HIV-1, ≥9.6; infectious bovine rhinotracheitis (IBR; model for hepatitis B virus and herpesviruses), 10.1; pseudorabies virus, ≥8.5; BVDV ≥10.4; Sindbis virus, ≥10.8; EMC, 8.8; and porcine parvovirus, 6.2.
FDA class: Biologic BLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 20031215; BLA (BL 125077/0)
Date = 20061227; BLA supplement; Indication = approval of Flebogamma DIF formulation (addition of additional viral inactivation step)
Indications: [portion of the "INDICATIONS AND USAGE” section of product insert/labeling]:
Flebogamma 5% is indicated for replacement therapy in primary (inherited) humoral immunodeficiency disorders, such as common variable immunodeficiency, x-linked agammaglobulinemia, severe combined immunodeficiency, and Wiskott-Aldrich Syndrome. Flebogamma 5% is especially useful when rapid replacement of IgG or the attainment of high serum levels of IgG is desired. Some clinical trials conducted with Flebogamma 5% included infants, children, and adolescents with primary and secondary immunodeficiency diseases to assess clinical efficacy. Data have also been obtained from postmarketing studies and postmarketing surveillance....
Medical: Flebogamma 5% is generally used for replacement therapy in primary humoral immunodeficiency diseases at a dosage of 300-600 mg/kg body weight administered every 3-4 weeks.
Market: Worldwide sales of Flebogamma were well in excess of 3 million grams (3,000 kg) in 2002, an increase of 12% compared to 2001. Probitas Pharma has sold this product for more than 10 years in European and Latin American markets. Flebogamma is the most used IVIG in the European market.
The 2007 Average Wholesale Price (AWP) is $48.43/-10 mL vial, with a Direct Price (DP; manufacturer’s discount price) of $40.32; $241.92/50 mL vial, with DP of $201.60; $483.84/100 mL vial, with DP of $403.20; and $967.68/200 mL vial, with DP of $806.40 (Red Book, 2007). These prices are unchanged from 2004.
R&D: Instituto Grifols/Probitas is developing a next generation IGIV product. This will be manufactured in a new plant currently under construction in Barcelona, Spain.
Companies involvement:
Full monograph
766 Immune Globulin (IGIV)/Flebogamma
Nomenclature:
Immune Globulin (IGIV)/Flebogamma [BIO]
Flebogamma [TR]
Immune Globulin Intravenous (Human) [FDA]
gamma globulin, intravenous [SY]
IGIV [SY]
intravenous immune globulin (IVIG) [SY]
NDC 61953-0003-2, NDC 61953-0003-3, NDC 61953-0003-4 [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 2003
Date of 1st FDA approval = 20031215
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blood products
human materials used<!-- humansource -->
immune globulins, human <!-- immunoglobulins -->
ethanol
heat treatment (pasteurization)
Plasma (Human)
polyethylene glycol (PEG)
sorbitol
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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