Immune Globulin Intravenous (Human) - Gammagard S/D; Kiovig; Gammagard Liquid; Iveegam
Status: approved; marketed
Organizations involved:
Baxter Hyland Immuno – Manuf.; R&D; Tech.; World mark.
Baxter Healthcare Corp. – Parent co.
New York Blood Center, Inc. – Tech.
Cross ref: See the Immune Globulin Products entry (#743) and the entries for other IGIV products.
Description: Immune Globulin Intravenous (Human), Solvent/Detergent Treated or Gammagard S/D refers to lyophilized (freeze-dried) and 10% aqueous formulations of highly purified immunoglobulin G, primarily IgG, obtained from pooled human Plasma, with manufacture including virus inactivation/removal by solvent detergent viral inactivation (with polysorbate 80 and octoxynol); nanofiltration (35 nm filter); and a low pH incubation at elevated temperature. The manufacturing process for Gammagard S/D isolates IgG without additional chemical or enzymatic modification, and the Fc and Fab portions are maintained intact.
Note, substantially the same or identical product was sold to the American Red Cross (ARC), now is sold to Baxter Hyland Immuno, and is marketed by under the trade name Polygam S/D (see related entry).
Gammagard S/D (and Polygam S/D) lyophilized (freeze-dried) powder is packaged at 5% and 10% concentrations. Excipients include glycine, glucose, polyethylene glycol (PEG), sodium chloride and albumin (human). IgG content is 96%. When lyophilized product is reconstituted with the diluent (Sterile Water for Injection, USP) supplied, Gammagard S/D contains approximately 50 mg of protein per mL (5%), of which at least 90% is IgG, at a physiological concentration of sodium chloride (approximately 8.5 mg/mL), with pH of 6.8 ± 0.4. Stabilizing agents and additional components are present in the following maximum amounts for a 5% solution of the lyophilized formulation: 3 mg/mL Albumin (Human), 22.5 mg/mL glycine, 20 mg/mL glucose, 2 mg/mL polyethylene glycol (PEG), 1 µg/mL tri-n-butyl phosphate (TNBP; residual from solvent detergent viral inactivation), 1µg/mL octoxynol 9 (residual from solvent detergent viral inactivation), and 100 µg/mL polysorbate 80 (P; residual from solvent detergent viral inactivation).
Gammagard S/D (powder) contains only trace amounts of IgA (<3.7 µg/mL in a 5% solution). IgM is also present in trace amounts. The product contains no preservatives. IgG subclasses include 57% IgG1, 30% IgG2, 8% IgG3 and 5% IgG4.
Gammagard S/D (powder) is stored at a temperature < 25°C (77°F) and has a shelf life of two years. The in vivo half-life of Gammagard S/D is ~37.7 ± 15 days.
Gammagard Liquid,10% (marketed as Kiovig in Europe) is packaged in 10, 25, 50, 100 and 200 mL vials, respectively containing 1.0, 2.5, 5.0, 10.0, and 20.0 gram of protein. At least 98% of the protein is gammaglobulin. The average immunoglobulin A (IgA) concentration is 37µg/mL, and immunoglobulin M (IgM) is present in trace amounts. Glycine (0.25M) serves as a stabilizing and buffering agent. The pH is 4.6 to 5.1. The osmolality is 240-300 mOsmol/kg, which is similar to physiological osmolality (285 to 295 mOsmol/kg). To help ensure viral safety, three validated, independent and effective virus inactivation/removal steps have been integrated into processing and formulation -– solvent/detergent (S/D) treatment, 35 nanometer filtration, and low pH incubation. Gammagard Liquid 10% offers improved convenience for healthcare professionals and patients. Gammagard Liquid contains no added sugars, no added sodium, no added preservatives and has latex-free packaging.
Gammagard Liquid has a shelf life of 36 months storage at 2-8°C (refrigerated). It may be stored for 9 months storage at room temperature 25°C (77°F) within the first 24 months of the date of manufacture.
Nomenclature: Immune Globulin (IGIV)/Baxter [BIO]; Gammagard S/D [TR]; Kiovig [TR Europe]; Gammagard Liquid [TR]; Immune Globulin Intravenous (Human) [FDA]; gamma globulin, intravenous [SY]; IVIG [SY]; immune globulin, intravenous [SY]; intravenous immune globulin (IVIG) [SY]; Iveegam [TR former, for OIH/Immuno product]
History: Gammagard and Polygam, the equivalent product manufactured for the American Red Cross (now Baxter), were associated with over 100 cases of infection with hepatitis C virus (non-A, non-B hepatitis) and were recalled in 1994. Their manufacturing process was changed to include a solvent detergent (S/D) virus inactivation step, and the products were reintroduced as Gammagard S/D and Polygam S/D.
Companies.: Gammagard S/D is manufactured by Baxter Hyland Immuno, FDA CBER est. no. 0140, at facilities in Los Angeles, CA; Vienna, Austria; and Lessines, Belgium. Fraction II is prepared in Los Angeles, and Fraction II is processed into IGIV in Belgium. Gammagard S/D is marketed in the U.S. by Baxter Hyland Immuno, and internationally by Baxter affiliates.
Immune Globulin Intravenous (Human) or Iveegam formerly manufactured by Immuno AG (formerly Oesterreichisches Institut fur Haemoderivate GmbH) was formerly marketed in the U.S., before the acquisition of Immuno by Baxter. With Baxter’s establishment lic. 0140 including Immuno’s former facilities in Austria, Gammagard S/D could be manufactured in U.S. and/or Austrian facilities.
Manufacture: The product is manufactured by Cohn-Oncley cold ethanol fractionation (methods 6 and 9) followed by ultrafiltration and ion exchange chromatography. Fraction II from fractionation is suspended, filtered, and subjected to solvent detergent viral inactivation using an organic solvent/-detergent mixture, composed of tri-n-butyl phosphate (solvent), and octoxynol 9 and polysorbate 80 (detergents). IgG is adsorbed onto a CM Sepharose cation-exchange chromatography column, including removal of solvent detergent components. IgG is eluted from the column with tris/glycine buffer, followed by diafiltration, pH adjustment to 8.0, ion-exchange chromatography with diethylaminoethyl (DEAE)-Sephadex A-50 matrix (removes IgA), ultrafiltration, pH adjustment to 7.0, and stabilization by addition of 0.3 M glycine, 3 mg/mL Albumin (Human), 8.5 mg/ml sodium chloride, and other excipients. The formulated product is sterile filtered (ultrafiltration), filled into vials, lyophilized, sealed, and packaged.
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19860218; first approval, PLA (STN 125105.0), for product manufactured by Baxter in the U.S.; Indication = primary immune deficiency
Date = 19880408; first approval, PLA, for product manufactured by Oesterreichisches Institut fur Haemoderivate GmbH; This product and manufacturing facilities were much later acquired by Baxter; Indication = primary immune deficiency
Date = 19990107; PLA supplement; granted to Baxter; Indication = for treatment of Kawasaki Disease in conjunction with high dose aspirin (80-100 mg/kg/day in four divided doses)
Date = 19940500; PLA supplement; granted to Baxter; introduction of Gammagard S/D manufactured with addition of a solvent detergent virus inactivation step
Date = 20050427; BLA supplement; Indication = approval of Gammagard Liquid [Immune Globulin Intravenous (Human)] (IGIV) 10% Solution for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity
Indications: [full text of the "Indications and Usage” section of the product insert/labeling, Gammagard Liquid]:
GAMMAGARD LIQUID is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. These include but are not limited to congenital X-linked agammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.
Status: In the summer of 1998, the FDA granted Baxter Hyland Immuno a license to manufacture one of the main ingredients used to produce Gammagard S/D at its plasma fractionation facility in Rochester, Michigan (formerly Immuno-U.S.).
In Dec. 1999, Baxter Healthcare Corp. proposed settlement of a class action suit involving individuals who contracted or were exposed to hepatitis C virus (HCV) through the use of Gammagard from Jan. 1, 1993 to Feb. 24, 1994 (prior to introduction of a solvent detergent viral inactivation step in manufacture). Baxter voluntarily temporarily withdrew Gamma-gard from the market in Feb. 1994 after reports of patients contracting hepatitis C. Baxter asserted that the hepatitis C activity was a result of changes to the blood screening process required by the FDA. There have been no reports of hepatitis C associated with Gammagard S/D use.
In April 2005, a new 10% liquid formulation was approved. Gammagard Liquid 10% was launched in the U.S. on Sept. 26, 2005. his ready-to-use, sterile liquid preparation eliminates the need for reconstitution. Its high concentration, compared to 5% concentrations, allows for a reduction in the length of infusion, reducing the infusion volume, and saving time for both patients and healthcare professionals. Baxter will continue to supply its current Gammagard S/D only for use with patients who require a low Immunoglobulin A (IgA) therapy.
On Jan. 25, 2005, Baxter received European Union approval of Kiovig for replacement therapy in primary immunodeficiency disorders (PID), myeloma or chronic lymphocytic leukemia (CLL) with severe secondary hypogammaglobulinemia and recurrent infections, children with congenital AIDS and recurrent infections, Kawasaki syndrome, allogeneic bone marrow transplantation, Guillain Barre syndrome, and idiopathic thrombocytopenic purpura (ITP) in children or adults at high risk of bleeding or prior to surgery to correct the platelet count.
Tech. transfer: The product insert/labeling cites U.S. patent 4,439,421, “Stabilized Gamma Globulin concentrate,” March 27, 1984, assigned to Baxter Travenol Labs., Inc. This discloses addition of a “nonsurface-active hydrophilic macromolecule” stabilizer, polyethylene glycol (PEG), to facilitate lyophilization and reduce anticomplement activity (IgG aggregate formation). The only example in the patent apparently describes aspects of Gamma-gard S/D manufacture.
Solvent detergent viral inactivation technology was developed by and nonexclusively licensed from the New York Blood Center, e.g., U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma) (#799) for further information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).
Trials: In Aug. 2007, Baxter and the Alzheimer's Disease Cooperative Study Group initiated a Phase III trials with Gammagard Liquid for treatment of mild to moderate Alzheimer's disease. Promising results had been seen in a Phase II trial.
In Jan. 2009, Baxter and Halozyme started a Phase III clinical trial of Gammagard Liquid with Enhanze (Hyaluronidase, rDNA; rHuPH20) for the treatment of primary immunodeficiency (PID). The purpose of this trial is to evaluate the safety and efficacy and gain regulatory approval for the treatment of PID using IVIG and rHuPH20 via subcutaneous injection at a single site. Gammagard Liquid is currently administered intravenously (IV). Subcutaneous (SC) administration could allow patients to receive a full monthly dose of IVIG in a single injection site in their home setting.
In July 2012, results from a small Phase II trial showed that Gammagard may have potential for treatment of Alzheimers' disease, with 11 of 16 patients demonstrating improvements in thinking and behavior as well as routine, day-to-day functions. Also, four of these patients in the most effective treatment arm experienced no decline across a range of symptoms.
Medical: For patients with primary immunodeficiency, monthly doses of approximately 300 – 600 mg/kg infused at 3 to 4 week intervals are commonly used.
Market: The 2007 Average Wholesale Price (AWP) for Gammagard S/D is $71.28/0.5 gr vial; $277.56/2.5 gr vial; $555.12/5 gr vial; and $1.110.23/10 gram vial (Red Book, 2007). The AWP for Gammagard Liquid is $121.57/10 mL vial; $303/93/25 mL; $607.86/50 mL; $1,215.72/100 mL; and $2,431.44/200 mL.
In Aug. 2007, Baxter launched the GARDian program provide continued access for patients relying on Gammagard S/D and Liquid
Companies involvement:
Full monograph
761 Immune Globulin (IGIV)/Baxter
Nomenclature:
Immune Globulin (IGIV)/Baxter [BIO]
Gammagard Liquid [TR]
Gammagard S/D [TR]
Immune Globulin Intravenous (Human) [FDA]
Kiovig [TR Europe]
gamma globulin, intravenous [SY]
immune globulin, intravenous [SY]
intravenous immune globulin (IVIG) [SY]
IVIG [SY]
Iveegam [TR former, for OIH/Immuno product]
NDC 0944-2700-02; NDC 0944-2700-03; NDC 0944-2700-04; NDC 0944-2700-05; NDC 0944-2700-06 [NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1986
Date of 1st FDA approval = 19860218
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blood products
human materials used<!-- humansource -->
immune globulins, human <!-- immunoglobulins -->
Albumin (Human)
ethanol
glucose
glycine
lyophilized (freeze-dried)
Namalva cells
octoxynol (Triton X-100)
Plasma (Human)
polyethylene glycol (PEG)
polysorbate 80 (Tween 80)
Sephadex
Sepharose
sodium chloride
sodium thiocyanate
Sterile Water for Injection
tri-n-butyl phosphate (TNBP)
viral (nano)filtration
viral inactivation, acid (low pH)
viral inactivation, solvent detergent
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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