Status: approved; marketed

Organizations involved:

Octapharma AG – Manuf.; R&D; Tech.; Intl. mark.

Octapharma USA, Inc. – USA mark.

New York Blood Center – Tech.

Description: lmmune Globulin Intravenous (Human) or Octagam is a aqueous ready-to-use formulation of 5% highly refined immune globulin obtained from pooled fractionated Plasma, with manufacture including double viral inactivation using the solvent-detergent process and incubation at low (acid) pH. Octagam is derived from Plasma (Human) from U.S. sources. Octagam is the only liquid and double virus inactivated IVIG which can be stored at room temperature (2-25°C) up to 24 months, and Octapharma claims it is a “4th generation intravenous immume globulin (IVIG).” Octagam is free from stabilizers.

Octagam is physiologically similar to normal plasma in concentration, nativity, osmolality, and distribution of IgG subclasses. Octagam contains on average 99.8% IgG molecules in a monomeric or dimeric structure. Less than 1% are polymeric IgG, and IgG aggregates are not found. IgG aggregates are associated with adverse events, and only monomers and dimers have therapeutic action. Dimers seem to play an important role in immunomodulatory properties of IVIG. The IgG subclass distribution in Octagam is similar to that of human plasma. The IgG molecules in Octagam are native and are neither chemically nor enzymatically treated. The Fc function of the IgG molecules is approximately 100%. This is unlike IVIG subjected to chemical or enzymatical modifications of the IgG molecule, such as the use of beta-propiolactone, sulfitolysis or pepsin in the manufacturing process, which may affect the Fc-portion of the molecule. A reduced Fc function (<100%) is a marker for impaired opsonizing capacity and complement activation of the IgG molecule as well as for its capacity to bind to monocytes or macrophages, with reduce Fc function likely adversely affecting efficacy. Octagam contains very high titers of cytomegalovirus (CMV) antibodies (mean 47 PEI-U/ml.), with plasma donations with high titers of CMV antibodies pooled to produce Octagam. In vitro studies show Octagam to be as effective as a hyper-CMV immunoglobulin, e.g., CytoGam, in its ability to neutralize CMV (an added feature for transplant recipients). Octagam is a liquid preparation, unlike lyophilized IGIV products which can take ≥20 minutes to reconstitute prior to use.

Octagam contains ~50 mg of protein/mL (5%), of which not less than 96% is human normal immunoglobulin G (IgG), with ≤ 3% aggregates, ≥ 90% monomers and dimers, and ≤ 3% fragments. Greater than 90% of the IgG molecules in Octagam are monomers and dimers, the only molecular forms of IgG thought to provide therapeutically meaningful activity. IgG subclasses are fully represented with the following approximate percents of total IgG: IgG1 is 65%, IgG2 is 30%, IgG3 is 3% and IgG4 is 2%. The sodium content of the final solution is ≤ 30 mmol/L, with pH between 5.1 and 6.0.1, and osmolality 310 - 380 mosmol/kg. Octagam contains the IgG antibody activities present in the donor population. Octagam provides high functionality, because the integrity of the Fc portion of the IgG molecule is maintained. Octagam contains no preservative and no sucrose, sugars, or other stabilizers. Octagam contains traces of tri-n-butyl phosphate (TNBP; solvent) and Triton X-100 (octoxynol; detergent) from solvent-detergent viral inactivation. The usual replacement therapy dose (300 to 600 mg/kg every 3 to 4 weeks) results in maximum doses of TNBP and Triton X-100 of 12 mg/kg and 60 mg/kg, respectively, per single injection.

Octagam is supplied in 1.0, 2.5, 5 and 10 gram single-use bottles as a ready-to-use liquid requiring no filtration prior to intravenous infusion. Octagam can be stored at room temperature for up to 18 months (or up to 24 months when stored at 2-8 °C/refrigerated) from the date of manufacture, defined as the date of final sterile filtration of the formulated drug product.

Nomenclature: Immune Globulin (IGIV)/Octapharma [BIO]; Octagam [TR]; Immune Globulin Intravenous (Human) [FDA]; Immune Globulin Intravenous, Human 5% [FDA]; gamma globulin [SY]; immune globulin, intravenous [SY]; intravenous immune globulin (IVIG) [SY]; IGIV [SY]

Companies.: Octagam was developed and is manufactured by Octapharma Pharmazeutika Produktions GmbH, Octapharma AG, FDA/CBER est. no. 1648, at facilities in Vienna, Austria. Octagam is marketed in the U.S. by Octapharma USA, Inc.

Manufacture: Plasma is purified by the Cohn-Oncley cold ethanol fractionation process followed by ultrafiltration and chromatography. Viral inactivation/reduction is achieved through a combination of process steps including Cohn fractionation, viral inactivation by solvent detergent (S/D) treatment and 24 hour incubation at pH 4 (37°C). The manufacturing process includes treatment with solvent/detergent (S/D) mixture composed of 0.3% tri-n-butyl phosphate (TNBP; solvent) and 1% Triton X-100 (octoxy-nol; detergent). Unlike solvent detergent inactivation methods used with many other products, the combination of TNBP/Triton X-100 is superior to TNBP/polysorbate 80 and TNBP/cholate. The manufacturing process for Octagam isolates IgG without additional chemical or enzymatic modification, and the IgG Fc portion is maintained intact. Octapharma claims, “Octagam represents two decades of intensive investment in technology and process refinement.” Octapharma was the first company to adopt the solvent detergent process in the routine production of plasma derivatives, including Octagam.

The global in vitro viral reduction factor (entire manufacturing process) as reduction (log10) of virus titer is ≥20.1 for HIV-1; ≥23.4 for pseudorabies virus (PRV); ≥23.1 for sindbis virus (SBV); ≥11.1 for mouse encephalitis virus (MEV); ≥10.2 for porcine parvovirus (PPV); and ≥6.7 for SV40 virus (with HIV-1, PRV and SBV being enveloped viruses). For Cohn fractionation, reduction factors are HIV-1, ≥5.5; PRV, ≥7.5; SBV, ≥6.4; MEV, ≥4.9; PPV, ≥.7.8; and SV40, ≥5.5. For solvent-detergent treatment, reduction factors are HIV-1, ≥6.0; PRV, ≥8.4; SBV, ≥7.8; MEV, N.A.; PPV, N.A.; and SV40, N.A. For pH 4 treatment, reduction factors are HIV-1, ≥8.6; PRV, ≥7.7; SBV, ≥8.9; MEV, ≥6.2; PPV, 2.4; and SV40, 1.2.

FDA class: Biologic BLA

CBER class: Blood and Blood Products

Approvals: Date = 20040521; BLA (BL 125062/0)

Date = 20060203; BLA supplement; Indication = labeling changes to the “Warnings/Blood Glucose Testing” and “Precautions/Drug/Laboratory Test Interactions” sections of the package insert strengthening the warning of effects of maltose in the product

Indications: [full text of "INDICATIONS AND USAGE” section of product insert]:

Primary Immune Deficiency Diseases: OCTAGAM is indicated for the treatment of primary immune deficient diseases, such as: congenital agammaglobulinemia and hypogammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome and severe combined immunodeficiencies. This indication was supported by a study in 46 patients who received a total of 654 infusions.

Status: The BLA was submitted on June 14, 2002; and filed on August 14, 2002. Accelerated approval was granted in May 21, 2004 (approval time =~2.06 years). Octagam received approval in Europe in 1995, and is currently licensed in 54 countries.

On Sept. 23, 2009, Octapharma filed a BLA (not sBLA) for 10% Octagam.

In Sept. 2010, after seeing increased adverse events reported, Octapharma initiated a voluntary market withdrawal of all lots of Octagam in the US market.

Tech. transfer: Solvent detergent viral inactivation was developed by and nonexclusively licensed from the New York Blood Center. For example, see 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: The efficacy of Octagam was documented in an open-label, multicenter, U.S. study in 46 patients (including 11 patients <15 years) with primary immunodeficiencies who received a total of 694 infusions over a 12 month period. Results were published in the May 2004 issue of the Journal of Clinical Immunology. The study utilized a new surrogate marker/endpoint criterion established by the FDA for IGIV products – the observed rate of serious infections (the lower the rate, the greater the presumed protection provided by the IGIV product). The Immune Deficiency Foundation (IDF) worked with FDA to design a clinical trial protocol for evaluating new IGIV products in primary immune deficiencies, and to attract European manufacturers to pursue U.S. approvals. In the study, Octagam was associated with 0.1 serious infections per patient per year, which compared favorably with the efficacy standard of 1 serious infection per patient per year set by the FDA for approval of IGIV products. Safety data from this pivotal U.S. study were supported by data from non-U.S. clinical trials including 217 patients and data from European post-marketing surveillance studies including ~4,700 patients.

Medical: Octagam, 300-600 mg/kg body weight, is administered every 3-4 weeks. Doses may be adjusted to achieve desired trough levels and clinical responses.

No virus transmission has been reported in ~10 years with >1,000,000 doses of Octagam in Europe.

Market: Octagam is the leading IGIV product in Europe, and has been a market leader in Europe for more than 10 years. Octagam held a 22% share of the European IGIV market in 2002, the largest of any licensed manufacturer (Marketing Research Bureau).

The 2007 Average Wholesale Price (AWP) is $108.00/20 mL (50 mg/mL); $270.00/50 mL; $540.00/100 mL; and $1,080.00/200 mL (Red Book, 2007).