Status: marketed in U.S. and EU

Cross ref: See Immune Globulin Products (entry #743).

Organizations involved:

CSL Behring AG – Manuf.; R&D; Tech.; Intl. mark.; Parent

CSL Behring LLC – U.S. mark.

CSL Ltd. – Parent

Description: Vivaglobulin is an aqueous formulation of highly purified immunoglobulin G (IgG) obtained from fractionated pooled human Plasma for subcutaneous infusion, with manufacture including two viral inactivation/reduction processes – ethanol-fatty alcohol/pH precipitation and pasteurization (wet heat) in aqueous solution at 60°C for 10 hours. Vivaglobin is a 16% (160 mg/mL) protein solution, with a content of at least 96% IgG, with a distribution of IgG subclasses similar to that present in normal human plasma. The serum IgG profile of Vivaglobulin is representative of that seen in the healthy U.S. population. Vivaglobin also contains 2.25% glycine, 0.3% sodium chloride, and Water for Injection, U.S.P. The pH is 6.4-7.2. Vivaglobin contains no antimicrobial preservatives. Vivaglobin is manufactured from large pools of human plasma by cold alcohol (Cohn-Oncley ) fractionation and is not chemically altered or enzymatically degraded.

Vivaglobulin is packaged in single-use glass vials. It is stored at 2-8°C (refrigerated) for the period indicated on the U.S, label.

This was the first subcutaneously-administered immune globulin approved in the U.S.

Nomenclature: Immune globulin (SCIG) 16% [BIO]; Vivaglobin [TR], Immune Globulin Subcutaneous (Human), 16% Liquid [FDA]; immune globulin, subcutaneous [SY]; gamma globulin [SY]; NDC 0053-7596-03; NDC 0053-7596-03; NDC 0053-7596-15; NDC 0053-7596-25 [NDC]

Biological.: Various factors, such as the site of administration and IgG catabolism, can affect IgG absorption. Subcutaneously administered immune globulin, e.g., Vivaglobulin, has decreased bioavailability compared to intravenous administration. The bioavailability of Vivaglobin is ~73% relative to immune globulin intravenous (IGIV), so an appropriately increased dosage is required (for overall delivery of comparable levels of IgG into the bloodstream). With subcutaneous administration, peak serum IgG levels are lower than those achieved with IGIV., but results in relatively stable steady-state serum IgG levels when administered on a weekly basis.

Companies.: Vivaglobin is manufactured by CSL Behring AG, CBER/FDA est. no. 1766 (formerly est. 1598), a subsidiary of CSL Behring AG, a subsidiary of CSL Ltd., at facilities in Marburg, Germany, or King of Prussia, PA, from human plasma collected at U.S. licensed plasma center (from U.S. blood centers operated by CSL Behring LLC). It is marketed in the U.S. by CSL Behring LLC, a subsidiary of CSL Ltd.

Manufacture: As with all other current immune globulin products, plasma used in the manufacture of Vivaglobin is tested using FDA-licensed serological assays for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (HCV) and human immunodeficiency virus types 1 and 2 (HIV-1/2) as well as FDA-licensed Nucleic Acid Testing (NAT; PCR) for HCV and HIV-1 and found to be nonreactive (negative). For hepatitis B virus (HBV), an investigational NAT procedure is used and the plasma found to be negative. Plasma is also tested by NAT for hepatitis A virus (HAV) and parvovirus B19 (B19). Only plasma that passes virus screening is used. The limit for B19 in the fractionation pool is set not to exceed 104 IU of B19 DNA/mL.

Manufacture includes multiple processing steps that reduce the risk of virus transmission. Total mean cumulative virus reductions from in vitro virus spiking tests ranged from 9.0 to ≥ 14.1 log10. The total cumulative marker virus reduction (log10) for both ethanol-fatty alcohol/pH precipitation and pasteurization for enveloped viruses is ≥12.7 for HIV-1; ≥14.0 for bovine viral diarrhea virus (BVDV); ≥13.7 for West Nile virus (WNV); ≥14/1 for pseudorabies virus (PRV); and for non-enveloped viruses is ≥10.4 for porcine enterovirus (PEC) and 9.0 for canine parvovirus (CPV). The reduction factors for the ethanol-fatty alcohol/pH precipitation step are ≥6.2 for HIV-1; ≥5.3 for BVDV; ≥4.4 for WNV; ≥6.2 for PRV; ≥6.7 for PEV; and 6.7 for CPV. The reduction factors for the pasteurization step are ≥6.5 for HIV-1; ≥8.7 for BVDV; ≥9.3 for WNV; ≥7.9 for PRV; ≥3.7 for PEV; and 2.3 for CPV. Reduction of parvovirus B19, evaluated using porcine IgG, by pasteurization was ≥ 3.5 log10.

FDA class: Biologic BLA

CBER class: Blood And Blood Derivatives

Approvals: Date = 20060109; original BLA

Date = 20100210; BLA supplement; Indication = approval of Hizentra 20% Liquid, for treating patients diagnosed with primary immunodeficiency (PI).

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

Immune Globulin Subcutaneous (Human), Vivaglobin is indicated for the treatment of patients with primary immune deficiency (PID).

Status: Vivaglobulin is the first immune globulin product for subcutaneous injection, providing a new option for patients with primary immune deficiency diseases. Note, other approved immune globulin products are approved for more indications:.

Vivaglobin was previously approved and is marketed in a number of European countries. A market application has been submitted in Canada.

In March 2010, FDA approved Hizentra 20%, the first SCIg treatment with a 20 percent concentration of immunoglobulin. With no need for refrigeration, Hizentra represents an effective, convenient choice of at-home Ig therapy that will allow people with PI to schedule treatment around their busy lives instead of scheduling their lives around treatment. Hizentra is the first 20 percent subcutaneous immunoglobulin (SCIg) approved by the FDA. This high-concentration product is stabilized with L-proline, a naturally-occurring amino acid. L-proline allows Hizentra to be stored at room temperature (up to 25°C [77°F]). Because no refrigeration is necessary, Hizentra is ready to use, offering patients and physicians convenience and portability. Hizentra can be safely self-administered by PI patients under a physician's care.

On April 21, 2011, the EU granted an MAA to Hizentra 20% solution for subcutaneous injection, for treating patients diagnosed with primary immunodeficiency (PI) as well as secondary immunodeficiencies. The European Commission has cleared Hizentra with an initial storage shelf life of two years.

Trials: In a pivotal open-label, prospective, multicenter clinical study in the U.S and Canada, 65 adult and pediatric primary immunodeficiency subjects previously treated monthly with IGIV were switched to weekly subcutaneous administrations of Vivaglobin for 12 months, for a total of 3,655 infusions. Subjects received a weekly mean Vivaglobin dose of 158 mg/kg body weight, which was 136% of their previous weekly-equivalent IGIV dose. The annual rate of serious bacterial infections (bacterial pneumonia, meningitis, sepsis, osteomyelitis, and visceral abscesses), the primary endpoint, was 0.04 infections per subject per year. Pneumonia was reported in two subjects. The annual rate of any infections, a secondary endpoint, was 4.4 infections per subject per year. A 6-month, non-IND study of Vivaglobin in Europe and Brazil and provided safety and efficacy data similar to those reported in this study.

Vivaglobin was well tolerated in trials, and its efficacy was comparable to the of immune globulin administered by either intravenous (IGIV) or intramuscular (IGIM) routes. The most common side effect is mild or moderate injection site reaction such as swelling, redness and itching. The contraindications: for Vivaglobin are similar to other immune globulin products.

Medical: Some patients develop problems that make chronic intravenous administration of immune globulin and other needed medicines difficult. They may have poor venous access or experience serious side effects from intravenous and/or intramuscular injections. Vivaglobin also is appropriate for those who want the convenience and cost savings of self-administration.

Vivaglobulin is administered under the skin (subcutaneously) on a weekly basis using a portable infusion pump. Patients can self-administer the product at home. With Vivaglobin administration, peak serum Ig levels are lower than those achieved with intravenous immune globulin. Subcutaneous administration results in relatively stable steady-state serum immunoglobulin G (Ig) levels when administered on a weekly basis.

In Sept. 2006, ZLB Behring launched the [Vivaglobin Investigator Research Trial on Use and Experience], VIRTUE U.S. Phase IV clinical trial to evaluate patient satisfaction and annual rate of serious bacterial infection using Vivaglobin subcutaneous administration for one year after conversion from intravenous immunoglobulin therapy. VIRTUE is enrolling 100 primary immunodeficiency patients at 50 sites, making it the largest-ever trial of subcutaneous immunoglobulin therapy in the U.S. Patients enrolled in the study will self-administer the study medication for one year. During the trial period, patients will be asked to assess overall health-related quality of life, comparing experience receiving the study medication and their previous intravenous treatment experience. VIRTUE will also identify which patients use SC treatment because of improvement in their quality of life.

Market: The 2007 Average Wholesale Price (AWP) is $576/00/10 3 mL vials; $192.00/10 ml vial; $1,920.00/10 10 mL vials; $384.00/20 mL vial; and $3,840.00/10 20 mL vials (Red Book, 2007).