Hepatitis B Immune Globulin (Human) Solvent-/-Detergent Treated and Filtered - Nabi-HB; HEBIG
Status: approved; marketed
Organizations involved:
Biotest AG – Manuf.; R&D; Tech.; USA mark.
Nabi – Former
Cangene Corp. – Former
Apotex Holdings Inc. – Parent; Former
IDIS World Medicines – Intl. mark.
New York Blood Center, Inc. – Tech.
Kamada Ltd. – Latin Amer. mark.; Asia mark.
Cross ref: See the entries for Hepatitis B Immune Globulin Products (#751) and Immune Globulin Products (#743). See also the other hepatitis B virus immune globulin products. See the Hepatitis B Vaccine Products entry (#468) for background about hepatitis B virus and chronic hepatitis B.
Description: Hepatitis B Immune Globulin (Human) or Nabi-HB is an aqueous formulation of immune globulin for intravenous administration containing high titers of hepatitis B -virus (HBV) antibodies (IgG) obtained from pooled fractionated Plasma from donors not infected with HBV but having high titers of hepatitis B virus surface antigen (HBsAg) antibodies (from vaccination with one of the two available recombinant hepatitis B virus vaccines — Engerix-B or Recom-bi-vax HB). manufacture includes solvent detergent viral inactivation and removal of viruses using a 35 nm filter (nanofiltration). Nabi-HB is a sterile solution of immunoglobulin (5 ± 1% protein) containing a high titer of polyclonal IgG antibodies to HBsAg.
This was the first Hepatitis B Immune Globulin (Human) product formulated and of sufficient purity to enable intravenous injection. Prior hepatitis B immune globulin products were administered by intramuscular injection.
Nabi-HB is packaged in 1.0 mL single-dose vials, each containing > 312 IU, and in 5.0 mL single-dose vials, each containing > 1,560 IU. The product is formulated in 0.075 M sodium chloride, 0.15 M glycine, and 0.01% polysorbate 80 (Tween 80), with pH 6.25. Total protein concentration is 5%. Each mL of Nabi-HB contains greater than 312 IU/mL HBsAg antibody. This potency is expressed in international units (IU) by comparison to the World Health Organization (WHO) standard. Nabi-HB contains no preservatives and is intended for intravenous injection only. Nabi-HB is stored at 2-8°C (36-46 °F; refrigerated). The dating period is 24 months from the date of manufacture. The date of manufacture is defined as the date of the initial sterile filtration of the formulated bulk.
The potency of each vial of Nabi-HB exceeds the potency of HBsAg antibody in a U.S. reference hepatitis B immune globulin (maintained by CBER, FDA). The U.S. reference has been tested by Nabi against the WHO standard and found to be equal to 208 IU/mL.
Nomenclature: Hepatitis B Immune Globulin, i.m./Biotest [BIO]; Nabi-HB [TR]; HEBIG [TR Europe]; Hepatitis B Immune Globulin (Human) [FDA]; Hepatitis B Immune Globulin (Human) Solvent/Detergent Treated and Filtered [FDA; on insert]; H-BIG 5% SDF [TR used prior to launch]; NDC 59730-4402-1; NDC 59730-4403-1 [NDC]
Companies.: Until Sept. 2007, Nabi-HB was manufactured by Nabi, CBER/FDA est. no. 1687; and was exclusively marketed in the U.S. by Nabi. Nabi-HB was originally manufac-tured by Cangene Corp. (Winnipeg, Manitoba, Canada) under contract to Nabi.
Cangene originally concluded an agreement with Nabi in 1997 for manufacture of Nabi-HB for at least three years after U.S. product approval, while Nabi developed its own manufacturing plant. [Cangene now has its own intravenous hepatitis B immune globulin; see #755].
In Oct, 2002, Nabi signed a “named-patient” international (ex-U.S.) distribution agreement with IDIS World Medicines, a company specializing in worldwide supply of specialized pharmaceuticals. IDIS has “named-patient” rights, i.e., for distribution/sale to specific patients, in 43 countries (where Nabi-HB is unlikely to have received approval due to costs, low number of patients/users, and/or other reasons).
In Feb. 2004, Nabi licensed exclusive development and marketing rights to Kamada Ltd. for various countries, including Israel, Argentina, Brazil, Mexico and India.
In Sept. 2007, Biotest AG (CBER/FDA est. no. 0433) acquired the plasma products business of Nabi, including Nabi-HB and related manufacturing facilities. for $185 million.
Manufacture: Fractionated Plasma is further purified by an anion-exchange column chromatography method, and subjected to two viral reduction/inactivation steps — solvent detergent inactivation using 1% tri(n-butyl)-phosphate (TNBP) and 1% Triton X-100 (octoxynol; polyethylene glycol p-isooctyl-phenyl ether), and nanofiltration using a Planova brand 35 nanometer (nm) filter. The solvent detergent process is effective for inactivating enveloped viruses (e.g., HIV, hepatitis B and C viruses), and the 35 nm filter is effective for further removing some enveloped and non-enveloped viruses.
As originally approved (Manufactured by Cangene), the source high HBsAg antibody titer Plasma was fractionated by Centeon, later Aventis Behring (now CSL Bioplasma); and Plasma used to make Plasma Fraction II powder used for potency adjustment was fractionated by Centeon/Aventis Behring and/or Michigan Biologics Products Institute, now BioPort Corp., a subsidiary of Emergent Biosolutions Inc.). The license granted to Nabi includes collection of plasma at its various plasma collection facilities with bulk processing, fractionation of plasma, and manufacture in its own facilities.
FDA class: Biologic BLA
Approvals: Date = 19990324; first approval (BLA and an ELA supplement), granted to Nabi, with contract manufacture by Cangene Corp.
Date = 20011023; BLA, granted to Nabi for manufacture in its own facilities (est. no. 1022, now est. no. 1687)
Indications: [portion of the "INDICATIONS AND USAGE” section of product insert/labeling]:
Nabi-HB, Hepatitis B Immune Globulin (Human), is indicated for treatment of acute exposure to blood containing HBsAg, perinatal exposure of infants born to HBsAg-positive mothers, sexual exposure to HBsAg-positive persons and household exposure to persons with acute HBV infection in the following settings...[truncated].
Status: Nabi-HB Intravenous replaced another hepatitis B immune globulin product, H-BIG 16.5% Intramuscular (#754), manufactured by Abbott, originally approved in 1977, and formerly marketed by Nabi. H-BIG contained a much higher protein concentration (16.5%) than Nabi-HB, was not as highly purified, was only approved for intramuscular administration, contained thimerosal, a mercury-based preservative), and its manufacture did not include solvent detergent viral inactivation or nanofiltration for virus removal.
Nabi completed its original applications (BLA and ELA supplement) for Nabi-HB on August 17, 1998. The applications received priority review status, and the BLA was approved on March 24, 1999; review time of about 7 months (~.58 year). The BLA included collection of plasma at NAbi’s plasma collection facilities with bulk processing, fractionation of plasma and manufacture of Nabi-HB by a contract manufacturer, Cangene Corp.
Nabi submitted a BLA on Dec. 16, 1999 for approval of manufacture of Nabi-HB at its own new Boca Raton, FL, manufacturing facility. The BLA was granted on Oct. 23, 2001; approval time = ~1.8 years). With this, Nabi gained full control of manufacture of Nabi-HB, including vaccination of donors with hepatitis B vaccine and blood collection at its own blood centers, and immune globulin fractionation and purification. Nabi markets the product using its own sales force. FDA regulation of plasma fractionation was intensified during plant construction, and these facilities were the first to receive approval under these more stringent requirements and inspection standards.
On Nov. 26, 2002, Nabi filed a BLA [not a BLA supplement] for approval of intravenous Nabi HB for a new indication – for the prevention of hepatitis B disease in liver transplant recipients positive for hepatitis B virus (HBV; prevent recurrence of HBV infection in liver transplant patients), an indication for which Nabi-HB is often used off-label. Nabi has received orphan drug status for this indication. Nabi-HB would become the first hepatitis B immune globulin therapy approved by the FDA to help protect patients from HBV re-infection following liver transplant surgery. Nabi-HB Intravenous has orphan designation for this indication. The FDA accepted the BLA for priority review (6 month target) on January 23, 2003. In June 2003, FDA issued a complete response letter. In Aug. 2003, Nabi submitted additional analyses of its completed trials. FDA replied in May 2004, and requested longer-term follow-up data from previously completed trials, which NABI had expected to submit by the end of 2004.
In June 2004, Nabi filed a MAA in the European Union (EU) seeking approval to market intravenous HEBIG (Nabi-HB) for the protection of the transplanted liver from hepatitis B virus (HBV) infection in HBV-positive liver transplant patients. NABI had reformulated the product to comply with EU standards and to improve shelflife and the product’s safety profile. HEBIG will be marketed to transplant surgeons in Europe.
In June 2006, Nabi voluntarily withdrew its MAA for EU approval of HEBIG. Nabi plans to resubmit the MAA with 12-month stability data from the reformulated product in the first half of 2007. All other pieces of the MAA have already been reviewed and accepted, and accelerated turn-around will be provided upon re-submission.
In July 2006, the Blood Products Advisory Committee (BPAC), FDA, voted 9 to 2 in favor of recommending approval of Nabi-HB Intravenous for the prevention of recurrence of hepatitis B after liver transplant, with 3 abstentions. Specifically, the Committee concluded that the BLA supported the product candidate’s safety and efficacy. However, at the meeting FDA staff stated that Nabi had not sufficiently demonstrated efficacy in transplants.
In June 2007, Nabi received a “complete response” letter from FDA regarding its BLA for the prevention of recurrence of hepatitis B after liver transplant. The company expected to “to file a complete response to the FDA as soon as supplemental statistical analyses can be run on the data that was submitted.” The company was also finalizing important modifications to its Boca Raton to meet European regulatory requirements.
On Nov. 26, 2008, Nabi filed a BLA for use of Nabi-HB to prevent liver transplant patients from suffering re-infection of their transplanted livers with hepatitis B virus (HBV). If approved, this will be the the first hepatitis B immune globulin therapy approved by the FDA to protect patients from re-infection following liver transplant surgery.
In Jan. 2009, FDA accepted for priority review the BLA for Nabi-HB for the prevention of hepatitis B virus (HBV) infection of transplanted livers in HbsAg-positive liver transplant patients.
Tech. transfer: Solvent detergent viral inactivation was developed by and nonexclusively licensed from the New York Blood Center, e.g., 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).
Medical: Nabi-HB, like other hepatitis B immune globulin products, is used for post-exposure prophylaxis of acute exposure to blood and other biological fluid containing hepatitis B virus, such as after parenteral exposure (e.g., needle stick, bite), direct mucous membrane contact (accidental splash) or oral ingestion (pipetting accident); infants born to mothers positive for HBsAg; sexual exposure (partners of HBsAg-positive persons); and household exposure to persons with acute hepatitis B virus infection. Dosages and regimens vary depending on the indication (usually, mode of exposure). The Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), recommends simultaneous active immunization with a hepatitis B virus vaccine (Engerix-B or Recombivax HB) for post-exposure prophylaxis.
Nabi has reported that it is aware that its previous product, H-BIG, was used off-label (unapproved use) by many liver transplant recipients, e.g., those receiving a liver from a hepatitis B virus seropositive organ donor, and the company acknowledges that Nabi-HB is used in these patients (off-label, until this indication is approved). Chronic hepatitis B virus infection is a frequent cause of end-stage liver disease and is present in ~5% of liver transplant patients. During liver transplant surgery and in the period immediately following surgery, there are no other approved treatment options to prevent re- infection of the new liver. Re-infection of the transplanted liver in HBV- positive patients almost always occurs after surgery.
Market: The 2007 Average Wholesale Price (AWP) is $183.69/1 mL vial ($178.38 in 2004) and $804.44/5 mL vial ($781.00 in 2004) (Red Book, 2007).
Total sales of Nabi-HB were $32.7 million in 2006; $39.2 million in 2005; $40.2 million in 2004; $37.6 million in 2003; $41.2 million in 2002; and $30.3 million in 2001. Sales closely correlate with the number of liver transplants performed.
European Union approval will expand the market for Nabi-HB/HEBIG. According to the European Liver Transplant Registry (ELTR), 46,530 liver transplantations were performed in Europe between 1968 and 2001. The number of transplant centers and the annual number of liver transplants performed in Europe have increased from 292 liver transplants in 1985 to 4,240 in 2001. The size of the European market compares favorably to the U.S. where 5,187 liver transplants were performed in 2001.
U.S approval of Nabi-HB for prophylaxis in liver transplant recipients is expected to add about $3 million/year to sales of Nabi-HB.
Ongoing: Nabi has been conducting clinical trials and filed for approval of Nabi-HB for prevention of reinfection of transplanted livers in patients with chronic hepatitis B using intravenous administration of Nabi-HB. Nabi believes that the future growth of Nabi-HB sales outside the U.S. will be for intravenous use to prevent re-infection of hepatitis B disease in HBV-positive liver transplant patients. Besides losing their liver to hepatitis B-related damage, hepatitis B infected patients are often denied liver transplants due to the likelihood of reinfection of the new liver with hepatitis B virus. Liver transplant recipients will probably need to receive Nabi-HB (and/or other antiviral therapeutics) for the rest of their lives. An expanded access program for Nabi-HB has been in place for hepatitis B infected liver transplant recipients.
Companies involvement:
Full monograph
756 Hepatitis B Immune Globulin, i.v./Biotest
Nomenclature:
Hepatitis B Immune Globulin, i.m./Biotest [BIO]
Nabi-HB [TR]
HEBI G [TR Europe]
H-BIG 5% SDF [TR used prior to launch]
Hepatitis B Immune Globulin (Human) [FDA]
Hepatitis B Immune Globulin (Human) Solvent/Detergent Treated and Filtered [FDA full name on insert]
NDC 59730-4402-1; NDC 59730-4403-1 [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 1999
Date of 1st FDA approval = 19990324
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blood products
human materials used<!-- humansource -->
immune globulins, human <!-- immunoglobulins -->
glycine
Namalva cells
octoxynol (Triton X-100)
Planova 35 nm Virus Filter
Plasma (Human)
polysorbate 80 (Tween 80)
sodium chloride
tri-n-butyl phosphate (TNBP)
viral (nano)filtration
viral inactivation, solvent detergent
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
orphan status
priority review status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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