Rho(D) Immune Globulin (Human) - RhoGAM Ultra-Filtered and MICRhoGAM Ultra-Filtered
Status: approved; marketed
Organizations involved:
Ortho-Clinical Diagnostics, Inc. – Manuf.; R&D; Tech.; USA mark.
Johnson & Johnson Co. – Intl. mark.; Parent
Millipore Corp. – Tech.
Cross ref: See the entries for Rho(D) Immune Globulin Products (#776) and Immune Globulin Products (#743).
Description: Rho(D) Immune Globulin Intravenous (Human) refers to aqueous formulations, RhoGAM Ultra-Filtered and MICRhoGAM Ultra-Filtered, of immune globulin (IgG) containing high titers of Rho(D) antigen-neutralizing antibodies obtained from fractionated pooled Plasma from donors with high levels of Rho(D) antibodies, generally from vaccination with Rho(D)-positive cells. Ultra-Filtered refers to the use of virus exclusion ultrafiltration (nanofiltration with Viresolve 180 filter from Millipore Corp.) during manufacture to remove enveloped and nonenveloped viruses 18-200 nm or larger. RhoGAM and MICRhoGAM are administered by intramuscular injection.
RhoGam and MICRhoGAM marketed in the U.S. were manufactured with addition of thimerosal as a preservative until about April 2001. The products are now thimerosal-free. The original formulation contained 0.003% or 30 µf/mL of thimerosal (sodium ethylmercurithiosalicylate; mercury derivative; see entry #939) as preservative. A patient receiving a dose of this formulation (0.7 ml RhoGAM on average) received 10.5 µg of ethyl mercury.
A single dose of RhoGAM Ultra-Filtered contains sufficient D(RH1) antibodies (about 300 µg) to suppress immune responses to 15 mL (or less) of Rh-positive red blood cells. The final product contains approximately 5 ± 1% gamma glo-bu-lin (immune globulin), 2.9 mg/mL sodium chloride, 0.01% polysorbate 80 and 15 mg/ mL glycine. Small amounts of immunoglobulin A (IgA), typically less than 15 µg per dose, are present. The pH range is 6.20- 6.55. The product contains no preservative and utilizes a latex- free delivery system. Rho-GAM is stored at 2-8˚C (refrigerated) and has a 2-year dating period.
MICRhoGAM Ultra-Filtered is an identical formulation to RhoGAM, but contains a smaller, approximately 50 µg, dose of D(RH1) antibodies (1/6 the dose of RhoGAM Ultra-Filtered), sufficient to suppress immune responses to 2.5 mL or less of Rh-positive red blood cells. MICRhoGAM Ultra-Filtered may be used in cases where the Rh-negative woman’s exposure is to D-positive red blood cells is low, e.g., in association with abortion procedures up to 12 weeks gestation. In the first 12 weeks of gestation, the volume of red blood cells in the fetus is <2.5 mL.
The anti-D dose is measured by comparison to the RhoGAM in-house reference standard, the potency of which is established relative to the International Reference Preparation 68/ 419. The anti-D content of RhoGAM/ MICRhoGAM is expressed as µg per dose. It can be expressed as International Units (IU) per dose. The conversion factor is 1 µg = 5 IU.
RhoGAM and MICRhoGAM are supplied in prefilled single-dose syringes. Each RhoGAM syringe contains a standard 300 µg dose, the usual dose unless there is evidence of fetal-maternal hemorrhage in excess of 15 mL Rh positive red blood cells (in which case, multiple doses may be required). The products are stored at 2-8˚C (refrigerated).
Ortho/J&J claims that RhoGAM is the highest purity Rho(D) Immune Globulin (Human) product marketed in the U.S., i.e., that is has a higher specific activity (activity per weight of protein) than other products (less extraneous protein, more concentrated). The standard 300 µg dose is contained in less than 1 mL of solution. RhoGAM also has 99.9% of plasminogen removed, providing stability throughout its shelf life. Plasminogen is a precursor of plasmin, a proteolytic enzyme. RhoGAM has the lowest viscosity of the Rho(D) Immune Globulin (Human) products in the U.S., simplifying intravenous administration.
Nomenclature: Rho(D) Immune Globulin/Ortho [BIO]; RhoGAM Ultra-Filtered [TR]; MICRhoGAM Ultra-Filtered [TR]; Rho(D) Immune Globulin (Human) [FDA]; Rho(D) Immune Globulin [USAN]; Rho(D) Immune Human Globulin [former USAN]; Rho(D) Immune Globulin USP [USP]; NDC 0562-7807-05; NDC 0562-7807-25; NDC 0562-7807-10; NDC 0562-7807-05 [NDC]
Companies.: RhoGAM products are manufactured by Ortho-Clinical Diagnostics, Inc. (Raritan, NJ; a subsidiary of Johnson and Johnson Co.), CBER/FDA est. no. 1236. The products are marketed in the U.S. by Ortho-Clinical Diagnostics, Inc., and internationally by Johnson and Johnson Co. affiliates.
Manufacture: Plasma selected for high levels of antibody is fractionated using a modification of the Cohn cold ethanol procedure. Following fractionation, the immune globulin is filtered through a tangential-flow Viresolve 180 (Millipore Corp.) size exclusion ultrafiltration (nanofiltration) membrane with defined pore distribution. The filter is inert and has been documented to remove viruses in the range from 18 to 200 nm in diameter, including both enveloped and nonenveloped viruses (e.g., parvovirus and hepatitis A virus). The CorrTest using a small bacteriophage, phiX-174 (28 nm) is used to confirm membrane integrity and virus clearance.
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19680410; first approval, granted to Ortho Diagnostics Systems Inc.
Date = 19960000; supplemental approval for inclusion of virus removal step (size exclusion ultrafiltration)
Date = 19980423; approval revoked and granted (reissued) to new owner, Ortho-Clinical Diagnostics, Inc.
Date = 20010416; BLA supplement; Indication = preservative (thimerosal) free formulation
Indications: [full text of the "INDICATIONS AND USAGE” section of RhoGAM Ultra-Filtered/MICRhoGAM Ultra-Filtered product insert/labeling; Indications: and dosages for RhoGAM/MICRhoGAM are also summarized in a table in a separate section of the product insert]:
Pregnancy and Other Obstetrical Conditions in Rh- Negative Women, Unless the Father or Baby are Conclusively Rh Negative [in bold]:
• Pregnancy/ delivery of an Rh- positive baby irrespective of the ABO groups of the mother and baby
• Abortion/ threatened abortion at any stage of gestation
• Ectopic pregnancy
• Antepartum fetal- maternal hemorrhage (suspected or proven) resulting from antepartum hemorrhage (e.g., placenta previa), amniocentesis, chorionic villus sampling, percutaneous umbilical blood sampling, other obstetrical manipulative procedure (e.g., version) or abdominal trauma
• Transfusion of Rh incompatible blood or blood products: Transfusion [in bold]:
• Prevention of Rh immunization in any Rh- negative person after incompatible transfusion of Rh- positive blood or blood products (e.g., red cells, platelet concentrates, granulocyte concentrates)
Status: With the approval of the thimerosal-free product, Ortho distributes this formulation only in the U.S.
Tech. transfer: The product inserts/labeling cites U.S. patent 3,449,314, “Preparation of Anti-Rh Globulin from Human Plasma, assigned to Ortho Pharm. Corp.((J&J), June 10, 1969. This describes preparation of Rho(D) immune globulin isolated from human plasma with a high ionic strength buffer containing a non-ionic detergent, nano-filtration using a 30 nm filter.
U.S. patent 5,019,292, “Membrane, Process, and System for Isolating Virus from Solution,” assigned to Millipore Corp., 1991, covers aspects of the Millipore Viresolve size exclusion ultrafiltration (nanofiltration) membrane used for virus removal. U.S. patent 5,282,380, “Integrity Test for Membranes,” assigned to Millepore, covers the method used for testing and validating the membranes.
Medical: Clinical studies have shown that the normal 12-13% incidence of Rh immunization (by exposure of Rh- mother to red blood cells from her Rh+ fetus) was reduced to 1-2% when RhoGAM was administered within 72 hours following delivery. Administration of RhoGAM antepartum at 28-32 weeks and postpartum reduced the risk of Rh immunization to less than 0.1%.
MICRhoGAM is used in Rh negative woman following spontaneous or induced abortion or termination of ectopic pregnancy up to and including 12 weeks gestation, unless the father can be shown conclusively to be Rh negative.
Market: The 2007 Average Wholesale Price (AWP) for RhoGAM is $127/20/1 mL prefilled syringe; $636.00 for five, and $3,180.00 for 25 (Red Book, 2007). The 2007 AWP for MicRhoGAGM is $54.36/1 mL prefilled syring, $271,80 for five, and $1,359.00 for 25.
RhoGAM Ultra-Filtered is the leading Rho(D) Immune Globulin product in the U.S., with the Ortho/J&J claiming, “In the U.S., RhoGAM has prevented more cases of Rh hemolytic disease than all other Rh immune globulins combined.”
Companies involvement:
Full monograph
779 Rho(D) Immune Globulin/Ortho
Nomenclature:
Rho(D) Immune Globulin/Ortho [BIO]
MICRhoGAM Ultra-Filtered [TR]
RhoGAM Ultra-Filtered [TR]
Rho(D) Immune Globulin (Human) [FDA]
Rho(D) Immune Globulin [USAN]
Rho(D) Immune Human Globulin [former USAN]
Rho(D) Immune Globulin USP [USP]
NDC 0562-7807-05; NDC 0562-7807-25; NDC 0562-7807-10; NDC 0562-7807-05 [NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1968
Date of 1st FDA approval = 19680410
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blood products
human materials used<!-- humansource -->
immune globulins, human <!-- immunoglobulins -->
Rho(D) red blood cell antibodies
human Rho(D) cells
phiX-174
Rho(D) (D-positive) red blood cells
CorrTest
D(RH1) antibodies
ethanol
glycine
Namalva cells
Plasma (Human)
plasminogen
polysorbate 80 (Tween 80)
sodium chloride
thimerosal (mercury derivative)
viral (nano)filtration
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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