Status: approved, marketed

Organizations involved:

Cangene Corp. – Manuf.; R&D; Tech.

Apotex Holdings Inc. – Parent

Baxter Hyland Immuno – USA mark.; Europe mark.

Nabi – Former

Univax, Inc. – Former

Rh Pharmaceuticals Inc. – Former

New York Blood Center – Tech.

CSL Ltd – Australia mark.

Cross ref: See the entries for Rho(D) Immune Globulin Products (#776) and Immune Globulin Products (#743).

Description: Rho(D) Immune Globulin Intravenous (Human) or WinRho SDF refers to aqueous formulations (freeze-dried formulations discontinued in 2007) 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. Win-Rho SDF is prepared from Plasma by an anion-exchange column chromatography method. Manufacturing includes a solvent detergent viral inactivation step, which is primarily effective against enveloped viruses such as hepatitis B virus, hepatitis C virus, and HIV. Viruses are further removed by nanofil-tra-tion using a Planova 35 nm Virus Filter, which removes some nonlipid enveloped viruses.

Currently, WinRho SDF is a ready to use solution in single dose vials of 600 international unit (120 mcg), 1,500 international unit (300 mcg), 2,500 international unit (500 mcg), 5,000 international unit (1000 mcg) and 15,000 international unit (3,000 mcg).

The newer liquid formulation is stabilized with 10% maltose and 0.03% polysorbate 80 (Tween 80). There are no preservatives in the formulation. WinRho® SDF does not contain mercury. This product contains approximately 5 micrograms/mL IgA.

Lyophilized WinRho SDF was formerly packaged in 2.5 mL single dose vials containing either 120 µg (600 IU), 300 µg (1,500 IU), or 1,000 µg (5,000 IU) of Rho(D) immune globulin (1 µg = 5 IU) for intramuscular injection. The product was stored at 2-8˚C (refrigerated). A 300-microgram vial of WinRho SDF contained 300 µg of anti-Rho (D) antibody and less than 100 mg of total protein. WinRho SDF contains trace amount of IgA (less than 40 µg/mL).

Potency is expressed in international units by comparison to the World Health Organization (WHO) standard. A 300 µg (1,500 International Unit [IU]) vial contains sufficient anti-Rho(D) to effectively suppress the immunizing potential of approximately 17 mL of Rho(D) (Dpositive) red blood cells (RBCs). WinRho SDF contains approximately 5 µg/mL IgA.

Besides use for prevention/minimization of Rho(D) immunization of Rho(D)-negative mothers with suspected Rho(D)-positive fetuses, like other Rho(D) Immune Globulin products, WinRho SDF is also used for treatment of idiopathic thrombocytopenic purpura (ITP) in children and adults, characterized by destruction of platelets by macrophages. The mechanism of action for WinRho SDF is not completely understood, but is thought to be due to the formation of Rho(D) antibody-coated red blood cells complexes resulting in Fc receptor blockade, thus sparing antibody-coated platelets.

Nomenclature: Rho(D) Immune Globulin/Cangene [BIO]; WinRho SDF [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]; WinRho SD [TR former]; anti-D immunoglobulin [SY]

Companies.: WinRho was originally developed by Rh Pharmaceuticals Inc., now Cangene Corp. (Winnipeg, Manitoba, Canada; 82% owned by Apotex Holdings, Inc.). WinRho SDF is manufactured by Cangene Corp., CBER/FDA lic. no. 1201. It was formerly marketed in the U.S. by Univax, Inc. which merged with North American Biologicals, Inc. to form Nabi.

In July 2004, Nabi announced that Cangene would not be renewing its agreement with Nabi for U.S. marketing of WinRho SDF when the contract expires in March 2005. Cangene concluded an agreement for exclusive U.S. marketing and distribution with Baxter Healthcare Corp. (which already marketed WinRho SDF in Europe). Baxter is now the exclusive U.S. and European marketer of WinRho SDF.

WinRho is marketed in Canada by Cangene, and in Australia by CSL Ltd.

Manufacture: The product is manufactured from pooled source plasma selected for high titers of Rho(D) antibody. The IgG is separated by anion-exchange chromatography and concentrated by ultrafiltration. Inactivation of lipid enveloped viruses is accomplished by solvent detergent (SD) inactivation using a mixture of 0.3% tri(n-butyl)-phosphate (TNBP) and 1.0% Triton X-100 (octoxynol). The SD mixture is removed by reverse phase chromatography. The plasma protein (IgG) fraction is formulated to give a final concentration of 0.15 M sodium chloride and 0.1 M glycine, and is sterile filtered using a Planova 20 (originally 35) nm Virus Filter. The purified, inactivated bulk is filled into vials and lyophilized.

The final product is routinely tested for antibody potency (anti-D); residual solvent and detergent; identity; IgG, IgA, and IgM antibody content; purity; anti-C, anti-E, anti-A and anti-B antibodies; safety; sterility; appearance; reconstitution time; and bacterial endotoxin.

FDA class: Biologic PLA (converted to BLA 103649/0)

CBER class: Blood And Blood Derivatives

Approvals: Date = 19950324; first approval, PLA ref. no. 93-0581, ELA supplement no. 93-0581; orphan status (expired 3/24/2002); granted to Rh Pharmaceuticals, Inc. (est. no. 580); Indication = for the suppression of Rh isoimmunization in nonsensitized Rho(D) negative women; and for treatment of immune thrombocytopenic purpura (ITP), including treatment of children with chronic or acute ITP, adults with ITP, and children or adults with ITP secondary to HIV-infection

Date = unknown; PLA supplement; Indication = the suppression of Rh isoimmunization in Rho(D) negative female children and female adults in their childbearing years after transfusion with Rho(D) positive red blood cells or blood products containing Rho(D) positive red blood cells

Date = 19960402; approval revoked and granted (reissued) to new owner, Cangene Corp.

Date = 19970918 (U.S. launch date); PLA supplement; Indication = new SDF formulation (i.e., nanofiltration sterilization added); and approval for treatment of immune thrombocytopenic purpura (ITP)

Date = 20000103; PLA supplement; product insert/labeling modified to state that “Rho(D) positive ITP patients treated with WinRho SDF should be monitored for signs and/or symptoms of intravascular hemolysis (IVH), clinically compromising anemia, and renal insufficiency.”

Date = 20050331; BLA supplement; Indication = approval of a new liquid formulation

Indications: [portions of the "Indications AND CLINICAL USE” section from product insert/labeling]:

Treatment of ITP: WinRho SDF, Rho(D) Immune Globulin Intravenous (Human), is recommended for the treatment of non-splenectomized, Rho(D) positive children with chronic or acute ITP, adults with chronic ITP, or children and adults with ITP secondary to HIV infection in clinical situations requiring an increase in platelet count to prevent excessive hemorrhage. The safety and efficacy of WinRho have not been evaluated in clinical trials for patients with non-ITP causes of thrombocytopenia or in previously splenectomized patients.

Suppression of Rh Isoimmunization: Pregnancy and Other Obstetric Conditions – WinRho SDF is recommended for the suppression of Rh isoimmunization in non-sensitized, Rho(D) negative (D-negative) women within 72 hours after spontaneous or induced abortions, amniocentesis, chorionic villus sampling, ruptured tubal pregnancy, abdominal trauma or transplacental hemorrhage or in the normal course of pregnancy unless the blood type of the fetus or father is known to be Rho(D) negative. In the case of maternal bleeding due to threatened abortion, WinRho SDF should be administered as soon as possible. Suppression of Rh isoimmunization reduces the likelihood of hemolytic disease in an Rho(D) positive fetus in present and future pregnancies.

The criteria for an Rh-incompatible pregnancy requiring administration of WinRho SDF at 28 weeks gestation and within 72 hours after delivery are: the mother must be Rho(D) negative, the mother is carrying a child whose father is either Rho(D) positive or Rho(D) unknown, the baby is either Rho(D) positive or Rho(D) unknown, and the mother must not be previously sensitized to the Rho(D) factor.

Status: WinRho (without solvent detergent viral inactivation and nanofiltration steps) was first introduced in Canada in 1980.

The new WinRho SDF Liquid formulation approved in April 2005 provides an alternative to the lyophilized (freeze-dried) formulation, and eliminates the need for reconstitution prior to administration.

In Dec. 2004, Cangene received European Union (EU) approval for WinRho SDF through the European Mutual Recognition Procedure (MRP). It is now approved in 10 European countries for use in preventing hemolytic disease of the newborn and treating ITP. WinRho SDF was approved in the U.K in 1999. The newly approving European Union countries mutually recognized the U.K. license after Cangene’s completion of the MRP. Cangene plans to follow the same process for approval in additional EU countries in the future. Cangene’s European distribution partner, Baxter, will launch the product once national licences have been issued.

The FDA approval of the lyophilized formulations was "discontinued" on Oct. 1, 2007, meaning it remains approved but is no longer marketed and no annual user fees are collected.

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).

Trials: In April 2006, Cangene initiated a trial of WinRho SDF in chronic hepatitis C virus (HCV)-infected patients. This study is evaluating the safety and efficacy of WinRho SDF to offset thrombocytopenia in patients with HCV infection who are starting, or already receiving, treatment with a peginterferon alfa-2 product (PEG-Intron or Pegasys) and ribavirin. Patients with and without HIV co-infection are eligible for the trial.

Medical: Prior to the launch of Rhophylac, WinRho SDF was the only U.S. licensed anti-Rho(D) immune globulin that can be administered intravenously (in addition to intramuscularly). A 1,500 IU (300 µg) dose contains sufficient anti-Rho(D) to effectively suppress the immunizing potential of approximately 17 mL of Rho(D) positive red blood cells. WinRho SDF also increases platelet counts in non-splenectomized, Rho(D) positive patients with idiopathic thrombocytopenic purpura (ITP). Platelet counts usually rise within one to two days and peak within seven to 14 days after initiation of therapy, and the average duration is approximately 30 days.

Disease: Immune thrombocytopenic purpura (ITP) is an autoimmune disease involving reduction in platelets in the blood (see Platelets, #802), apparently due to the patient’s own antibodies mediating destruction and elimination of circulating platelets. Platelets are components of the blood that are necessary for blood to clot properly (See the Platelets entry) Individuals with ITP may have symptoms such as bruising on skin and gums, nosebleeds, or mucosal bleeding. The most serious risk in patients who develop ITP is intracranial hemorrhage (bleeding into the brain). Thrombocytopenia, involving platelet counts below 150,000/mm3, is associated with recurring bleeding episodes. WinRho SDF is used to elevate the platelet level in patients with ITP. Other Rho(D) immune globulin products cannot be administered intravenously, so they cannot be used for ITP.

It is estimated that ~30,000 people develop ITP in the U.S. every year, and about half of those affected are children. There are an estimated 100,000 ITP patients in the U.S. This includes about one-half (50,000) with ITP secondary to HIV-infection; 18,000 with primary ITP; and 30,000 with ITP due to other diseases. Other than HIV disease-associated ITP, most serious cases occur in women. The disease generally resolves itself in children after about six months, but is a chronic and potentially life-threatening disease in adults.

Market: The 2007 Average Wholesale Price (AWP) or powder for solution is $142.00/600 IU vial; $324.50/1,500 IU; and $1081.50/5,000 IU (prices unchanged from 2004) (Red Book, 2007). The AWP for liquid in vials is $153.36/600 IU, 0.5 mL vial; $367.98/1,500 IU 1.3 mL vial; $613.21/2500 IU 2.2 mL vial; $1,226,43/5000 IU 4.4 mL vial; and $3,679.97/15,000 IU 13 mL vial.

In its March 2006 price list, FFF Enterprises reported its price as $120.50/120 µg vial ($96.83 in 2005; $90.54 in 2004); $272.60/300 µg vial ($219.50 in 2005); and $908.00/1000 µg vial ($732.50 in 2005).

Nabi’s sales of WinRho SDF, for which its ten-year distribution agreement ended in March 2005, were $6.2 million in 2005; $47.9 million in 2004; $50.0 million in 2003; $34.0 million in 2002, and $34.8 million in 2001.

WinRho SDF has the largest market share in the U.S. market for ITP treatment (but not the overall leading Rho hyperimmune globulin product, nor for Rh isoimmunization). Cangene reports that U.S. sales of WinRho SDF are almost entirely for the treatment of idiopathic thrombo-cytopenic purpura (ITP), an indication for which orphan designation expired in 2002. This is unlike in Canada, where WinRho sales are almost exclusively for suppression of Rh isoimmunization (hemolytic disease of the newborn). In early 2003, Cangene reported that 2.5 million high-risk pregnancies had been treated with WinRho in 35 countries. In 2002, WinRho contributed over 82% of Cangene’s total revenue (Cangene since launching multiple products).

Ongoing: In March 2004, Cangene initiated a trial with WinRho SDF for treatment of dengue hemorrhagic fever. In a pilot study in the Philippines, critically-ill young patients had showed rapid improvement and were discharged from hospital soon after receiving WinRho SDF.