Status – approved; marketed

Organizations involved:

Baxter Hyland Immuno – Manuf.; R&D; Tech.; Intl. mark.

Biotest AG – Manuf. other; USA Mark..

Nabi – Former

Cross ref: See the Factor VIII Products entry (#715) for discussion of Factor VIII inhibitors. See also Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA VH Immuno; #704); and Prothrombin Complex (Octaplex).

Description: Anti-Inhibitor Coagulant Complex, Heat Treated or Autoplex T is a lyophilized (freeze-dried) formulation containing variable amounts of activated and precursor vitamin K-dependent clotting factors (activated prothrombin complex) obtained from pooled human Plasma with subsequent alcohol fractionation (to Cohn Fraction IV), with manufacture including viral inactivation of lyophilized final product by dry heat (60˚C for six days). Factors of the kinin generating system are also present in Autoplex T. This product is primarily used in hemophilia A patients with inhibitors (antibodies to Factor VIII).

The Factor VIII correctional activity of Autoplex T is apparently related to its Factor Xa content. It is also hypothesized that the elevated Factor VII-VIIa content of the product is a contributing factor to the in vivo reestablishment of normal hemostasis by way of Factor X activation in conjunction with tissue factor, phospholipid, and ionic calcium (i.e., it acts on the coagulation pathway at Factor X, at a later stage than Factor VIII).

The product is standardized by its ability to correct the clotting time of Factor VIII deficient plasma and Factor VIII deficient plasma containing inhibitors (antibodies) to Factor VIII. Potency is based on ability to correct clotting time of hemophilic plasma in the presence of Factor VIII inhibitors using a lyophilized reference standard. The unit of activity is defined by the reference standard, and is approximately the amount of Autoplex T needed to correct the partial thromboplastin time of hemophilic plasma. Upon approval, FDA reported, “There is extreme variability from lot to lot. Each bottle is labeled with the number of Factor VIII Correctional Units it contains (labeled for units of Hyland Factor VIII correctional activity). Factor VIII correctional activity may not be exclusively related to the efficacious component(s).” One Hyland Factor VIII Correctional Unit is that quantity of activated prothrombin complex which, upon addition to an equal volume of Factor VIII deficient or inhibitor plasma, corrects the clotting time (ellagic acid-activated partial thromboplastin time) to 35 seconds (normal).

Autoplex T is packaged in vials along with a suitable volume of Sterile Water for Injection, USP, for reconstitution; a double-ended needle; and a filter needle. After reconstitution, Autoplex T contains a maximum of 2 Hyland Factor VIII Correctional Units/mL of heparin, a residual amount of polyethylene glycol (PEG; 2 mg/mL, maximum), and 0.02 M sodium citrate (sodium content is 177 ± 15 meq/L). Autoplex T is stored at 2-8˚C (refrigerated).

Nomenclature: Anti-Inhibitor Coagulant/Nabi [BIO]; Autoplex T [TR]; Anti-Inhibitor Coagulant Complex [FDA]; 78690-13-8 [CAS RN]; activated prothrombin complex [SY]

Companies.: Autoplex T is manufactured by Baxter Hyland Immuno (Glendale, CA), CBER/FDA est. no. 0140. Nabi acquired exclusive U.S., Canada and Mexico marketing rights from Baxter in May 1997. Baxter markets Autoplex T in other countries. Baxter will continue to manufacture the product until Nabi receives FDA approval for manufacture of the product in its own facilities (although this could change with Biotest acquiring Nabi's plasma business). Nabi’s contract with Baxter for supply of intermediate used in manufacture of Autoplex ended on May 11, 2004.

In Sept., 2007, Biotest AG acquired the plasma products business and manufacturing facilities of Nabi.

Manufacture: Autoplex T is prepared from pooled blood Plasma fractionated to Fraction IV by Cohn-Oncley cold ethanol fractionation, followed by calcium phosphate (CaPO4) adsorption. The product (non-activated clotting factors) is activated (to functional forms) by a proprietary method (using ethanol, calcium phosphate and polyethylene glycol). The final lyophilized product is heated to 60˚C for six days for viral inactivation. The 6-day heating step has been shown to reduce Sindbis virus by 10.0 log, vesicular stomatitis virus (VSV) by 5.0 log, herpes simplex virus (HSV) by 1.6 log, and HIV by 4.5 log. Additionally, cold-ethanol fractionation results in 1-4 log reduction with each fractionation step.

FDA class: Biologic PLA

Approvals: Date = 19791221; first approval, PLA, granted to Baxter Healthcare

Indications: [full text of "Indications and Usage” section from product insert/labeling, excluding a chart/graph]

Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex T, is indicated for use in patients with Factor VIII inhibitors who are bleeding or are to undergo surgery. The intravenous administration of this preparation is intended to control bleeding episodes in such patients.

Approximately 10% of individuals with hemophilia A (classical hemophilia) have laboratory-measurable inhibitors to Factor VIII. For these patients, the treatment of choice depends upon the following factors: the severity of the bleeding episode, the existing level of inhibitor and whether the patient responds to infusion of Factor VIII with increasing antibody titers (anamnestic rise of Factor VIII antibody).

The following table [not shown] is presented as a guide in determining the preferred therapy with respect to the use of Anti-Inhibitor Coagulant Complex or Antihemophilic Factor (Human) in patients with Factor VIII inhibitors. Inhibitor level categories are given in the bold text areas of the table and the corresponding recommended product or products are given in the italicized text areas. Other regimens have been proposed.

Patients whose present Factor VIII inhibitor levels are greater than 10 Bethesda Units, as well as patients whose inhibitor levels are historically known to rise to greater than 10 Bethesda Units following treatment with Antihemophilic Factor (Human), should be treated with Anti-Inhibitor Coagulant Complex.

Patients whose present Factor VIII inhibitor levels are between 2 and 10 Bethesda Units and whose inhibitor levels are historically known to remain in this range following treatment with Antihemophilic Factor (Human) may be treated with either Antihemophilic Factor (Human) or Anti-Inhibitor Coagulant Complex, depending on the patient’s clinical history and the severity of the bleeding episode.

Patients with Factor VIII inhibitor levels <2 Bethesda Units whose inhibitor levels are historically known to remain at 2 Bethesda Units or less following treatment with Antihemophilic Factor (Human) may be treated with appropriate doses of Antihemophilic Factor (Human).

For patients who have low levels of Factor VIII inhibitor and whose history does not include adequate laboratory indications: of an anamnestic response to Antihemophilic Factor (Human), the treatment of choice should be based on clinical judgement. In such patients who are having non-critical or minor bleeding episodes, the use of Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex T, will maintain the inhibitor at a low level and allow the use of other coagulant therapeutic agents in subsequent major emergencies.

Medical: The recommended dosage range is 25 to 100 Hyland Factor VIII Correctional Units per kg of body weight, depending upon the severity of hemorrhage. If no hemostatic improvement is observed about 6 hours following the initial administration, the dosage should be repeated. Subsequent dosage and administration intervals are adjusted according to the patient’s clinical response (as shown by laboratory testing).

Market: Total 2006 revenue from Autoplex T sales was $7.4 million, which included a $4.5 million arbitration award related to the cancellation of a customer agreement (without this, sales were $2.9 million). Revenue was $2.9 million in 2005, and $6.2 million in 2004. Combined sales of Autoplex and Aloprim (Allopurinol sodium) by Nabi were $14.3 million in 2002, and $8.4 million in 2001.

Nabi estimates that the U.S. market potential for anti-inhibitor products, such as Autoplex T, is ~$75 million, and the worldwide market potential is ~$150 million.

The 2007 Average Wholesale Price (AWP) was $1.50/IU (no change from 2004) (Red Book, 2007). Medicare reimbursement is set at $1.43/IU for inpatient and home care, and at $1.01/IU for outpatient care. Estimated Acquisition Costs (for hospitals, treatment centers) is $0.98/IU [data from NHF].

In its April 18, 2005 price list, FFF Enterprises, a major biologics distributor, reported $0.96/IU.