Caution: This product is to be used only in patients with inhibitors to Factor VIII.
Warning: This is a potent drug with potential hazards. For maximal safety and efficacy, carefully read and follow directions below.
Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T*, is a sterile product prepared from pooled human plasma with subsequent alcohol fractionation to Cohn Fraction IV 1 . It contains, in concentrated form, variable amounts of activated and precursor vitamin K-dependent clotting factors. Factors of the kinin generating system are also present. The product is standardized by its ability to correct the clotting time of Factor VIII deficient plasma or Factor VIII deficient plasma which contains inhibitors to Factor VIII.
When reconstituted, this product contains a maximum of 2 units per mL of heparin and a residual amount of polyethylene glycol (2 mg per mL, maximum). It also contains 0.02 M sodium citrate and the sodium content is 177 ±15 milliequivalents per liter.
Laboratory testing of several lots of Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, has shown the presence of Factor VIII coagulant antigen (VIII:CAg). Although anamnestic response to this antigen following administration of the product was not observed during the clinical trials, the possibility of such a response does exist.
Each lot of Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, is assayed and labeled for units of Hyland Factor VIII correctional activity. Factor VIII correctional activity may not be exclusively related to the efficacious components(s). (See Clinical Pharmacology .)
During the manufacturing process, this product was heated for 6 days at 60°C. This heating step is designed to reduce the risk of transmission of hepatitis and other viral diseases. However, no procedure has been shown to be totally effective in removing hepatitis infectivity from Anti-Inhibitor Coagulant Complex.
Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, must be administered intravenously.
The Factor VIII correctional activity of Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, is thought to be, in part, related to the Factor Xa content of the product. It is additionally hypothesized that the elevated Factor VII-VIIa content of this product is also a contributing factor in the in vivo reestablishment of normal hemostasis by way of Factor X activation in conjunction with tissue factor, phospholipid and ionic calcium.
Control of thrombin formation is regulated by (1) the presence of antithrombin III and other serine protease inhibitors which neutralize Factors IXa and Xa, (2) the short biological half-lives of Factors VII and VIIa and (3) the presence of the circulating Factor VIII inhibitor which additionally controls overactivation of the intrinsic coagulation system.
In work with human immunodeficiency virus (HIV), substantial reduction in viral content has been reported in a recent study of the effects of ethanol fractionation, the process by which Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, is manufactured. Wells, et al , report 1 to 4 log reduction in each fractionation step they examined. 1
The effectiveness of the 6-day heating step in reducing viral infectivity was assessed by in vitro viral inactivation studies, using as markers, viruses not commonly found in plasma. When known quantities of these viruses were added to the product, the heat treatment employed inactivated the following quantities of virus:
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In separate experiments, HIV was also studied and these data are reported in the table above.
A retrospective study conducted with patients receiving unheated Anti-Inhibitor Coagulant Complex, Autoplex®, supports the effectiveness of the purification process in reducing viral burden in the product. In the study, none of the patients who received that product exclusively seroconverted for HIV antibodies, while 56% of those patients who received other treatment modalities seroconverted during the three year study. 2
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. 3-6 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. 7 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 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 shaded areas of the table and the corresponding recommended product or products are given in the unshaded areas. Other regimens have been proposed. 8
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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' clinical history and the severity of the bleeding episode. Patients with Factor VIII inhibitor levels of less than 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.
The use of Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, is contraindicated in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC).
Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses (See ). Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to the U.S. distributor, Nabi®, at 1-800-327-7106. The physician should discuss the risks and benefits of this product with the patient. Physicians should also report adverse reactions or any disease condition which may occur concomitantly with the administration of this product to the U.S. distributor, Nabi®.
If the infusion of the concentrate occurs more than 1 hour following reconstitution, there may be increased prekallikrein activator (PKA) with consequent hypotension.
Some viruses, such as parvovirus B19 or hepatitis A, are particularly difficult to remove or inactivate at this time. parvovirus B19 most seriously affects pregnant women, or immune-compromised individuals. Symptoms of parvovirus B19 infection include fever, drowsiness, chills, and runny nose followed about two weeks later by a rash, and joint pain. Evidence of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting, and pain in the belly. Dark urine and a yellowed complexion are also common symptoms. Patients should be encouraged to consult their physician if such symptoms appear.
Certain components used in the packaging of this product contain natural rubber latex.
Identification of the clotting deficiency as that caused by the presence of Factor VIII inhibitors is essential before the administration of Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, is initiated.
Signs and/or symptoms of hypotension may occur with this product. In these cases, stopping the infusion allows the symptoms to disappear. With all but the most reactive individuals, the infusion may be resumed at a slower rate.
If clinical signs of intravascular coagulation occur, the infusion should be stopped promptly and the patient monitored for DIC by the appropriate laboratory tests. Symptoms of DIC include changes in blood pressure and pulse rate, respiratory distress, chest pain and cough. Laboratory indications of DIC include prolonged thrombin time, prothrombin time and partial thromboplastin time tests. Other indications of DIC are decreased fibrinogen concentration, decreased platelet count and/or the presence of fibrinogen/fibrin degradation products.
Special caution should be taken in the use of this concentrate in newborns, where a high morbidity and mortality may be associated with hepatitis, and in individuals with pre-existing liver disease.
In some cases, laboratory tests such as the activated partial thromboplastin time test may not correlate with clinical response, in that the appearance of hemostatic improvement may occur without a reduction of partial thromboplastin time. However, the prothrombin time would be expected to be shortened.
In children, fibrinogen levels should be determined prior to the initial infusion and monitored during the course of the treatment.
Drug InteractionsSince only limited data are available on the administration of highly activated prothrombin complex products together with antifibrinolytic agents such as epsilon-aminocaproic acid (EACA) or tranexamic acid, 6 the concomitant use of Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, with such agents is not recommended.
Pregnancy Category C. Animal reproduction studies have not been conducted with Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T. It is also not known whether Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, should be given to a pregnant woman only if clearly needed.
As with other plasma preparations, reactions manifested by fever, chills or indications of protein sensitivity may be observed with the administration of Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T. Signs and/or symptoms of high prekallikrein activity, such as changes in blood pressure or pulse rate may also be observed. It is advisable that appropriate medications be available for the treatment of acute allergic reactions or acute vasoactive reactions, should they occur.
A rate of infusion that is too rapid may cause headache, flushing, and changes in pulse rate and blood pressure. In such instances, stopping the infusion allows the symptoms to disappear promptly. With all but the most reactive individuals, infusion may be resumed at a slower rate.
Each bottle of Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, is labeled with the number of Hyland Factor VIII Correctional Units that it contains. 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, will correct the clotting time (ellagic acid-activated partial thromboplastin time) to 35 seconds (normal).
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 approximately 6 hours following the initial administration, the dosage should be repeated.
Subsequent dosage and administration intervals should be adjusted according to the patient's clinical response. (See Laboratory Tests .)
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Note: Do not refrigerate after reconstitution.
It is recommended that Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, be infused initially at a rate of 2 mL/min. If infusion at this rate is well tolerated the administration rate may be gradually increased to 10 mL/min.
When reconstitution of Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, is complete, its infusion should commence as soon as practical; however, it must be completed within 1 hour.
The reconstituted solution should be at room temperature during infusion.
Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, is furnished with a suitable volume of Sterile Water for Injection, USP; a double-ended needle; a filter needle; and a package insert.
Storage
Anti-Inhibitor Coagulant Complex, Heat Treated, Autoplex® T, should be stored under ordinary refrigeration (2 - 8°C, 36 - 46°F). Avoid freezing to prevent damage to the diluent bottle.
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BIBLIOGRAPHY
Fekete LF, Holst SL, Peetoom F, et al : "Auto" Factor IX Concentrate: A new therapeutic approach to treatment of hemophilia A patients with inhibitors. Proceedings, 14th International Congress of Haematology . Sao Paulo, Brazil, 1972
Kelly P, Penner JA: Antihemophilic factor inhibitors: Management with prothrombin complex concentrates. JAMA 236 :2061, 1976
Seligsohn U, Kasper CK, østerud B, et al : Activated factor VII. Presence in factor IX concentrates and persistence in the circulation after infusion. Blood 53 :828, 1979
Abildgaard CF, Penner JA, Watson-Williams EJ: Anti-Inhibitor Coagulant Complex (Autoplex) for treatment of factor VIII inhibitors in hemophilia. Blood 56 :978, 1980
©Copyright 1987, 1988, 1989, 1990, 1998 Baxter Healthcare Corporation. All rights reserved.
NDC 59730-6059-7
Distributed by:
Nabi®
Boca Raton, FL 33487 USA
Manufactured by:
Baxter Healthcare Corporation
Hyland Division
Glendale, CA 91203 USA
U.S. License No. 140
6849
Revised April 1998