warnings and cautions
5 WARNINGS AND PRECAUTIONS Anaphylaxis and severe hypersensitivity reactions are possible. Should symptoms occur, treatment with Alphanate should be discontinued, and emergency treatment should be sought ( 5.1 ) Development of activity-neutralizing antibodies has been detected in patients receiving FVIII containing products. Development of alloantibodies to VWF in Type 3 VWD patients have been occasionally reported in the literature ( 5.2 ) Thromboembolic events may be associated with AHF/VWF Complex (Human) in VWD patients, especially in the setting of known risk factors ( 5.3 ) Intravascular hemolysis may be associated with infusion of massive doses of AHF/VWF Complex (Human) ( 5.4 ) Rapid administration of a FVIII concentrate may result in vasomotor reactions ( 5.5 ) Plasma products carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk ( 5.6 ) 5.1 Anaphylaxis and Severe Hypersensitivity Reactions Anaphylaxis and severe hypersensitivity reactions are possible. Should symptoms occur, treatment with Alphanate should be discontinued, and emergency treatment should be administered. 5.2 Neutralizing Antibodies Development of procoagulant activity-neutralizing antibodies (inhibitors) has been detected in patients receiving FVIII-containing products. Carefully monitor patients treated with AHF products for the development of FVIII inhibitors by appropriate clinical observations and laboratory tests. No studies have been conducted with Alphanate to evaluate inhibitor formation. Therefore, it is not known whether there are greater, lesser or the same risks of developing inhibitors due to the use of this product than there are with other FVIII preparations. If expected plasma FVIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay that measures FVIII inhibitor concentration should be performed. Patients with these inhibitors may not respond to treatment with Antihemophilic Factor/von Willebrand Factor Complex (Human), or the response may be much less than would otherwise be expected; therefore, larger doses of Antihemophilic Factor/von Willebrand Factor Complex (Human) are often required. The management of bleeding in patients with inhibitors requires careful monitoring, especially if surgical procedures are indicated. 4-6 Depending on the level of the inhibitor and/or clinical response, it may be appropriate to use an alternative ‘bypass’ therapeutic agent. Reports in the literature suggest that patients with Type 3, severe von Willebrand Disease, may develop alloantibodies to von Willebrand factor (VWF) after replacement therapy. 13 The risk of developing alloantibodies in patients with von Willebrand disease due to the use of this product is not known. 5.3 Thromboembolic Events Thromboembolic events have been reported in von Willebrand Disease patients receiving AHF/VWF Complex (Human) replacement therapy, especially in the setting of known risk factors for thrombosis. 14-16 In addition, endogenous high levels of FVIII have also been associated with thrombosis but no causal relationship has been established. In all VWD patients in situations of high thrombotic risk receiving coagulation factor replacement therapy, caution should be exercised and antithrombotic measures should be considered. See also ADVERSE REACTIONS ( 6 ) . 5.4 Intravascular Hemolysis Massive doses of AHF/VWF Complex (Human) have rarely resulted in acute hemolytic anemia, increased bleeding tendency or hyperfibrinogenemia. 17 Alphanate contains blood group specific isoagglutinins and, when large and/or frequent doses are required in patients of blood groups A, B, or AB, the patient should be monitored for signs of intravascular hemolysis and falling hematocrit. Should this condition occur, thus leading to progressive hemolytic anemia, the administration of serologically compatible Type O red blood cells should be considered, the administration of Alphanate should be discontinued, and alternative therapy should be considered. 5.5 Vasomotor Reactions Rapid administration of a FVIII concentrate may result in vasomotor reactions. Alphanate should not be administered at a rate exceeding 10 mL/minute. 5.6 Transmissible Infectious Agents Because Alphanate is made from pooled human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob Disease (CJD) agent. Stringent procedures designed to reduce the risk of adventitious agent transmission have been employed in the manufacture of this product, from the screening of plasma donors and the collection and testing of plasma, through the application of viral elimination/reduction steps such as solvent detergent and heat treatment in the manufacturing process. 18,19 Despite these measures, such products can still potentially transmit disease; therefore, the risk of infectious agents cannot be totally eliminated. See also DESCRIPTION ( 11 ) .