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warnings
WARNINGS General The clinical response to RECOMBINATE may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined and a sufficient dose of RECOMBINATE should be administered to achieve a satisfactory clinical response. If the patient's plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and appropriate testing performed. (see PRECAUTIONS - Monitoring Laboratory Tests ). Anaphylaxis and Severe Hypersensitivity Reactions Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with RECOMBINATE and have been manifested as dizziness pruritus, rash, urticaria, flushing, angioedema/face swelling, laryngeal edema, dyspnea, pallor, pyrexia, nausea, paresthesia, hypotension, and loss of consciousness. Discontinue RECOMBINATE if symptoms occur and seek immediate emergency treatment. RECOMBINATE contains trace amounts of bovine proteins, mouse immunoglobulin G (MuIgG), and hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Neutralizing Antibodies Patients treated with antihemophilic factor (AHF) products should be carefully monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of RECOMBINATE predominantly in previously untreated and minimally treated patients. The risk of developing inhibitors is highest during the first 20 exposure days. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor VIII inhibitor concentration should be performed ( see PRECAUTIONS - Monitoring Laboratory Tests ).
ADVERSE REACTIONS Adverse Reactions from Clinical Trials During controlled clinical studies with RECOMBINATE enrolling 210 subjects, the most commonly reported adverse drug reactions were chills, flushing, rash and epistaxis.. System Organ Class (SOC) Preferred MedDRA Term Number of Subjects Percent of Evaluable Subjects Number of evaluable subjects experiencing the event/total number of evaluable subjects [% relative to 210, the total number of unique subjects who received at least 1 infusion of RECOMBINATE]. GASTROINTESTINAL DISORDERS Nausea 1 0.48 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills Fatigue Pyrexia 3 1 1 1.43 0.48 0.48 INFECTIONS AND INFESTATIONS Ear infections 1 0.48 INVESTIGATIONS Acoustic stimulation tests abnormal 1 0.48 MUSCULOSKELETAL AND CONNECTIVE TISSUES DISORDERS Pain in extremity 1 0.48 NERVOUS SYSTEM DISORDERS Dizziness Tremors 1 1 0.48 0.48 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Pharyngolaryngeal pain 1 0.48 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Hyperhidrosis Pruritus Rash Rash maculopapular 1 1 2 1 0.48 0.48 0.95 0.48 VASCULAR DISORDERS Epistaxis Flushing Hematoma Hypotension Pallor Peripheral coldness 1 One subject experienced 11 events of epistaxis 2 1 1 1 1 0.48 0.95 0.48 0.48 0.48 0.48 During the Previously Treated Patients (PTP) study, none of the 71 subjects developed de novo evidence of Factor VIII inhibitor. However, during the phase II/III portion of the study, 1 subject with a history of inhibitors exhibited inhibitor activity at 6 months (0.8 Bethesda Units [BU]), which resolved by 9 months. One other subject in this study had detectable Factor VIII inhibitor at baseline (1.26 BU) and exhibited an anamnestic response at 6 months (10.3 BU). During a prospective pharmaco-surveillance study of subjects who received batches of RECOMBINATE containing modestly increased Chinese Hamster Ovary (CHO) cell protein levels, none of the 34 treated subjects developed a Factor VIII inhibitor. During the Previously Untreated Patients (PUP) study, 22 of the 73 evaluable subjects developed inhibitors to Factor VIII. Of these, 13 subjects displayed no detectable Factor VIII inhibitors at study exit. Post-Marketing Adverse Reactions In addition to the adverse reactions noted in clinical trials, the following adverse reactions have been reported in the post-marketing experience. These adverse reactions are listed by MedDRA (version 12.1) System Organ Class (SOC), then by MedDRA coding system Preferred Term in order of severity. BLOOD AND LYMPHATIC SYSTEM DISORDERS: Factor VIII inhibition CARDIAC DISORDERS: Tachycardia, Cyanosis GASTROINTESTINAL DISORDERS: Vomiting, Abdominal pain GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Malaise, Injection site reactions, Chest pain, Chest discomfort IMMUNE SYSTEM DISORDERS: Anaphylactic reaction, Hypersensitivity NERVOUS SYSTEM DISORDERS: Loss of consciousness, Headache, Paresthesia RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: Dyspnea, Cough, Laryngeal edema SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Angioedema, Urticaria, Erythema