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adverse reactions
6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in clinical trials of another drug, and may not reflect rates observed in practice. In clinical trials, the most common adverse reactions are pyrexia, hemorrhage, injection site reaction, arthralgia, headache, hypertension, hypotension, nausea, vomiting, pain, edema and rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-877-668-6777 or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Thrombotic events following the administration of NovoSeven occurred in 0.28% of bleeding episodes treated, with the incidence in acquired hemophilia of 4% and in hemophilia patients of 0.20% in clinical trials within the approved indications. [ See Warnings and Precautions (5.1) ] . Adverse reactions observed in clinical trials for all labeled indications of NovoSeven included pyrexia, hemorrhage, injection site reaction, arthralgia, headache, hypertension, hypotension, nausea, vomiting, pain, edema, rash (including allergic dermatitis and rash erythematous), pruritus, urticaria, hypersensitivity, cerebral artery occlusion, cerebrovascular accident, pulmonary embolism, deep vein thrombosis, angina pectoris, increased levels of fibrin degradation products, disseminated intravascular coagulation and related laboratory findings including elevated levels of D-dimer and AT-III, thrombosis at i.v. site, non-specified thrombosis, thrombophlebitis, superficial thrombophlebitis. The following sections describe the adverse event profile observed during clinical studies for each of the labeled indications. Hemophilia A or B Patients with Inhibitors Two studies (Studies 1 and 2) are described for hemophilia A or B patients with inhibitors treated for bleeding episodes [ See Clinical Studies (14.1) ] . The table below lists adverse events that were reported in ≥2% of the 298 patients with hemophilia A or B with inhibitors that were treated with NovoSeven for 1,939 bleeding episodes. The events listed are considered to be at least possibly related or of unknown relationship to NovoSeven administration. Body System Event # of episodes reported (n=1,939 treatments) # of unique patients (n=298 patients) Body as a whole Fever 16 13 Platelets, Bleeding, and Clotting Hemorrhage NOS Fibrinogen plasma decreased 15 10 8 5 Skin and Musculoskeletal Hemarthrosis 14 8 Cardiovascular Hypertension 9 6 Events which were reported in 1% of patients and were considered to be at least possibly or of unknown relationship to NovoSeven administration were: allergic reaction, arthrosis, bradycardia, coagulation disorder, DIC, edema, fibrinolysis increased, headache, hypotension, injection site reaction, pain, pneumonia, prothrombin decreased, pruritus, purpura, rash, renal function abnormal, therapeutic response decreased, and vomiting. Serious adverse events that were probably or possibly related, or where the relationship to NovoSeven was not specified, occurred in 14 of the 298 patients (4.7%). Six of the 14 patients died of the following conditions: worsening of chronic renal failure, anesthesia complications during proctoscopy, renal failure complicating a retroperitoneal bleed, ruptured abscess leading to sepsis and DIC, pneumonia, and splenic hematoma and gastrointestinal bleeding. Thrombosis was reported in two of the 298 patients with hemophilia. Surgery Studies Two clinical trials (Studies 3 and 4) were conducted to evaluate the safety and efficacy of NovoSeven administration during and after surgery in hemophilia A or B patients with inhibitors [See Clinical Studies (14.1) ]. In Study 3, six patients experienced serious adverse events: two of these patients had events which were considered probably or possibly related to study medication (acute post-operative hemarthrosis, internal jugular thrombosis). No deaths occurred during the study. In Study 4, seven of 24 patients had serious adverse events (4 for bolus injection, 3 for continuous infusion). There were 4 serious adverse events which were considered probably or possibly related to NovoSeven treatment (2 events of decreased therapeutic response in each treatment arm). No deaths occurred during the study period. Congenital Factor VII Deficiency Data collected from the compassionate/emergency use programs, the published literature, a pharmacokinetics study, and the Hemophilia and Thrombosis Research Society (HTRS) registry showed that at least 75 patients with Factor VII deficiency had received NovoSeven - 70 patients for 124 bleeding episodes, surgeries, or prophylaxis regimens; 5 patients in the pharmacokinetics trial. In the compassionate/emergency use programs, 28 adverse events in 13 patients and 10 serious adverse events in 9 patients were reported. Non-serious adverse events in the compassionate/emergency use programs were single events in one patient, except for fever (3 patients), intracranial hemorrhage (3 patients), and pain (2 patients). The most common serious adverse event in the compassionate/emergency programs was serious bleeding in critically ill patients. All nine patients with serious adverse events died. One adverse event (localized phlebitis) was reported in the literature. No adverse events were reported in the pharmacokinetics reports or for the HTRS registry. No thromboembolic complications were reported for the 75 patients included here. As with all therapeutic proteins, there is a potential for immunogenicity. Isolated cases of factor VII deficient patients developing antibodies against factor VII were reported after treatment with NovoSeven. These patients had previously been treated with human plasma and/or plasma-derived factor VII. In some cases the antibodies showed inhibitory effect in vitro . The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to NovoSeven RT with the incidence of antibodies to other products may be misleading. Acquired Hemophilia Data collected from four compassionate use programs, the HTRS registry, and the published literature showed that 139 patients with acquired hemophilia received NovoSeven for 204 bleeding episodes, surgeries and traumatic injuries. Of these 139 patients, 10 experienced 12 serious adverse events that were of possible, probable, or unknown relationship to treatment with NovoSeven. Thrombotic serious adverse events included cerebral infarction, cerebral ischemia, angina pectoris, myocardial infarction, pulmonary embolism and deep vein thrombosis. Additional serious adverse events included shock and subdural hematoma. Data collected for mortality in the compassionate use programs, the HTRS registry and the publications spanning a 10 year period, was overall 32/139 (23%). Deaths due to hemorrhage were 10, cardiovascular failure 4, neoplasia 4, unknown causes 4, respiratory failure 3, thrombotic events 2, sepsis 2, arrhythmia 2 and trauma 1. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of NovoSeven. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship. The following additional adverse events were reported following the use of NovoSeven in labeled and unlabeled indications that included individuals with and without coagulopathy: high D-dimer levels and consumptive coagulopathy, thrombosis, thrombophlebitis, arterial thrombosis, and thromboembolic events including myocardial ischemia, myocardial infarction, bowel infarction, cerebral ischemia, cerebral infarction, hepatic artery thrombosis, renal artery thrombosis, portal vein thrombosis, phlebitis, peripheral ischemia, deep vein thrombosis and related pulmonary embolism, injection site pain and isolated cases of hypersensitivity/allergic reactions including anaphylactic shock, flushing, urticaria, rash, and angioedema. [See Warnings and Precautions (5.1) ] Fatal and non-fatal thromboembolic events have been reported with use of NovoSeven when used for off-label or labeled indications. The Hemophilia and Thrombosis Research Society (HTRS) Registry surveillance program is designed to collect data on the treatment of congenital and acquired bleeding disorders. 8 All prescribers can obtain information regarding contribution of patient data to this program by calling 1-877-362-7355 or at www.novosevensurveillance.com.