ASH Clinical News May 2016 | Page 50

NovoSeven ® RT Coagulation Factor VIIa (Recombinant) Rx only BRIEF SUMMARY. Please consult package insert for full prescribing information. WARNING: THROMBOSIS: Serious arterial and venous thrombotic events following administration of NovoSeven ® RT have been reported. Discuss the risks and explain the signs and symptoms of thrombotic and thromboembolic events to patients who will receive NovoSeven ® RT. Monitor patients for signs or symptoms of activation of the coagulation system and for thrombosis. [See Warnings and Precautions] INDICATIONS AND USAGE: NovoSeven® RT (Coagulation Factor VIIa [Recombinant]) is a coagulation factor indicated for: Treatment of b leeding episodes and peri-operative management in adults and children with hemophilia A or B with inhibitors, congenital Factor VII (FVII) deficiency, and Glanzmann’s thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets; Treatment of bleeding episodes and peri-operative management in adults with acquired hemophilia CONTRAINDICATIONS: None known. WARNINGS AND PRECAUTIONS: Thrombosis: Serious arterial and venous thrombotic events have been reported in clinical trials and postmarketing surveillance. Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with aPCCs/PCCs (activated or nonactivated prothrombin complex concentrates) and uncontrolled post-partum hemorrhage have an increased risk of developing thromboembolic events due to circulating tissue factor (TF) or predisposing coagulopathy [See Adverse Reactions and Drug Interactions]. Exercise caution when administering NovoSeven ® RT to patients with an increased risk of thromboembolic complications. These include, but are not limited to, patients with a history of coronary heart disease, liver disease, disseminated intravascular coagulation, postoperative immobilization, elderly patients and neonates. In each of these situations, the potential benefit of treatment with NovoSeven® RT should be weighed against the risk of these complications. Monitor patients who receive NovoSeven ® RT for development of signs or symptoms of activation of the coagulation system or thrombosis. When there is laboratory confirmation of intravascular coagulation or presence of clinical thrombosis, reduce the dose of NovoSeven ® RT or stop the treatment, depending on the patient’s condition. Hypersensitivity Reactions: Hypersensitivity reactions, including anaphylaxis have been reported with NovoSeven® RT. Administer NovoSeven ® RT only if clearly needed in patients with known hypersensitivity to NovoSeven ® RT or any of its components, or in patients with known hypersensitivity to mouse, hamster, or bovine proteins. Should symptoms occur, discontinue NovoSeven ® RT, administer appropriate treatment and weigh the benefit/risks prior to restarting treatment with NovoSeven ® RT. Antibody Formation in Factor VII Deficient Patients: Factor VII deficient patients should be monitored for prothrombin time (PT) and factor VII coagulant activity before and after administration of NovoSeven ® RT. If the factor VIIa activity fails to reach the expected level, or prothrombin time is not corrected, or bleeding is not controlled after treatment with the recommended doses, antibody formation may be suspected and analysis for antibodies should be performed. Laboratory Tests: Laboratory coagulation parameters (PT/INR, aPTT, FVII:C) have shown no direct correlation to achieving hemostasis. Assays of prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), and plasma FVII clotting activity (FVII:C), may give different results with different reagents. Treatment with NovoSeven ® has been shown to produce the following characteristics: PT: As shown below, in patients with hemophilia A/B with inhibitors, the PT shortened to about a 7-second plateau at a FVII:C level of approximately 5 units per mL. For FVII:C levels > 5 units per mL, there is no further change in PT. The clinical relevance of prothrombin time shortening following NovoSeven ® RT administration is unknown. PT (sec) PT versus FVII:C INR: NovoSeven® has demonstrated the ability to 14 normalize INR. However, INR 13 values have not been shown 12 to directly predict bleeding 11 outcomes, nor has it been 10 possible to demonstrate the 9 impact of NovoSeven® on 8 bleeding times/volume in 7 models of clinically-induced 6 bleeding in healthy volunteers who had received Warfarin, 5 when laboratory parameters 4 (PT/INR, aPTT, thromboelas3 togram) have normalized. 2 aPTT: While administration of 1 NovoSeven® shortens the 0 30 40 prolonged aPTT in hemo0 10 20 philia A/B patients with FVII:C (unit per mL) NOSV15CDPR3303_Leadership_HCP_Journal_Ad_KING_BS_r2_FSU.indd 1 inhibitors, normalization has usually not been observed in doses shown to induce clinical improvement. Data indicate that clinical improvement was associated with a shortening of aPTT of 15 to 20 seconds. FVIIa:C: FVIIa:C levels were measured two hours after NovoSeven ® administration of 35 micrograms per kg body weight and 90 micrograms per kg body weight following two days of dosing at two hour intervals. Average steady state levels were 11 and 28 units per mL for the two dose levels, respectively. ADVERSE REACTIONS: The most common and serious adverse reactions in clinical trials are thrombotic events. Thrombotic adverse reactions following the administration of NovoSeven ® in clinical trials occurred in 4% of patients with acquired hemophilia and 0.2% of bleeding episodes in patients with congenital hemophilia. Clinical Trials Experience: 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. Adverse reactions outlined below have been reported from clinical trials and data collected in registries. Hemophilia A or B Patients with Inhibitors: In two studies for hemophilia A or B patients with inhibitors treated for bleeding episodes (N=298), adverse reactions were reported in ≥2% of the patients that were treated with NovoSeven® for 1,939 bleeding episodes (see Table below). Table: Adverse Reactions Reported in ≥2% of the 298 Patients with Hemophilia A or B with Inhibitors Body System Reactions Body as a whole Fever Platelets, Bleeding, and Clotting Fibrinogen plasma decreased Cardiovascular Hypertension # of adverse reactions (n=1,939 treatments) (n=298 patients) 16 13 10 5 9 6 # of patients Serious adverse reactions included thrombosis, pain, thrombophlebitis deep, pulmonary embolism, decreased therapeutic res ponse, cerebrovascular disorder, angina pectoris, DIC, anaphylactic shock and abnormal hepatic function. The serious adverse reactions of DIC and therapeutic response decreased had a fatal outcome. There have been no confirmed reports of inhibitory antibodies against NovoSeven ® or FVII in patients with congenital hemophilia A or B with alloantibodies. In two clinical trials evaluating safety and efficacy of NovoSeven ® administration in the perioperative setting in hemophilia A or B patients with inhibitors (N=51), the following serious adverse reactions were reported: acute post-operative hemarthrosis (n=1), internal jugular thrombosis adverse reaction (n=1), decreased therapeutic response (n=4) 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 75 patients with Factor VII deficiency had received NovoSeven® : 70 patients for 124 bleeding episodes, surgeries, or prophylaxis; 5 patients in the pharmacokinetics trial. The following adverse reactions were reported: intracranial hypertension (n=1), IgG antibody against rFVIIa and FVII (n=1), localized phlebitis (n=1). As with all therapeutic proteins, there is a potential for immunogenicity. Patients with factor VII deficiency treated with NovoSeven ® RT should be monitored for factor VII antibodies. The incidence of antibody formation is 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, 6 patients experienced 8 serious adverse reactions. Serious adverse reactions included shock (n=1), cerebrovascular accident (n=1) and thromboembolic events (n=6) which included cerebral artery occlusion, cerebral ischemia, angina pectoris, myocardial infarction, pulmonary embolism and deep vein thrombosis. Three of the serious adverse reactions had a fatal outcome. Glanzmann’s Thrombasthenia: Data collected from the Glanzmann’s Thrombasthenia Registry (GTR) and the HTRS registry showed that 140 patients with Glanzmann’s thrombasthenia received NovoSeven® RT for 518 bleeding episodes, surgeries or traumatic injuries. The following adverse reactions were reported: deep vein thrombosis (n=1), headache (n=2), fever (n=2), nausea (n=1), and dyspnea (n=1). 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. 9/11/15 2:24 PM