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warnings and cautions
5 WARNINGS AND PRECAUTIONS Thromboembolic events may result from intravascular application of RAPLIXA. ( 5.1 ) Air or gas embolism can occur using air- or gas-pressurized sprayers to administer fibrin sealants. Operate the device according to the manufacturer's instructions. ( 5.2 ) RAPLIXA may carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agents, despite manufacturing steps designed to reduce the risk of viral transmission. ( 5.3 ) Allergic type hypersensitivity reactions may occur.If allergic type hypersensitivity symptoms occur, discontinue administration immediately. ( 5.4 ) 5.1 Thrombosis Life-threatening thromboembolic events may result from intravascular application of RAPLIXA. 5.2 Air or Gas Embolism Air or gas embolism has occurred with the use of spray devices employing pressure regulators to administer fibrin sealants. This appears to be related to the use of the spray device at higher than manufacturer recommended pressures and in close proximity to the tissue surface. Reports with the use of other devices describe air emboli that are life-threatening and include fatality. To minimize this risk, operate the RaplixaSpray device according to the manufacturer's instructions. In the absence of instructions, operate at a maximum air pressure of 1.5 bar (22 psi) and at a minimum distance of 5 cm (2 inches) from the bleeding surface. Monitor changes in blood pressure, pulse, oxygen saturation, and end tidal CO 2 for signs and symptoms of embolism. 5.3 Transmissible Infectious Agents Because the biological components of this product are made of human plasma, RAPLIXA may carry a risk of transmitting infectious agents, such as viruses the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite manufacturing steps designed to reduce the risk of infectious agent transmission. The risk of transmitting an infectious agent has been minimized by screening plasma donors for prior exposure to certain infectious agents, by testing for the presence of certain current virus infections, and by inactivating and removing certain viruses. 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 considered by a physician to possibly have been transmitted by this product should be reported by the physician or other healthcare provider to Mallinckrodt Hospital Products Inc. at 1-800-778-7898. 5.4 Hypersensitivity Reactions Allergic type hypersensitivity reactions may occur. Signs of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur, discontinue administration immediately.
6 ADVERSE REACTIONS The most commonly reported adverse reactions (> 5% subjects) were procedural pain, nausea, constipation, pyrexia, and hypotension. The most commonly reported adverse reactions (> 5% subjects) were procedural pain, nausea, constipation, pyrexia, and hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt Hospital Products Inc. at 1-800-778-7898 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience The RAPLIXA clinical trials safety data base consists of two randomized, single-blind, controlled Phase 2 trials and one randomized single-blind controlled Phase 3 trial. All of the trials evaluated the safety and immunogenicity of RAPLIXA topically applied with a gelatin sponge and included patients undergoing spinal surgery, vascular surgery, hepatic resection, soft tissue dissection/general surgery. These trials resulted in an overall safety database of 566 patients treated with RAPLIXA with gelatin sponge. Most patients (94%) were exposed to a 1 gram vial of RAPLIXA. Overall, the incidence of adverse reactions was similar between treatment groups (Table 2). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 2: Commonly Reported Adverse Reactions (> 5% subjects) in RAPLIXA Clinical Trials a FC-002 US and FC-002 NL clinical trials combined b FC-004 Pivotal Phase 3 clinical trial c Sorted on Total RAPLIXA + Gelatin Sponge subjects d R+G = RAPLIXA + Gelatin Sponge; G = Gelatin Sponge Alone Phase 2 a Phase 3 b Total c N (%) of Patients Preferred Term R+G d (N=86) G d (N=39) R+G d (N=480) G d (N=239) R+G d (N=566) G d (N=278) Procedural pain 40 (47) 16 (41) 257 (54) 134 (56) 297 (52) 150 (54) Nausea 26 (30) 13 (33) 120 (25) 48 (20) 146 (26) 61 (22) Constipation 21 (24) 9 (23) 72 (15) 31 (13) 93 (16) 40 (14) Incision site pain 5 (6) 3 (8) 63 (13) 32 (13) 68 (12) 35 (13) Pyrexia 7 (8) 5 (13) 37 (8) 11 (5) 44 (8) 16 (6) Anemia 4 (5) 2 (5) 33 (7) 17 (7) 37 (7) 19 (7) Vomiting 11 (13) 2 (5) 26 (5) 12 (5) 37 (7) 14 (5) Hypotension 2 (2) 2 (5) 38 (8) 16 (7) 40 (7) 18 (6) Pruritus 3 (3) 1 (3) 33 (7) 8 (3) 36 (6) 9 (3) Hypertension 1 (1) 0 25 (5) 10 (4) 26 (5) 10 (4) Immunogenicity The incidence of antibody formation in the Phase 3 trial was evaluated. Antibodies were detectable at baseline in 9/440 of RAPLIXA-treated patients (2%) and 9/222 of gelatin sponge-treated patients (4%). Nine of 440 patients (2%) in the RAPLIXA group and 6 of 222 patients (3%) in the gelatin sponge alone group developed anti-thrombin antibodies (non-neutralizing) during the trial. The clinical significance of these antibodies is not known. Anti-fibrinogen antibodies were not detected pre- or post-treatment in any subjects that were positive for anti-thrombin antibodies. The detection 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 RAPLIXA with the incidence of antibodies to other products may be misleading.