FDA label 8ae2021b-cf90-4f2f-8c4f-45643cff93eb

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions may occur. If necessary, discontinue administration and institute appropriate treatment ( 5.1 ). Inhibitory antibodies have been detected in patients receiving Corifact. If expected FXIII activity levels are not attained, or if breakthrough bleeding occurs while receiving prophylaxis treatment, an assay that measures FXIII inhibitory antibody concentrations should be performed ( 5.2 ). Thrombotic events have been reported in patients receiving Corifact. Weigh the benefits of the administration versus the risks of thrombosis ( 5.3 ). Corifact is made from human blood and may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent ( 5.4 ). 5.1 Hypersensitivity Hypersensitivity reactions (including allergy, rash, pruritus, and erythema) have been observed with Corifact. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including urticaria, rash, tightness of the chest, wheezing, hypotension) occur, immediately discontinue administration ( see Patient Counseling Information [17] ) and institute appropriate treatment. 5.2 Immunogenicity Development of inhibitory antibodies against FXIII has been detected in patients receiving Corifact. Monitor patients for possible development of inhibitory antibodies. Presence of inhibitory antibodies may manifest as an inadequate response to treatment. If expected plasma FXIII activity levels are not attained, or if breakthrough bleeding occurs while receiving prophylaxis, an assay that measures FXIII inhibitory antibody concentrations should be performed. One case of inhibitory antibodies against FXIII has been reported in the clinical studies (see Clinical Trials Experience [6.1] ). Cases of inhibitory antibodies against FXIII in patients with congenital FXIII deficiency have also been reported in postmarketing surveillance. 5.3 Thromboembolic Risk Thromboembolic complications have been reported in postmarketing surveillance ( see Postmarketing Experience [6.2] ). Benefits and risks should be carefully assessed in pregnant women because of their hypercoagulable state and potential for increased risk of thromboembolic events. 5.4 Transmission of Infectious Agents Corifact is made from human plasma. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may be present in such products. The risk that such products could transmit viruses has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and removing certain viruses during manufacture ( see Description [11] ). Despite these measures, such products may still potentially transmit disease. Consider appropriate vaccination (against hepatitis A and B virus) for patients in regular/repeated receipt of Corifact. All infections thought by a physician to have been possibly transmitted by this product should be reported by the physician or other healthcare provider to the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 5.5 Monitoring Laboratory Tests Monitoring of patient's trough FXIII activity level ( see Dosing Schedule [2.2] ) is recommended during treatment with Corifact. If breakthrough bleeding occurs, or if expected peak plasma FXIII activity levels are not attained ( see Pharmacokinetics [12.3] ), an investigation to determine the presence of FXIII inhibitory antibodies should be performed.

6 ADVERSE REACTIONS The most common adverse reactions reported in clinical trials in greater than one subject (frequency >1%) following Corifact treatment are hypersensitivity reactions (including allergy, rash, pruritus, and erythema), chills/rise in temperature, arthralgia, headache, elevated thrombin-antithrombin levels, and an increase in hepatic enzymes. Adverse reactions are those adverse events (AEs) considered to be "at least possibly related" to the infusion of Corifact. The most common adverse reactions reported in Corifact clinical studies, in greater than one subject (frequency >1%), are hypersensitivity reactions (including allergy, rash, pruritus, and erythema), chills/rise in temperature, arthralgia, headache, elevated thrombin-antithrombin levels, and an increase in hepatic enzymes ( 6 ). Neutralizing antibodies against FXIII were reported in a clinical study ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies 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. Twelve clinical studies were conducted and included 187 unique subjects, 90 subjects were <16 years of age ( see Pediatric Use [8.4] ). These 187 subjects received a total of approximately 3930 infusions of Corifact. The most common adverse events reported in clinical trials in greater than three subjects (frequency >2%) are flu-like syndrome, abdominal pain, diarrhea, contusion, joint injury, limb injury, road traffic accident, upper respiratory tract infection, arthralgia, headache, epistaxis, vomiting, fever, hematoma, head injury, and rash. Adverse events (AEs) are defined as treatment-emergent AEs that started after the first Corifact study infusion. In the 12-week prospective, open-label, multicenter, pharmacokinetic and safety study conducted in 7 females and 7 males with congenital FXIII deficiency, ranging in age from 5 to 42 years (3 children, 2 adolescents, and 9 adults), there were no reports of deaths, life-threatening events, or adverse events that led to discontinuation or withdrawal from the study. No breakthrough bleeding episodes were reported in this study. A case of neutralizing antibodies against FXIII was reported in the ongoing postmarketing clinical study. The patient received prophylactic treatment with Corifact for ten years. Concomitant medications included interferon for hepatitis C infection. This patient presented with bruising, and post-infusion FXIII levels were found to be lower than expected. Over several weeks, FXIII recovery values decreased, so the dose and frequency of treatments were increased. Neutralizing antibodies to FXIII were detected, interferon treatment was discontinued, and the subject underwent plasmapheresis. Within a month, neutralizing antibodies were no longer detectable, FXIII recovery levels improved, and the previous prophylactic regimen was resumed. 6.2 Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. The adverse reactions spontaneously reported after administration of Corifact during postmarketing surveillance outside the US since 1993, identified by system organ class are provided in Table 2. Table 2: Postmarketing Adverse Reactions MedDRA System Organ Class MedDRA Preferred Term/Symptoms Immune system disorders Allergic/anaphylactic reaction (including cutaneous reactions, alteration in blood pressure, nausea, dyspnea, fever, and chills) General disorders and administration site conditions Pyrexia Blood and lymphatic system disorders Factor XIII inhibitor formation Vascular disorders Thrombosis, embolism Infections and infestations Transmission of an infectious agent via medicinal products Causality to Corifact could not be established for any virus transmission case report. made from human plasma ( see Transmission of Infectious Agents [5.4] )

<table width="100%"> <caption>Table 2: Postmarketing Adverse Reactions</caption> <col width="40%" align="left" valign="top"/> <col width="60%" align="left" valign="top"/> <thead> <tr> <th align="center" styleCode="Lrule Rrule">MedDRA System Organ Class</th> <th align="center" styleCode="Rrule">MedDRA Preferred Term/Symptoms</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Immune system disorders</td> <td styleCode="Rrule">Allergic/anaphylactic reaction (including cutaneous reactions, alteration in blood pressure, nausea, dyspnea, fever, and chills)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">General disorders and administration site conditions</td> <td styleCode="Rrule">Pyrexia</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Blood and lymphatic system disorders</td> <td styleCode="Rrule">Factor XIII inhibitor formation</td> </tr> <tr> <td styleCode="Lrule Rrule Botrule" rowspan="2">Vascular disorders</td> <td styleCode="Rrule">Thrombosis, embolism</td> </tr> <tr styleCode="Botrule"> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule">Infections and infestations</td> <td styleCode="Rrule">Transmission of an infectious agent via medicinal products<footnote ID="table4a">Causality to Corifact could not be established for any virus transmission case report.</footnote> made from human plasma (<content styleCode="italics">see<linkHtml href="#S5.4"> Transmission of Infectious Agents [5.4]</linkHtml> </content>)</td> </tr> </tbody> </table>