Sevenfact

1 INDICATIONS AND USAGE SEVENFACT is indicated for the treatment and control of bleeding episodes occurring in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors. Limitation s of Use: SEVENFACT is not indicated for the treatment of patients with congenital Factor VII deficiency. SEVENFACT is a coagulation factor VIIa concentrate indicated for the treatment and control of bleeding episodes occurring in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors ( 1 ). Limitation s of Use: SEVENFACT is not indicated for treatment of congenital factor VII deficiency.

2 DOSAGE AND ADMINISTRATION For i ntravenous u se after reconstitution only . Type of Bleeding Dosing Regimen Recommendation For Mild or Moderate bleeds 75 mcg/kg repeated every 3 hours until hemostasis is achieved or Initial dose of 225 mcg/kg. If hemostasis is not achieved within 9 hours, additional 75 mcg/kg doses may be administered every 3 hours as needed to achieve hemostasis For Severe bleeds 225 mcg/kg, followed if necessary 6 hours later with 75 mcg/kg every 2 hours Consider alternative treatments if successful control of bleeding does not occur within 24 hours of the first administration of SEVENFACT. The vial includes a rubber stopper under the plastic cap. The syringe plunger rod has a wide top end and threaded end. The pre-filled syringe with Water for Injection diluent has a plastic backstop, rubber stopper, syringe tip (luer lock top under syringe cap), and syringe cap. The SEVENFACT 1 mg and 2 mg vial adapter and SEVENFACT 5 mg vial adapter each contain a plastic cover, paper protective cover, and spike (under protective paper). 2.1 Dose For intravenous use after reconstitution only. Dose and duration of SEVENFACT depend on the location and severity of the bleeding, need for urgent hemostasis, frequency of administration, and known patient responsiveness to FVIIa-containing bypassing agents during prior bleeding events. Treatment with SEVENFACT should be initiated as soon as a bleeding event occurs. The dose, frequency, and duration of SEVENFACT therapy should be based on the patient’s clinical response and hemostasis evaluation. The use of laboratory assessment(s) of coagulation (PT/INR, aPTT, FVII:C) does not necessarily correlate with or predict the hemostatic effectiveness of SEVENFACT. Dose adjustment may be required if the patient has received other procoagulant therapies prior to treatment with SEVENFACT. Based on the clinical trial program for SEVENFACT, the recommended initial dose should be adjusted based on the criteria provided in Table 1. Table 1 Dosing for Treatment and Control of Bleeding Type of Bleeding Dosing Regimen Recommendation Duration of Therapy Mild and Moderate Joint, superficial muscle, soft tissue and mucous membranes. 75 mcg/kg repeated every 3 hours until hemostasis is achieved or Initial dose of 225 mcg/kg. If hemostasis is not achieved within 9 hours, additional 75 mcg/kg doses may be administered every 3 hours as needed to achieve hemostasis. Consider alternative treatments if successful control of bleeding does not occur within 24 hours of the first administration of SEVENFACT. Continue therapy to support healing and prevent recurrent hemorrhage after hemostasis to maintain the hemostatic plug. The site and severity of bleeding should determine therapy duration. Severe Life or limb threatening hemorrhage, iliopsoas and deep muscle with neurovascular injury, retroperitoneum, intracranial, or gastrointestinal. Patients should seek immediate medical care if signs or symptoms of severe bleeding occur in the home setting. 225 mcg/kg initially, followed if necessary 6 hours later with 75 mcg/kg every 2 hours until hemostasis is achieved. Subsequent Dosing: After achieving hemostasis, base the decision for dosing on clinical assessment and the type of bleeding. Consider the risk of thrombosis with subsequent dosing after achieving hemostatic efficacy. Continue therapy to support healing and prevent recurrent hemorrhage. The site and severity of bleeding and the use of other procoagulant therapies should determine therapy duration. 2.2 Reconstitution Follow the procedures below for reconstitution of SEVENFACT. Calculate the amount of SEVENFACT required and select the appropriate SEVENFACT packages containing the matching pre-filled syringe of sterile Water for Injection, and the vial adapters. Reconstitute each vial with the pre-filled syringe provided with each vial of SEVENFACT. Overview of SEVENFACT P ackage : Figure 1 Vial with SEVENFACT L yophilized P owder Lyophilized Powder Drug…

5 WARNINGS AND PRECAUTIONS Patients with hemophilia A or B with inhibitors who have other risk factors for thrombosis may be at increased risk of serious arterial and venous thrombotic events ( 5.1 ). Hypersensitivity reactions, including anaphylaxis, are possible with SEVENFACT. Should symptoms occur, patients should discontinue SEVENFACT and seek appropriate medical intervention ( 5.2 ). 5.1 Thrombosis Serious arterial and venous thrombosis can occur with coagulation factor VIIa containing products including SEVENFACT. The following patients may have increased risk of thrombosis with use of SEVENFACT: History of congenital or acquired hemophilia receiving concomitant treatment with aPCC/PCC (activated or non-activated prothrombin complex) or other hemostatic agents History of atherosclerotic disease, coronary artery disease, cerebrovascular disease, crush injury, septicemia, or thromboembolism. Monitor patients who receive SEVENFACT for the development of signs and 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 SEVENFACT or stop treatment, depending on the patient’s condition. 5.2 Hypersensitivity and Infusion-Related Reactions Hypersensitivity and infusion-related reactions including anaphylaxis can occur with coagulation factor VIIa containing products including SEVENFACT. Sign and symptoms may include hives, itching, rash, difficulty breathing, swelling around the mouth and throat, tightness of the chest, wheezing, dizziness or fainting, and low blood pressure. Patients with known IgE-based hypersensitivity to casein may be at higher risk of hypersensitivity reactions. In the event of hypersensitivity or infusion-related reactions, discontinue SEVENFACT and manage according to clinical practice guideline. 5.3 Neutralizing Antibodies Neutralizing antibodies may occur with the use of SEVENFACT. If treatment with SEVENFACT does not result in adequate hemostasis, then suspect development of neutralizing antibody as the possible cause and perform testing as clinically indicated. Neutralizing antibodies to other Factor VIIa-containing products have been observed in congenital Factor VII-deficient patients. SEVENFACT has not been studied in this patient population. [ See limitation of use statement under Indications and Usage ( 1 )] . 5.4 Laboratory Tests Laboratory coagulation parameters (PT/INR, aPTT, FVII:C) do not correlate with clinical response to SEVENFACT treatment.

4 CONTRAINDICATIONS SEVENFACT is contraindicated in patients with: known allergy to rabbits or rabbit proteins. Exposure to SEVENFACT in these patients can result in severe hypersensitivity reaction. severe hypersensitivity reaction to SEVENFACT or any of its components. Exposure to SEVENFACT in these patients can result in severe hypersensitivity reaction. Known allergy to rabbits or rabbit proteins. Severe hypersensitivity reaction to SEVENFACT or any of its components ( 4 ).

7 DRUG INTERACTIONS Clinical experience with pharmacologic use of FVIIa-containing products indicates an elevated risk of serious thrombotic events when used simultaneously with activated prothrombin complex concentrates. Clinical experience with pharmacologic use of FVIIa-containing products indicates an elevated risk of serious thrombotic events when used simultaneously with activated prothrombin complex concentrates ( 7 ).

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies using SEVENFACT in pregnant women to determine whether there is a drug-associated risk. Animal studies evaluating the embryo-fetal teratogenic potential of SEVENFACT have not been conducted. It is unknown whether SEVENFACT can cause fetal harm when administered to a pregnant woman or can affect fertility. In the U.S. general population, the estimated background risks of major birth defect and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥1%) were headache, dizziness, infusion-site discomfort, infusion-site hematoma, infusion-related reaction, and fever ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact HEMA Biologics at 855-718-HEMA (4362) or FDA at 1-800-FDA-1088 or https://www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. The safety database described in this section reflect exposure to SEVENFACT in two clinical studies, Study 1 and Study 2. A total of 42 patients with Hemophilia A or B with or without inhibitors received SEVENFACT: 27 patients in Study 1 at doses 75 mcg/kg and 225 mcg/kg and 15 patients in Study 2 at three escalating dose levels 25 mcg/kg, 75 mcg/kg and 225 mcg/kg [see Clinical Studies ( 14 )] . The most common adverse reactions (incidence ≥1%) reported in clinical trials for SEVENFACT were headache, dizziness, infusion-site discomfort, infusion-site hematoma, infusion-related reaction, and fever. Adverse reactions reported in the two clinical studies are shown in Table 2. Table 2 Adverse Reactions Occurring in Clinical Studies Preferred Terms Number of Patient Adverse Reactions (% Incidence Rate) Study 2 (N=15) Number of A dverse R eactions * Study 2 Number of Patient Adverse Reactions (% Incidence Rate) Study 1 (N=27) Number of A dverse R eactions * Study 1 Infusion site discomfort - - 1 (4) 4 Infusion site hematoma - - 1 (4) 2 Dizziness 1 (7) 2 - - Headache 1 (7) 1 - - Body temperature increase - - 1 (4) 1 Infusion related reaction** 1 (7) 1 - - * Three patients experienced adverse reactions in Study 2 and two patients experienced adverse reactions in Study 1. ** Symptoms resolved without any intervention and did not recur with subsequent administration.