Concizumab

12.1 Mechanism of Action Concizumab-mtci is a monoclonal antibody antagonist of endogenous Tissue Factor Pathway Inhibitor (TFPI). Through the inhibition of TFPI, concizumab-mtci acts to enhance FXa production during the initiation phase of coagulation which leads to improved thrombin generation and clot formation with the goal of achieving hemostasis in patients with Hemophilia A or B regardless of their inhibitor status. The effect of concizumab-mtci is not influenced by the presence of inhibitory antibodies to FVIII or FIX. There is no structural relationship or sequence homology between concizumab-mtci and FVIII or FIX and, as such, treatment with concizumab-mtci does not induce or enhance the development of direct inhibitors to FVIII or FIX.

1 INDICATIONS AND USAGE Alhemo is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with: • hemophilia A (congenital factor VIII deficiency) with or without FVIII inhibitors • hemophilia B (congenital factor IX deficiency) with or without FIX inhibitors Alhemo is a tissue factor pathway inhibitor (TFPI) antagonist indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with: • hemophilia A (congenital factor VIII deficiency) with or without FVIII inhibitors • hemophilia B (congenital factor IX deficiency) with or without FIX inhibitors ( 1 )

2 DOSAGE AND ADMINISTRATION Administer Alhemo by subcutaneous injection to the abdomen or thigh with daily rotation of injection sites. ( 2.2 ) Recommended dosing regimen: • Day 1: Loading dose of 1 mg/kg • Day 2: Once daily dose of 0.2 mg/kg until individualization of maintenance dose ( 2.1 ) o 4 weeks after initiation of treatment: For dose optimization, measure concizumab‑mtci plasma concentration by Concizumab Enzyme-Linked Immunosorbent Assay (ELISA) prior to administration of next scheduled dose using an FDA-authorized test for the measurement of concizumab-mtci concentration in plasma. See full Prescribing Information for important preparation and administration instructions and dosage adjustment. ( 2.1 , 2.3 , 2.4 ) 2.1 Recommended Dosage For subcutaneous use only. Alhemo should be administered once daily. Avoid missed doses. Recommended dosing regimen: • Day 1: Loading dose of 1 mg/kg • Day 2: Once daily dose of 0.2 mg/kg until individualization of maintenance dose (see below) • 4 weeks after initiation of treatment: For dose optimization measure concizumab-mtci plasma concentration by Concizumab Enzyme-Linked Immunosorbent Assay (ELISA) prior to administration of next scheduled dose using an FDA-authorized test. Information on the FDA-authorized test for the measurement of concizumab-mtci plasma concentration is available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/denovo.cfm. Once the concizumab-mtci concentration result is available, individualize the maintenance dose of Alhemo no later than 8 weeks after initiation of treatment, based on the following concizumab-mtci plasma concentrations: o Less than 200 ng/mL: adjust to a once daily dose of 0.25 mg/kg o 200 to 4,000 ng/mL: continue once daily dose of 0.2 mg/kg o Greater than 4,000 ng/mL: adjust to a once daily dose of 0.15 mg/kg The calculated dose is rounded off to the nearest injectable dose as follows: • 60 mg/1.5 mL (40 mg/mL) in increments of 0.4 mg (brown label) • 150 mg/1.5 mL (100 mg/mL) in increments of 1 mg (gold label) • 300 mg/3 mL (100 mg/mL) in increments of 1 mg (white label) Additional measurements of concizumab-mtci plasma concentration should be taken at routine clinical follow-ups provided the patient has been on the same maintenance dose for 8 weeks of treatment to ensure steady state plasma concentration. Maintenance of concizumab plasma concentration above 200 ng/mL is important to decrease the risk of bleeding episodes. If concizumab-mtci plasma concentration remains below 200 ng/mL at two consecutive measurements, evaluate the benefits of continued Alhemo treatment versus the potential risk of bleeding events, and consider alternative therapies if available. As Alhemo is dosed by body weight (mg/kg), it is important to recalculate the dose when patients experience body weight changes. Missed Dose Adherence to daily dosing of Alhemo is important to maintain protection against bleeding. This is especially important during the initial 4 weeks of treatment to ensure a correct maintenance dose is established. Patients who miss a dose during the initial 4-week period should inform their healthcare professional and resume once daily dosing at the initial 0.2 mg/kg dose level. Missed Doses Once the Maintenance Dose Has Been Established The following dosing guidelines should apply ONLY when a patient has forgotten to or neglected to take their once daily maintenance dose: • 1 missed dose: Resume once daily treatment at the maintenance dose level • 2 to 6 missed doses: Resume treatment with a double dose followed by once daily treatment at the maintenance dose level • 7 or more missed doses: Physician should be contacted, and a new loading dose should be considered [see Dosage and Administration ( 2.1 )] Management of Breakthrough Bleeds No dose adjustment of Alhemo is required in the case of breakthrough bleeds. Management in the Perioperative Setting No dose adjustment of Alhemo is required in the case of minor surgeries. As there is limited experience in the perioperative setting, it is generally recommended to pause Alhemo at least 4 days prior to major surgery. Alhemo therapy can be resumed 10-14 days after surgery on the same maintenance dose without a new loading dose, considering the overall clinical picture of the patient. If necessary, consult a physician experienced in surgery of patients with bleeding disorders. Immune Tolerance Induction The safety and efficacy of concomitant use of Alhemo in patients receiving ongoing Immune Tolerance Induction (ITI), a desensitization strategy for the eradication of inhibitors, have not been established, and no data are available. Careful assessment of the potential benefits and risks should be performed if continuation or initiation of Alhemo during ITI is considered. 2.2 Changing to Alhemo from Other Hemostatic Products • Discontinue treatment with rFVIIa at least 12 hours before starting Alhemo. • Discontinue treatment with activated prothrombin complex concentr

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Thromboembolic Events [see Warnings and Precautions ( 5.1 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] • Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment 1.2 [see Warnings and Precautions ( 5.3 )] The most frequently reported adverse reactions (incidence ≥5%) were injection site reactions, headache and urticaria. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or 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 clinical trials of another drug and may not reflect the rates observed in clinical practice. The data in the WARNINGS AND PRECAUTIONS reflect exposure to Alhemo based on pooled data from clinical trials explorer3 (phase 1b), explorer4 (phase 2), explorer5 (phase 2), explorer7 (phase 3) and explorer8 (phase 3), in which a total of 320 male patients with hemophilia A with and without inhibitors and hemophilia B with and without inhibitors received at least one dose of Alhemo as routine prophylaxis. The patients were exposed for a total of 475 exposure years. Patients with HAwI (hemophilia A with inhibitors) and HBwI (hemophilia B with inhibitors) The data described below reflect exposure of 52 patients with HAwI and HBwI who were previously treated on-demand therapy and who were randomized in explorer7 to arm 1 to receive on- demand treatment with bypassing agents (n = 19) or arm 2 to receive Alhemo prophylaxis (n = 33) at the recommended dosing regimen [see Clinical Studies ( 14.1 )] . The median duration of treatment was 31.1 weeks (range 3.9, 72.9 weeks) in arm 1 (on-demand arm) and 40.1 weeks (range 3.1, 56.3 weeks) in arm 2 (Alhemo prophylaxis). Serious adverse reactions were reported in 6.1% of patients who received Alhemo. These serious adverse reactions were renal infarct and hypersensitivity reaction. Permanent discontinuation of Alhemo due to an adverse reaction occurred in 1 patient due to a renal infarct. Dosage interruptions of Alhemo due to an adverse reaction occurred in 1 patient (3%) and was a hypersensitivity reaction. The most common adverse reactions (≥5%) were injection site reactions and urticaria (see Table 1 ). Table 1. Adverse Reactions Reported in ≥5% HAwI and HBwI Patients Randomized to Alhemo in Explorer7 Adverse Reaction Alhemo Prophylaxis N=33 (%) On-demand Treatment N=19 (%) Injection site reactions 18% 0% Urticaria 6% 0% Injection site reactions included: Injection site bruising, Injection site erythema, Injection site hematoma, Injection site hemorrhage, Injection site reaction and Injection site urticaria. Urticaria included: Urticaria and Injection site urticaria. Patients with HA (hemophilia A without inhibitors) and HB (hemophilia B without inhibitors) The data described below reflect exposure of 63 patients with HA and HB who were previously treated on-demand therapy and who were randomized in explorer8 to arm 1 to receive on- demand treatment with factor product (n = 21) or arm 2 to receive Alhemo prophylaxis (n = 42) at the recommended dosing regimen [see Clinical Studies ( 14.2 )] . The median duration of treatment was 24.1 weeks (range 23.6, 56.1 weeks) in arm 1 (on- demand arm) and 32.1 weeks (range 3.9, 33.6 weeks) in arm 2 (Alhemo prophylaxis). The most common adverse reactions (≥5%) were injection site reactions and headache (see Table 2 ). Table 2. Adverse Reactions Reported in ≥5% HA and HB Patients Randomized to Alhemo in Explorer8 Adverse Reaction Alhemo Prophylaxis N=42 (%) On-demand Treatment N=21 (%) Injection site reactions 7% 0% Headache 7% 0% Injection site reactions included: injection site reaction, injection site rash, and injection site nodule

7 DRUG INTERACTIONS Breakthrough Bleeding Treatment: While treatment with all bypassing agents (e.g., rFVIIa or aPCC) can be used for breakthrough bleeds, high and/or frequent doses of FVIII, FIX, or bypassing agents with Alhemo increases the risk of thromboembolism. ( 7.1 ) 7.1 Breakthrough Bleeding Treatment Take appropriate precautions when treating breakthrough bleeding events in hemophilia patients receiving Alhemo prophylaxis and FVIII or FIX or a bypassing agent [see Dosage and Administration ( 2.1 )] . For mild and moderate bleeds that require additional treatment with FVIII or FIX or bypassing agents (e.g., rFVIIa or aPCC), the lowest-approved dose in the approved product labeling is recommended. For aPCC, a maximum dose of 100 units/kg body weight within 24 hours is recommended. For severe bleeds, follow the dosing instructions provided in the approved labeling for the specific product based on clinical judgement. Additive and sometimes synergistic increase in thrombin peak as quantified in the thrombin generation assay has been observed in plasma from hemophilia patients who were on prophylactic treatment with concizumab-mtci with concomitant presence of rFVIII, rFIX or bypassing agents including rFVIIa and aPCC [see Clinical Pharmacology ( 12.2 )] .