Concizumab

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 concentrate (aPCC) at least 48 hours before starting Alhemo . • Discontinue prophylactic use of standard half-life factor VIII (FVIII) or factor IX (FIX) at least 24 hours before starting Alhemo. • When changing from other products to Alhemo, the half-life of the previous product should be considered. Healthcare providers should discuss with patients receiving Alhemo and/or their caregivers the dose and schedule of bypassing agents or FVIII or FIX, if required, while receiving Alhemo prophylaxis. 2.3 Instructions and Dosage Modification for Breakthrough Bleeding Treatment with FVIII or FIX or all bypassing agents (e.g., rFVIIa or aPCC) can be used for breakthrough bleeds, and the dose and duration will depend on the location and severity of the bleed. 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 and the dose interval 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. 2.4 Administration and Use Instructions Treatment is intended for use under the guidance of a healthcare provider. Treatment should be initiated in a nonbleeding state. Alhemo may be self-administered or administered by a caregiver after appropriate training and reading the Instructions for Use, if a healthcare provider determines that is appropriate. Administer Alhemo by subcutaneous injection to the abdomen or thigh with rotation of injection site every day. Subcutaneous injections should not be given in areas where the skin is tender, bruised, red or hard, or areas where there are moles, scars, or stretch marks. Children and lean patients should be instructed to use injection techniques that minimize risk of intramuscular injection, e.g. injecting into a pinched fold of skin. Always use a new needle for each injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Alhemo is a clear to slightly opalescent and colorless to slightly yellow solution that may contain translucent to white particles. Do not use if the solution is discolored. Each Alhemo prefilled pen is for use by a single patient. An Alhemo pen must not be shared between patients, even if the needle is changed. Alhemo is recommended to be used with NovoFine ® or NovoFine ® Plus needles with a gauge of 32 and a length of 4 mm. If needles longer than 4 mm are used, injection techniques that minimize the risk of intramuscular injection should be used. Instructions for delivering the dosage are provided in the Instructions for Use leaflet enclosed with each Alhemo single-patient-use prefilled pen.

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

12.3 Pharmacokinetics Peak and trough geometric mean plasma concizumab-mtci concentrations at steady state are shown in Table 3 . Following a single Alhemo loading dose of 1 mg/kg, the steady state concentrations were reached around Day 4 and remained within a stable exposure range with daily maintenance doses. Concizumab-mtci AUC and C max increased with increasing dose in a greater than dose-proportional manner following subcutaneous administration. Table 3. Steady State Concizumab-mtci Concentrations During 24-hour Dosing Interval at Week 24 Parameters Hemophilia A and B without inhibitors All maintenance doses N=127 a HAwI and HBwI All maintenance doses N=99 a C max,ss (ng/mL), geometric mean (CV%) N 893.4 (144.5%) N=103 1167.1 (128%) N=69 C trough,ss (ng/mL), geometric mean (CV%) N 647.3 (178.8%) N=116 665.4 (221%) N=94 C max / C trough ratio, mean (SD) N 1.5 (0.5) N=103 2.2 (5.2) N=69 Abbreviations: C max,ss, maximum plasma concentration at steady state; C trough,ss, trough plasma concentration at steady state; HAwI, hemophilia A with inhibitors; HBwI, hemophilia B with inhibitors. a On concizumab-mtci dosing regimen. Absorption Concizumab-mtci time to maximum plasma concentration ranged from 8 hours to 99 hours (4.1 days) following a single Alhemo subcutaneous dose of 0.05 to 3 mg/kg in healthy and hemophilia subjects. Distribution Concizumab-mtci volume of distribution for a typical 70 kg patient is about 3 L. Elimination Concizumab-mtci is cleared via linear and nonlinear mechanisms. Concizumab-mtci exhibited nonlinear pharmacokinetics due to target-mediated drug disposition (TMDD) which occurs when it forms concizumab-mtci/TFPI complex. Once the target becomes saturated, linear pathway (i.e., catabolism) dominates. Based on population pharmacokinetic analysis, 90% of concizumab-mtci is expected to be eliminated by the end of approximately 4 days after the last dose (time for 50% of drug to be eliminated is approximately 1 day). Metabolism Concizumab-mtci is expected to be metabolized into small peptides by catabolic pathways. Specific Populations No clinically significant differences in the pharmacokinetics of concizumab-mtci were observed based on age (12 years to 79 years), race (White 64.3%, Asian 25.9%, Black 4.9%), hemophilia type (A and B with or without inhibitors). No dedicated studies have been conducted to evaluate the impact of renal or hepatic impairment. As concizumab-mtci is a monoclonal antibody, there is no expectation for concizumab-mtci exposures to be different in patients with renal or hepatic impairment. Body weight The exposure of concizumab-mtci increased with increasing body weight (27 kg to 130.7 kg) [see Use in Specific Populations ( 8.6 )] .