Concizumab

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

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.

Administer Alhemo by subcutaneous injection to the abdomen or thigh with daily rotation of injection sites. 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 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.

Alhemo is contraindicated in patients with a history of known serious hypersensitivity to Alhemo or its components or the inactive ingredients.

• Thromboembolic Events: Monitor patients for thromboembolic events. Advise patients to report signs and symptoms, and if they occur discontinue prophylaxis. • Hypersensitivity Reactions: In the event of a severe hypersensitivity reaction, discontinue Alhemo. • Increased Laboratory Values of Fibrin D dimer and Prothrombin Fragment 1.2: Alhemo increases values of fibrin D dimer and prothrombin fragment 1.2.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Thromboembolic Events • Hypersensitivity Reactions • Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment The most frequently reported adverse reactions (incidence ≥5%) were injection site reactions, headache and urticaria.

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.

Before first use: Store in a refrigerator at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not freeze. After first use: Store in a refrigerator at 36℉ to 46˚F (2℃ to 8˚C) or at room temperature below 86˚F (30˚C) for up to 28 days. Do not freeze or store it close to a cooling element in a refrigerator (the part that cools the refrigerator). Store Alhemo with the cap on and in the original carton to protect from light. Alhemo should not be stored in direct sunlight, and the Alhemo pen should be kept away from direct heat. Do not use Alhemo if it has been frozen or stored at temperatures above 86˚F (30˚C).