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 ( 1 )

Alhemo injection is a clear to slightly opalescent and colorless to slightly yellow solution that may contain translucent to white particles, available in the following presentations:

• 60 mg/1.5 mL (40 mg/mL) in a single-patient-use prefilled pen
• 150 mg/1.5 mL (100 mg/mL) in a single-patient-use prefilled pen
• 300 mg/3 mL (100 mg/mL) in a single-patient-use prefilled pen Injection:
• 60 mg/1.5 mL (40 mg/mL) in a single-patient-use prefilled pen ( 3 )
• 150 mg/1.5 mL (100 mg/mL) in a single-patient-use prefilled pen ( 3 )
• 300 mg/3 mL (100 mg/mL) in a single-patient-use prefilled pen ( 3 )

Alhemo is contraindicated in patients with a history of known serious hypersensitivity to Alhemo or its components or the inactive ingredients [see Warnings and Precautions ( 5.1 )and Description ( 11 )]. Alhemo is contraindicated in patients with a history of known serious hypersensitivity to Alhemo or its components or the inactive ingredients. ( 4 )

• Thromboembolic Events: Monitor patients for thromboembolic events. Advise patients to report signs and symptoms, and if they occur discontinue prophylaxis. ( 5.1 )
• Hypersensitivity Reactions: In the event of a severe hypersensitivity reaction, discontinue Alhemo. ( 5.2 )
• Increased Laboratory Values of Fibrin D dimer and Prothrombin Fragment 1.2: Alhemo increases values of fibrin D dimer and prothrombin fragment 1.2. ( 5.3 )

5.1 Thromboembolic Events Alhemo may cause thromboembolic events. Venous and arterial thromboembolic events were reported in 1.9% of patients (6/320) in Alhemo clinical trials. These cases occurred in patients with multiple risk factors for thromboembolism, including the use of high doses or prolonged treatment with factor product or bypassing agent (2 of 6 patients). Risk factors for thromboembolism may include the use of high and/or frequent doses of breakthrough bleed treatments (factor products or bypassing agents) or conditions in which tissue factor is overexpressed (e.g., atherosclerotic disease, crush injury, cancer, disseminated intravascular coagulation, thrombotic microangiopathy, or septicemia). Inform Alhemo treated patients of signs and symptoms of thromboembolic events. Monitor patients for thromboembolic events. In case of suspicion of thromboembolic events, discontinue Alhemo and initiate further investigations and management strategies.

5.2 Hypersensitivity Reactions Alhemo can cause hypersensitivity reaction, including serious cases. Alhemo is contraindicated in patients with a history of known serious hypersensitivity to Alhemo or its components or the inactive ingredients. Hypersensitivity reactions including erythema, rash, pruritus, and abdominal pain have occurred in Alhemo treated patients. One patient (less than 1% of patients treated in the clinical studies) experienced anaphylaxis which resolved after treatment with antihistamines and corticosteroids. Instruct patients of the signs of acute hypersensitivity reactions. Instruct patients to contact their healthcare provider for mild reactions and to seek urgent medical attention for moderate to severe reactions. Discontinue Alhemo if severe hypersensitivity symptoms occur and initiate medical management.

5.3 Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment

1.2 Alhemo can cause increased levels of fibrin D-dimer and prothrombin fragment 1.2. Increased levels of fibrin D-dimer and increased levels of prothrombin fragment 1.2 were seen in 29 (9.1%) and 26 (8.1%) of patients, respectively. The plasma concentration of concizumab-mtci is positively correlated with fibrin D-dimer and prothrombin fragments 1.2 indicating a hemostatic effect of concizumab-mtci. For patients taking Alhemo, these coagulation biomarkers may not be reliable predictive markers for clinical decision-making with suspicion of thrombosis such as deep vein thrombosis (DVT) and pulmonary embolism (PE).

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

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 )] .

8.1 Pregnancy Risk Summary Based on its mechanism of action, Alhemo may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on Alhemo use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with Alhemo. Although there are no data on concizumab-mtci, monoclonal antibodies can be actively transported across the placenta, and concizumab-mtci may cause fetal harm. It is unknown whether Alhemo can affect reproductive capacity. Alhemo should only be used during pregnancy if the potential benefit for the mother outweighs the potential risk to the fetus. The estimated background risk of birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.2 Lactation Risk Summary There is no information regarding the presence of Alhemo in either human or animal milk, the effect on the breastfed child, or the effects on milk production. Clinical Considerations Human IgGs are known to be excreted in breast milk during the first few days after birth, decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards, Alhemo could be used during breast-feeding if clinically needed.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential. Contraception Women of childbearing potential should use a highly effective form of contraception during treatment with Alhemo and for 7 weeks after ending treatment. The benefits and thromboembolic risks of the type of contraceptives used should be evaluated by the treating physician.

8.4 Pediatric Use The safety and effectiveness of Alhemo for hemophilia A and B with and without inhibitors have been established in pediatric patients aged 12 years and older. Use of Alhemo for this indication is supported by evidence from adequate and well-controlled studies in adult and pediatric patients aged 12 years and older [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14 )] . The safety and effectiveness of Alhemo for hemophilia A and B with and without inhibitors have not been established in pediatric patients younger than 12 years of age.

8.5 Geriatric Use Clinical studies of Alhemo did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

8.6 Body Weight The exposure of concizumab-mtci increased with increasing body weight [see Clinical Pharmacology ( 12.3 )] . However, patients should receive the approved recommended Alhemo dosage titration and concizumab-mtci plasma concentration monitoring regardless of body weight [see Dosage and Administration ( 2.1 )] .

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.