Garadacimab

INDICATIONS AND USAGE ANDEMBRY is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older. ANDEMBRY is an activated Factor XII (FXIIa) inhibitor (monoclonal antibody) indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older. ( 1 )

DOSAGE AND ADMINISTRATION Recommended Dosage : Initial loading dose of 400 mg (two 200 mg injections) administered subcutaneously followed by maintenance dosage of 200 mg once monthly. ( 2.1 ) Subcutaneous use only. ( 2.2 ) Patients may self-administer. See full prescribing information for preparation and administration instructions. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of ANDEMBRY is an initial loading dose of 400 mg (two injections of 200 mg) administered subcutaneously on the first day of treatment followed by a maintenance dosage of 200 mg administered subcutaneously every month. Missed Dose(s) If a dose of ANDEMBRY is missed, administer the dose as soon as possible. 2.2 Preparation and Administration Instructions for ANDEMBRY Prefilled Autoinjector and Prefilled Syringe with Needle Safety Device For subcutaneous use only. ANDEMBRY is intended for self-administration or administration by a caregiver. Prior to treatment initiation, train patients/caregivers on proper preparation and subcutaneous (SC) administration technique of ANDEMBRY [see Instructions for Use ] . Prior to administration, remove ANDEMBRY from the refrigerator and allow to sit for 30 minutes at room temperature before use. Inspect ANDEMBRY visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ANDEMBRY is a slightly opalescent to clear, brownish-yellow to yellow solution. Administer ANDEMBRY subcutaneously into the thigh or abdomen ensuring to stay 1 inch (2 cm) away from the navel. The upper arm can also be used if a caregiver administers the subcutaneous injection. Discard the used ANDEMBRY into a sharps disposal container (closed puncture-resistant container). For detailed instructions on the preparation and administration of ANDEMBRY [see Instructions for Use] .

WARNINGS AND PRECAUTIONS None. None. ( 5 )

CONTRAINDICATIONS None. None. ( 4 )

DRUG INTERACTIONS Drug Interference with Laboratory Test: ANDEMBRY can prolong activated partial thromboplastin time (aPTT) due to an interaction of garadacimab-gxii with the aPTT assay. ( 7.1 ) 7.1 Drug Interference with Laboratory Test Coagulation Tests ANDEMBRY can prolong activated partial thromboplastin time (aPTT) due to an interaction of garadacimab-gxii with the aPTT assay. The reagents used in the aPTT laboratory test initiate intrinsic coagulation through the activation of FXII in the contact system, therefore inhibition of plasma FXIIa by ANDEMBRY can prolong aPTT in this assay [see Adverse Reactions (6.1) ] .

ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 7%) are nasopharyngitis and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-915-6958 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 the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ANDEMBRY reflects the exposure in a total of 164 adult and pediatric patients aged 12 years and older with hereditary angioedema (HAE) from a placebo-controlled study, VANGUARD [see Clinical Studies (14) ] , and an open-label clinical study. Among the 164 patients who received at least one dose of ANDEMBRY 200 mg subcutaneously, 153 (93%) patients were exposed for at least one year. The median duration of ANDEMBRY treatment was 2.6 years. The safety data below is based on the 6-month placebo-controlled study (VANGUARD), in which ANDEMBRY 400 mg was administered subcutaneously as a loading dose followed by 200 mg (N=39) every month in patients with HAE. Demographics of the patients in this study are summarized in Clinical Studies [see Clinical Studies (14) ]. The safety of ANDEMBRY was similar across all subgroups of patients, including analysis by age, sex and geographic region. Table 1 provides the most common adverse reactions with ANDEMBRY with incidence ≥7% and more common than placebo. Table 1 Adverse Reactions with ANDEMBRY with Incidence ≥7% and More Common than Placebo in Patients with HAE (VANGUARD) Adverse Reactions ANDEMBRY (N=39) Placebo (N=25) n (%) n (%) Nasopharyngitis Consists of nasopharyngitis, rhinitis, and upper respiratory infections 8 (21) 3 (12) Abdominal Pain Consists of abdominal pain and abdominal pain lower 3 (8) 0 Specific Adverse Reaction(s): Injection Site Reactions In VANGUARD and an open-label clinical study, which included 57 patients who rolled over from VANGUARD, 164 patients with HAE received ANDEMBRY 200 mg subcutaneously every month. Injection site reactions (e.g., injection site bruising, injection site erythema, injection site hematoma, injection site pruritus, injection site urticaria) were reported in 23 (14%) patients. Laboratory Abnormalities: Prolonged Coagulation Tests (aPTT and PT) In the VANGUARD trial, the incidence of prolonged activated partial thromboplastin time (aPTT), defined as >1.4×ULN, was 3 (8%) patients in the ANDEMBRY group compared to 0 patients in the placebo group. Additionally, the incidence of prolonged prothrombin time (PT) or international normalized ratio (INR), defined as >1.3× ULN, was 6 (15%) patients in the ANDEMBRY group compared to 1 (4%) patient in the placebo group. None of the increases in aPTT, PT and INR were associated with bleeding events [see Drug Interactions (7.1) ] .

Mechanism of Action Garadacimab-gxii is an inhibitor of activated FXII that binds to the catalytic domain of activated Factor XII (FXIIa and βFXIIa) and inhibits its catalytic activity. FXII is the first factor activated in the contact activation pathway and initiates the inflammatory bradykinin-producing kallikrein-kinin system. The inhibition of FXIIa decreases the activation of prekallikrein to kallikrein and the generation of bradykinin, which is associated with inflammation and swelling in HAE attacks, thus reducing the cascade of events leading to an HAE attack.