Garadacimab

1 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 )

2 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] .

6 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) ] .

12.3 Pharmacokinetics The pharmacokinetics of garadacimab-gxii are provided in Table 2 following subcutaneous administration of a single 200 mg dose to healthy volunteers and are presented as mean (SD), unless otherwise specified. Table 2 Garadacimab-gxii Pharmacokinetics Following Subcutaneous Administration The PK of garadacimab-gxii is similar between healthy volunteers and subjects with HAE Parameter Garadacimab-gxii Abbreviations: AUC = area under the plasma concentration-time curve; CI = confidence interval; C max = maximum plasma concentration; C trough,steady state = trough plasma concentration at steady state; T max = time to peak concentration T max is reported as median (range) and absolute bioavailability is reported as estimate (95% CI) Exposure C max 18.4 (7.23) mcg/mL AUC 0-inf 11470 (4103) mcg∙h/mL C trough,Steady State HAE patients enrolled in the VANGUARD trial , Garadacimab-gxii exposure (based on AUC tau and C max ) following the initial subcutaneous administration of loading dose of 400 mg (2 doses of 200 mg) is 133% of steady-state exposures following 200 mg subcutaneous once monthly. 8.09 (4.28) to 8.69 (3.93) mcg /mL Absorption Absolute Bioavailability 39 (34, 43)% T max 6 (2, 15) days Distribution Apparent Volume of Distribution 11.8 (5.17) Liters (L) Elimination Half-Life 17.4 (3.14) days Apparent Clearance 0.02 (0.008) L/h Metabolism Primary Pathway Expected to be metabolized into small peptides by catabolic pathways Specific Populations No clinically significant differences in the pharmacokinetics of garadacimab-gxii were observed based on age (age range: 12 to 73 years), gender, race, body weight (range: 43 to 153 kg), and mild to moderate renal impairment (eGFR 30 to <90 mL/min/1.73 m 2 ). The effect of severe renal impairment (eGFR <30 mL/min/1.73 m 2 ) on garadacimab-gxii pharmacokinetics is unknown. Pediatric Patients No clinically significant difference in garadacimab-gxii C max and AUC tau was observed between pediatric patients (age range: 12 to 17 years) and adults who received the recommended dosage of garadacimab-gxii (200 mg of garadacimab-gxii once monthly). Drug Interactions No dedicated drug interaction studies have been conducted in humans.