Lanadelumab-Flyo

1 INDICATIONS AND USAGE TAKHZYRO ® is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 2 years and older. TAKHZYRO is a plasma kallikrein inhibitor (monoclonal antibody) indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 2 years and older. ( 1 )

2 DOSAGE AND ADMINISTRATION For subcutaneous use only. Recommended Dosage: Adult and pediatric patients 12 years of age and older: administer 300 mg every 2 weeks by the patient or caregiver. Dosing interval every 4 weeks may be considered in some patients. ( 2.1 ) Pediatric patients 6 to less than 12 years of age: administer 150 mg every 2 weeks by a healthcare provider or caregiver. Dosing interval every 4 weeks may be considered in some patients. ( 2.2 ) Pediatric patients 2 to less than 6 years of age: administer 150 mg every 4 weeks by a healthcare provider or caregiver. ( 2.2 ) See Full Prescribing Information for Administration Instructions. ( 2.3 ) 2.1 Recommended Dosage for Adult and Pediatric Patients 12 Years of Age and Older The recommended starting dosage in adult and pediatric patients 12 years of age and older is 300 mg administered subcutaneously every 2 weeks (q2wks). A dosing interval of 300 mg every 4 weeks (q4wks) is also effective and may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months. 2.2 Recommended Dosage for Pediatric Patients 2 to Less Than 12 Years of Age Pediatric Patients 6 to Less Than 12 Years of Age The recommended starting dosage in pediatric patients 6 to less than 12 years of age is 150 mg administered subcutaneously q2wks. A dosing interval of 150 mg q4wks may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months. Pediatric Patients 2 to Less Than 6 Years of Age The recommended dosage in pediatric patients 2 to less than 6 years of age is 150 mg administered subcutaneously q4wks. 2.3 Preparation and Administration Instructions TAKHZYRO is administered subcutaneously only. TAKHZYRO is intended for administration by a healthcare provider, patient or caregiver. The patient or caregiver should be trained in subcutaneous injection technique by a healthcare professional. Adult and pediatric patients 12 years of age and older: TAKHZYRO may be administered by the patient or caregiver. Pediatric patients 2 to less than 12 years of age: TAKHZYRO should be administered by a healthcare provider or caregiver. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use TAKHZYRO if the solution appears discolored or contains visible particles. TAKHZYRO is a clear to slightly opalescent, colorless to slightly yellow solution. Administration Instructions for Single-Dose Prefilled Syringes Instruct patients and/or caregiver on proper use of the TAKHZYRO prefilled syringe and assess that they are well trained in subcutaneous injection technique prior to administration by patient and/or caregiver. Avoid vigorous agitation of the prefilled syringe. Take the TAKHZYRO prefilled syringe out of the refrigerator 15 minutes before injecting to allow it to equilibrate to room temperature. Using aseptic technique, inject TAKHZYRO subcutaneously into the abdomen, thigh, or upper arm. Discard any unused portion of drug remaining in the prefilled syringe. For detailed instructions on the preparation and administration of TAKHZYRO see Instructions for Use for either single-dose 1 mL prefilled syringe or single-dose 2 mL prefilled syringe. Administration Instructions for Single-Dose Vial TAKHZYRO vial is provided as a ready-to-use solution that does not require additional reconstitution or dilution for administration. Instruct patients and/or caregivers on proper use of TAKHZYRO from a vial and assess that they are well trained in subcutaneous injection technique prior to administration by patient and/or caregiver. Avoid vigorous agitation of the vial. Take the TAKHZYRO vial out of the refrigerator 15 minutes before injecting to allow it to equilibrate to room temperature. Using aseptic technique, withdraw the prescribed dose of TAKHZYRO from the vial using an 18-gauge needle. Change the needle on the syringe to a 27-gauge, ½-inch needle or other needle suitable for subcutaneous injection. Inject TAKHZYRO subcutaneously into the abdomen, thigh, or upper arm. In clinical studies, the majority of patients self-administered TAKHZYRO over 10 to 60 seconds. TAKHZYRO should be administered within 2 hours of preparing the dosing syringe. After the dosing syringe is prepared, it can be refrigerated at 36°F to 46°F (2°C to 8°C) and must be used within 8 hours. Discard any unused portions of drug remaining in the vial and dosing syringe. For detailed instructions on the preparation and administration of TAKHZYRO see single-dose vial Instructions for Use .

6 ADVERSE REACTIONS The most common adverse reactions (≥10%) are injection site reactions, upper respiratory infections, headache, rash, dizziness, diarrhea, and myalgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-TAKEDA-7 (1-877-825-3327) 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. Adult and Pediatric Patients 12 Years of Age and Older The safety of TAKHZYRO is primarily based on a 26-week, randomized, double-blind, parallel-group and placebo-controlled study (Trial 1) in 125 patients with Type I or II HAE. Eligible patients were also able to participate in an open-label extension study (Trial 2) up to 130 weeks. In Trial 1, a total of 84 patients with HAE aged 12 years and older received at least one dose of TAKHZYRO. Overall, 70% of patients were female and 90% of patients were Caucasian with a mean age of 41 years. The proportion of patients who discontinued study drug prematurely due to adverse events was 1.2% for TAKHZYRO-treated patients and 4.9% for placebo-treated patients. No deaths occurred in the trial. The safety profile of TAKHZYRO was generally similar across all subgroups of patients, including analysis by age, sex, and geographic region. Table 1 shows adverse reactions occurring in ≥10% of patients in any TAKHZYRO treatment group that also occurred at a higher rate than in the placebo treatment group in Trial 1. Table 1 Adverse Reactions Observed in ≥10% of Patients Treated with TAKHZYRO in Trial 1 Adverse Reaction Placebo (N=41) TAKHZYRO 150 mg q4wks (N=28) 300 mg q4wks (N=29) 300 mg q2wks (N=27) Total (N=84) n (%) n (%) n (%) n (%) n (%) N= number of patients; n =number of patients experiencing the event; q2wks = every 2 weeks; q4wks = every 4 weeks Injection site reactions Injection site reactions include: pain, erythema, bruising, hematoma, hemorrhage, pruritus, swelling, induration, paresthesia, reaction, warmth, edema and rash. 14 (34) 16 (57) 13 (45) 15 (56) 44 (52) Upper respiratory infection Includes upper respiratory infection, viral upper respiratory infection 13 (32) 3 (11) 9 (31) 12 (44) 24 (29) Headache Includes headache, tension headache, sinus headache 9 (22) 3 (11) 6 (21) 9 (33) 18 (21) Rash Includes rash, rash maculopapular, rash erythematous 2(5) 2 (7) 3 (10) 1 (4) 6 (7) Dizziness 0 1 (4) 3 (10) 1 (4) 5 (6) Diarrhea 2 (5) 3 (11) 0 1 (4) 4 (5) Myalgia 0 1 (4) 0 3 (11) 4 (5) Injection site reactions primarily consisted mainly of pain, erythema, and bruising at the injection site. There was no meaningful difference in injection site reactions with self-administration. Less Common Adverse Reactions Other adverse reactions that occurred at a higher incidence in TAKHZYRO-treated patients compared to placebo include hypersensitivity (1% vs 0%), increased aspartate transaminase (2% vs 0%), and increased alanine transaminase (2% vs 0%). Safety data from the open-label extension study, consisting of 109 rollover patients from Trial 1 and 103 non-rollover HAE patients, is consistent with controlled safety data from Trial 1. Laboratory Abnormalities Transaminase elevations During the placebo-controlled treatment period in Trial 1, the number of TAKHZYRO-treated patients with maximum transaminase (ALT or AST) levels >8, >5, or >3 times the upper limit of normal (ULN) was 1 (1.2%), 0 (0%), or 3 (3.6%) respectively, compared to 0 in the placebo-treated patients. These transaminase elevations were asymptomatic and transient. No patients had elevated total bilirubin >2× ULN. One TAKHZYRO-treated patient permanently discontinued treatment due to elevated transaminases (4.1× ULN AST). None of the patients were reported to have serious adverse reactions of elevated transaminases. Pediatric Patients 2 to Less Than 12 Years of Age The safety of TAKHZYRO was evaluated at 150 mg/mL (150 mg q4wks for patients 2 to <6 years or 150 mg q2wks with the option for 150 mg q4wks if the patient is well-controlled for 6 months for patients 6 to <12 years) in an open-label, multicenter study with 21 patients aged 2 to less than 12 years. No new safety signals were observed in these patients.

12.3 Pharmacokinetics Following subcutaneous administration, the pharmacokinetics of lanadelumab-flyo was approximately dose-proportional in the therapeutic dose range in patients with HAE (Table 2). The pharmacokinetic properties and exposure (steady state) of lanadelumab-flyo in HAE patients, following subcutaneous administration of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, are provided in Table 2 . Following subcutaneous administration of TAKHZYRO, peak plasma concentrations are reached within 5 days, and terminal elimination half-life is ~ 2 weeks. The anticipated time to reach steady state concentration was approximately 70 days. At steady-state, the mean accumulation ratio is approximately 1.44, 1.42, and 2.43 for dosing regimen of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, respectively. Table 2 Mean (SD) Pharmacokinetic Parameters of Lanadelumab-flyo Following Subcutaneous Administration (Trial 1) Pharmacokinetic Parameters Lanadelumab-flyo 150 mg q4wks (N=28) 300 mg q4wks (N=29) 300 mg q2wks (N=27) CL/F: apparent clearance; Vc/F: apparent volume of distribution; AUC tau,ss : area under the curve over the dosing interval at steady-state; C max,ss : maximum concentration at steady-state; C min,ss : minimum concentration at steady state; T max : time to maximum concentration; t 1/2 terminal elimination half-life. CL/F (L/day) 0.667 (0.162) 0.742 (0.239) 0.809 (0.370) Vc/F (L) 14.1 (2.93) 14.9 (4.45) 16.6 (4.79) AUC tau,ss (µg*day/mL) 233 (56.6) 441(137) 408 (138) C max,ss (µg/mL) 12.0 (3.01) 23.3 (7.94) 34.4 (11.2) C min,ss (µg/mL) 4.81 (1.40) 8.77 (2.80) 25.4 (9.18) t max (day) 5.17 (1.09) 5.17 (1.12) 4.11 (0.377) t 1/2 (day) 14.9 (2.00) 14.2 (1.89) 15.0 (2.48) Specific Populations Population pharmacokinetic analyses showed that age, gender and race did not meaningfully influence the pharmacokinetics of lanadelumab-flyo after correcting for body weight. Body weight was identified as an important covariate describing the variability of clearance and volume of distribution, resulting in higher exposure (AUC and C max ) in lighter patients. However, this difference is not considered to be clinically relevant and no dose adjustments are recommended for any of these demographics. Pediatric Population Based on population pharmacokinetics (PK) analyses, the geometric mean lanadelumab-flyo average concentration at steady state (C ave ) was approximately 25% higher following subcutaneous administration of TAKHZYRO 300 mg q2wks in pediatric patients 12 to less than 18 years of age than the mean C ave in adult patients under the same dosing regimen, due to lower body weight in pediatric patients. Lanadelumab-flyo exposures in pediatric patients 2 to less than 12 years of age receiving TAKHZYRO 150 mg q2wks or q4wks are comparable to those in adult patients receiving TAKHZYRO 300 mg q2wks. The geometric mean lanadelumab-flyo C ave was approximately 7% higher following subcutaneous administration of TAKHZYRO 150 mg q2wks in pediatric patients 6 to less than 12 years of age compared to the mean C ave in adult patients receiving 300 mg q2wks. The mean lanadelumab-flyo C ave was approximately 14% lower following subcutaneous administration of TAKHZYRO 150 mg q4wks in pediatric patients 2 to less than 6 years of age compared to the mean C ave in adult patients receiving 300 mg q2wks. Renal Impairment No dedicated studies have been conducted to evaluate the PK of lanadelumab-flyo in renal impairment patients. Based on population pharmacokinetic analysis, renal impairment (estimated GFR: 60 to 89 mL/min/1.73m 2 , [mild, N=98] and 30 to 59 mL/min/1.73m 2 , [moderate, N=9]) had no effect on the clearance or volume of distribution of lanadelumab-flyo. Concomitant medications The use of analgesic, antibacterial, antihistamine, anti-inflammatory and anti-rheumatic medications had no effect on clearance and volume of distribution of lanadelumab-flyo. For breakthrough HAE attacks, use of rescue medications such as plasma-derived and recombinant C1-INH, icatibant or ecallantide had no effects on clearance and volume of distribution of lanadelumab-flyo.