Takhzyro Drug Information

® 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.

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.

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.

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.

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 16 13 15 44 Upper respiratory infection Includes upper respiratory infection, viral upper respiratory infection 13 3 9 12 24 Headache Includes headache, tension headache, sinus headache 9 3 6 9 18 Rash Includes rash, rash maculopapular, rash erythematous 2 2 3 1 6 Dizziness 0 1 3 1 5 Diarrhea 2 3 0 1 4 Myalgia 0 1 0 3 4 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.

Drug-Laboratory Test Interactions Coagulation tests

TAKHZYRO can increase activated partial thromboplastin time (aPTT) due to an interaction of TAKHZYRO with the aPTT assay. The reagents used in the aPTT laboratory test initiate intrinsic coagulation through the activation of plasma kallikrein in the contact system. Inhibition of plasma kallikrein by TAKHZYRO can increase aPTT in this assay.

In Trial 1, prolongation of aPTT (>1× ULN) was observed at one or more time points in 3, 9, and 11 patients treated with TAKHZYRO 150 mg q4wks, 300 mg q4wks, and 300 mg q2wks, respectively, compared to 5 placebo-treated patients. Only one patient in the 300 mg q2wks treatment group experienced transient aPTT prolongation ≥1.5x ULN which was confounded by ongoing heparin therapy. None of the increases in aPTT in patients treated with TAKHZYRO were associated with abnormal bleeding adverse events.

There were no differences in INR values between treatment groups.

Pregnancy Risk Summary There are no available data on TAKHZYRO use in pregnant women to inform any drug associated risks. Monoclonal antibodies such as lanadelumab-flyo are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. An enhanced pre-and postnatal development (ePPND) study conducted in pregnant monkeys at doses resulting in exposures of up to 33 times the exposure achieved (on an AUC basis) at the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In the ePPND study, pregnant cynomolgus monkeys were administered lanadelumab-flyo once weekly at subcutaneous doses resulting in up to 33 times the exposure at the MRHD (on an AUC basis with maternal subcutaneous doses up to 50 mg/kg/week) from gestation day 20, at the beginning of organogenesis, through to parturition.

There were no lanadelumab-flyo-related effects on maintenance of pregnancy or parturition. Maternal lanadelumab-flyo treatment had no effects on embryo-fetal development, survival, growth, or postnatal development of offspring through 3 months of age. Lanadelumab-flyo crossed the placenta in monkeys.

Offspring were exposed to lanadelumab-flyo at approximately 50% of the maternal plasma concentration out to postnatal day 21 (PND 21). Lanadelumab-flyo concentrations were approximately equivalent in maternal and offspring plasma at PND 90.

Pediatric Use The safety and effectiveness of TAKHZYRO for prophylaxis to prevent attacks of hereditary angioedema (HAE) have been established in pediatric patients 2 years of age and older. Use of TAKHZYRO for this indication in patients 12 years of age and older was supported by a subgroup analysis by age of 10 patients aged 12 to <18 years in Trial 1 (a randomized, double-blind, placebo-controlled parallel-group study in adult and pediatric patients 12 years of age and older with HAE). Results of the subgroup analysis by age were consistent with overall study results. An additional 13 pediatric patients aged 12 to <18 years were enrolled in the open-label extension study.

Use of TAKHZYRO for this indication in patients 2 to less than 12 years of age was supported by extrapolation of efficacy data from Trial 1, an adequate and well controlled study in adult and pediatric (12 to less than 18 years of age) patients, with additional pharmacokinetic analyses showing similar drug exposures between adults (>18 years of age) and pediatric patients (2 to less than 12 years of age), and safety and pharmacodynamic data from an open-label, multicenter study in pediatric patients with HAE aged 2 to less than 12 years that enrolled 21 patients (4 patients were aged 2 to less than 6 years and 17 patients were 6 to less than 12 years of age) . The pharmacodynamic response observed in this trial for pediatric patients 2 to less than 12 years of age was similar to that seen in adult and pediatric patients 12 years of age and older . The safety and effectiveness of TAKHZYRO in pediatric patients less than 2 years of age have not been established.

There is no clinical experience with overdosage of TAKHZYRO.