TAKHZYRO

Lanadelumab, also known as DX-2930, is a human IgG1 monoclonal antibody designed for subcutaneous self-injection.

It is a fully human immunoglobulin, k-light-chain made in recombinant Chinese Hamster Ovary cells.

It has been granted priority review, breakthrough therapy, and orphan drug designations for rare diseases based on the results of clinical trials.

Lanadelumab was approved for use in patients with hereditary angioedema by the FDA in August 2018, 5 followed by Health Canada in October 2018 12 and the EMA in November 2018.

Lanadelumab is indicated for prophylaxis to prevent attacks in adult and pediatric patients aged 2 years and older with hereditary angioedema. 9, 11 In Canada, it is indicated for use only in adults and adolescents.

In phase 1 studies, the level of kininogen, the substrate of kallikrein, was studied as a marker of kallikrein activity.

In patients with

C1 deficiency, the level of cleaved kininogen is 4-fold higher when compared with C1-normal individuals.

When lanadelumab was administered, the levels of cleaved kininogen were significantly reduced with a dose of and 400 mg of lanadelumab with a maximum reduction at day 22 corresponding with time for maximum concentration.

This maximum reduction corresponded with the normal levels of cleaved kininogen.

Similarly, the decreases of cleaved kininogen corresponded with reductions in the levels of the activated factor XII.

Clinically, the attacks of angioedema completely vanished in the patients receiving a dose of 300 mg of lanadelumab.

In other doses such as 400 mg and combo 300/400 mg the attack reduction reached 90%.

In phase 3 clinical trials, lanadelumab showed an attack rate reduction of over 70% for all studied regimens.

Drug levels of lanadelumab are dose-dependent and the maximum plasma concentration increases correspondingly with increasing dosage.

The C max and

AUC ranged from 3800-45000 ng/ml and 64000-762000 ng.day/ml, respectively, across a dosing range of 30-400 mg.

The bioavailability of lanadelumab is approximately 66% with a time to reach peak drug concentration of approximately 7 days. 9, 4.

The apparent volume of distribution of lanadelumab is approximately 14-16 L depending on the dose administered.

As with other therapeutic proteins, the degradation of lanadelumab likely occurs via catabolism to smaller peptides and amino acids.

Lanadelumab has a half-life of approximately 2 weeks after subcutaneous administration.

The apparent clearance of lanadelumab ranges from 0.667-0.809 L/day depending on the administered dose.

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No significant toxicities related to the administration of lanadelumab have been reported.

Studies regarding the carcinogenic potential or overdosage effect have not been performed.

Published literature supports bradykinin, which is elevated in HAE, as a pro-tumorigenic molecule.

However, the malignancy risk in humans from an antibody that inhibits plasma kallikrein activity, such as lanadelumab-flyo, which lowers bradykinin levels, is currently unknown.

There are no available data on lanadelumab use in pregnant women to inform of 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.

For subcutaneous use only.

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.

Pediatric patients to less than 12 years of age: administer 150 mg every 2 weeks by a healthcare provider or caregiver.

Pediatric patients to less than 6 years of age: administer 150 mg every 4 weeks by a healthcare provider or caregiver.

See Full Prescribing Information for Administration

Instructions. 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 to Less Than 12 Years of Age Pediatric Patients to Less Than 12 Years of Age The recommended starting dosage in pediatric patients 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.

Than 6 Years of Age The recommended dosage in pediatric patients 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 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.

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.

TAKHZYRO subcutaneously into the abdomen, thigh, or upper arm.

In clinical studies, the majority of patients self-administered TAKHZYRO over 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.

TAKHZYRO (lanadelumab-flyo) injection is a ready-to-use, clear to slightly opalescent, colorless to slightly yellow solution supplied in the following presentations.

Single-dose prefilled syringe

Supplied in a carton containing one single-dose prefilled syringe with a bromobutyl rubber stopper, 27-gauge, ½-inch staked needle and rigid needle cap.

NDC 47783-645-01: 150 mg/mL prefilled syringe NDC 47783-646-01: 300 mg/2 mL (150 mg/mL) prefilled syringe Single-dose vial Supplied in a carton containing one single-dose glass vial with chlorobutyl rubber stopper, aluminum crimp seal and polypropylene flip-off cap.

NDC 47783-644-01: 300 mg/2 mL (150 mg/mL) vial Storage and Handling Store the prefilled syringes and vials refrigerated at 36°F to 46°F (2°C to 8°C).

Do not freeze.

Do not shake.

Keep the prefilled syringe and vial in the original carton to protect from light.

Store the prefilled syringes and vials refrigerated at 36°F to 46°F (2°C to 8°C).

Do not freeze.

Do not shake.

Keep the prefilled syringe and vial in the original carton to protect from light.

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 to 4% and to 20%, respectively.

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.

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 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 to <18 years were enrolled in the open-label extension study.

TAKHZYRO for this indication in patients 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 to less than 12 years that enrolled 21 patients (4 patients were aged to less than 6 years and 17 patients were to less than 12 years of age) .

The pharmacodynamic response observed in this trial for pediatric patients to less than 12 years of age was similar to that seen in adult and pediatric patients 12 years of age and older.

TAKHZYRO in pediatric patients less than 2 years of age have not been established.

The safety and effectiveness of

TAKHZYRO were evaluated in a subgroup of patients (N=5) aged ≥65 years in Trial 1.

Results of the subgroup analysis by age were consistent with overall study results.