2.1 Vaccination Prior to Treatment

Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with ADBRY [see Warnings and Precautions (5.4)].

2.2 Important Administration Instructions

• ADBRY is administered by subcutaneous injection.
• ADBRY is intended for use under the guidance of a healthcare provider. Provide proper training to patients and/or caregivers on the preparation and administration according to the "Instructions for Use" [see Instructions for Use]. A patient may self-inject after training in subcutaneous injection technique. In pediatric patients 12 years of age and older, it is recommended that ADBRY be given by or under supervision of an adult.

• For the initial loading dose of 600 mg, administer each of the four ADBRY 150 mg injections at different injection sites within the same body area.

  • For the subsequent 300 mg doses, administer the two ADBRY 150 mg injections at different injection sites within the same body area, rotating the body area with each subsequent set of injections.
• For the initial loading dose of 300 mg, administer the two ADBRY 150 mg injections at different injection sites within the same body area.
  • For the subsequent 150 mg doses, administer one ADBRY 150 mg injection, rotating the body area with each subsequent injection.
• Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection.
• DO NOT inject ADBRY into skin that is tender, damaged, bruised, or scarred.

2.3 Recommended Dosage

The recommended dosage of ADBRY for adults and pediatric patients 12 to 17 years old is:

After 16 weeks of treatment, for adult patients with body weight below 100 kg who achieve clear or almost clear skin, a dosage of 300 mg every 4 weeks may be considered.

2.4 Concomitant Topical Therapies

ADBRY can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas.

2.5 Missed Doses

If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.

2.6 Preparation for Use

• Before injection, remove ADBRY prefilled syringes from the refrigerator and allow to reach room temperature (30 minutes for the 150 mg/mL prefilled syringes) without removing the needle cap.
• After removal from the refrigerator, prefilled syringes may be kept at room temperature up to 30°C (86°F) and must be used within 14 days or discarded.
• Inspect visually for particulate matter and discoloration prior to administration. ADBRY injection is a clear to opalescent, colorless to pale yellow solution. Do not use if the liquid contains visible particulate matter, is discolored or cloudy (other than clear to opalescent, colorless to pale yellow).
• ADBRY does not contain preservatives; therefore, discard any unused product.

5.1 Hypersensitivity

Hypersensitivity reactions including anaphylaxis and angioedema, have been reported with use of ADBRY.

If a serious hypersensitivity reaction occurs, discontinue ADBRY immediately and initiate appropriate therapy.

5.2 Conjunctivitis and Keratitis

Conjunctivitis and keratitis occurred more frequently in atopic dermatitis subjects who received ADBRY. Conjunctivitis was the most frequently reported eye disorder. Most subjects with conjunctivitis or keratitis recovered or were recovering during the treatment period [see Adverse Reactions (6.1)].

Advise patients to report new onset or worsening eye symptoms to their healthcare provider.

5.3 Parasitic (Helminth) Infections

Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if ADBRY will influence the immune response against helminth infections by inhibiting IL-13 signaling.

Treat patients with pre-existing helminth infections before initiating treatment with ADBRY. If patients become infected while receiving ADBRY and do not respond to antihelminth treatment, discontinue treatment with ADBRY until the infection resolves.

5.4 Risk of Infection with Live Vaccines

ADBRY may alter a patient's immunity and increase the risk of infection following administration of live vaccines. Prior to initiating therapy with ADBRY, complete all age appropriate vaccinations according to current immunization guidelines. Avoid use of live vaccines during treatment with ADBRY. Limited data are available regarding coadministration of ADBRY with non-live vaccines [see Clinical Pharmacology (12.2)].

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.

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with ADBRY. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other tralokinumab products may be misleading.

In ECZTRA 1, ECZTRA 2, and ECZTRA 3, and the vaccine-response trial, the incidence of Anti-Drug-Antibodies (ADA) during the initial 16-week treatment period was 1.4% for subjects treated with ADBRY 300 mg every other week and in 1.3% for subjects treated with placebo; neutralizing antibodies were seen in 0.1% of subjects treated with ADBRY and 0.2% of subjects treated with placebo.

Across all trial periods, the ADA incidence for subjects who received ADBRY was 4.6%; 0.9% had persistent ADA and 1.0% had neutralizing antibodies.

No clinically meaningful differences in the pharmacokinetics, safety, or efficacy of tralokinumab-ldrm were observed in patients who tested positive for anti-tralokinumab-ldrm antibody (including neutralizing antibodies).

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of ADBRY have been established for the treatment of moderate-to-severe atopic dermatitis in pediatric patients 12 to 17 years of age whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable .

Use of ADBRY in this age group is supported by a multicenter, randomized, double-blind, placebo-controlled study (ECZTRA 6) in 289 pediatric subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis. The safety and effectiveness were consistent between pediatric subjects 12 to 17 years of age and adult subjects [see Adverse Reactions (6.1) and Clinical Studies (14)].

Safety and effectiveness of ADBRY have not been established in pediatric patients younger than 12 years of age.

8.5 Geriatric Use

Of the 1605 subjects exposed to ADBRY in 5 atopic dermatitis trials in the initial treatment period of up to 16 weeks, 77 subjects were 65 years or older. Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Tralokinumab-ldrm is a human IgG4 monoclonal antibody that specifically binds to human interleukin-13 (IL-13) and inhibits its interaction with the IL-13 receptor α1 and α2 subunits (IL-13Rα1 and IL-13Rα2). IL-13 is a naturally occurring cytokine of the Type 2 immune response. Tralokinumab-ldrm inhibits the bioactivity of IL-13 by blocking IL-13 interaction with IL-13Rα1/IL-4Rα receptor complex. Tralokinumab-ldrm inhibits IL-13-induced responses including the release of proinflammatory cytokines, chemokines and IgE.

12.2 Pharmacodynamics

ADBRY was associated with decreased concentrations of Th2 and Th22 immunity biomarkers in the blood, such as thymus and activation-regulated chemokine (TARC/CCL17), periostin, IL-22, lactate dehydrogenase (LDH) and serum IgE. ADBRY decreased expression of keratin 16 and Ki-67 in AD skin, and upregulated protein expression of loricrin. ADBRY suppressed expression of genes in the Th2 pathway, including CCL17, CCL18 and CCL26 as well as markers of Th17- and Th22-regulated genes in lesional skin. The clinical relevance of these is not fully understood.

12.3 Pharmacokinetics

In adults, the mean (SD) steady-state trough concentration of tralokinumab-ldrm ranged from 98.0 (41.1) mcg/mL to 101.4 (42.7) mcg/mL following administration of ADBRY at 300 mg every other week. Tralokinumab-ldrm exposure increased proportionally over a dosage range up to 2100 mg for a 70 kg subject (30 mg/kg IV) (3.5 times the maximum approved recommended dosage). Steady-state tralokinumab-ldrm concentrations were achieved by week 16 following a 600 mg starting dose and 300 mg every other week.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential for tralokinumab-ldrm.

No effects on fertility parameters such as reproductive organs, menstrual cycle and sperm analysis were observed in male or female sexually mature cynomolgus monkeys that were subcutaneously administered tralokinumab-ldrm at doses up to 350 mg/animal (10 times the MRHD on a mg/kg basis of 10 mg/kg/week) in females once a week for three consecutive menstrual cycles (maximum of 15 doses) or 600 mg/animal (10 times the MRHD on a mg/kg basis of 10 mg/kg/week) in males once a week for 13 weeks. The monkeys were not mated to evaluate fertility.

Adults

The efficacy of ADBRY was assessed in three randomized, double-blind, placebo-controlled trials [ECZTRA 1 (NCT03131648), ECZTRA 2 (NCT03160885), and ECZTRA 3 (NCT03363854)]. Efficacy was assessed in a total of 1934 subjects 18 years of age and older with moderate-to-severe atopic dermatitis (AD) not adequately controlled by topical medication(s). Disease severity was defined by an Investigator's Global Assessment (IGA) score ≥ 3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16 on a scale of 0 to 72, and a minimum body surface area (BSA) involvement of ≥10%. At baseline, 58% of subjects were male, 69% of subjects were White, 50% of subjects had a baseline IGA score of 3 (moderate AD), and 50% of subjects had a baseline IGA score of 4 (severe AD). The baseline mean EASI score was 32 and the baseline weekly averaged Worst Daily Pruritus Numeric Rating Scale (NRS) was 8 on a scale of 0-10.

In all three trials, subjects received subcutaneous injections of ADBRY 600 mg or placebo on Day 0, followed by 300 mg every other week or placebo for 16 weeks. Responders were defined as achieving an IGA 0 or 1 ("clear" or "almost clear") or EASI-75 (improvement of at least 75% in EASI score from baseline) at Week 16.

To evaluate maintenance of response in the monotherapy trials (ECZTRA 1 and ECZTRA 2), subjects responding to initial treatment with ADBRY 300 mg every other week were re-randomized to ADBRY 300 mg every other week, ADBRY 300 mg every 4 weeks or placebo every other week for another 36 weeks following first dose administration. Subjects randomized to placebo in the initial treatment period who achieved a clinical response at Week 16 continued to receive placebo every other week for another 36 weeks. Non-responders at Week 16, and subjects who lost clinical response during the maintenance period were placed on open-label treatment with ADBRY 300 mg every other week and optional use of TCS.

In the combination therapy trial (ECZTRA 3), subjects received either ADBRY 300 mg every other week with TCS or placebo with TCS and as needed topical calcineurin inhibitors (TCI) until Week 16. Subjects in the ADBRY 300 mg with TCS group who achieved clinical response at Week 16 were re-randomized to ADBRY 300 mg every other week with TCS or ADBRY every 4 weeks with TCS for another 16 weeks following first dose administration. Subjects in the placebo with TCS group who achieved clinical response at Week 16 continued on placebo with TCS for another 16 weeks. Subjects who did not achieve clinical response at Week 16 received ADBRY 300 mg every other week for another 16 weeks. A mid-potency TCS (i.e., mometasone furoate 0.1% cream) was dispensed at each dosing visit. Subjects were instructed to apply a thin film of the dispensed TCS as needed once daily to active lesions from Week 0 to Week 32 and were to discontinue treatment with TCS when control was achieved. An additional, lower potency TCS or TCI could be used at the investigator's discretion on areas of the body where use of the supplied TCS was not advisable, such as areas of thin skin.

All three trials assessed the primary endpoints of the proportion of subjects with an IGA 0 or 1 at Week 16 and the proportion of subjects with EASI-75 at Week 16. Secondary endpoints included the reduction of Worst Daily Pruritus NRS (weekly average) of at least 4 points on the 11-point itch NRS from baseline to Week 16.

Pediatric Subjects (12 to 17 Years of Age)

The efficacy and safety of ADBRY monotherapy in pediatric subjects 12 to 17 years of age was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial (ECZTRA 6; NCT03526861) in 289 pediatric subjects 12 to 17 years of age with moderate-to-severe AD defined by IGA score ≥ 3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an EASI score ≥ 16 at baseline, and a minimum BSA involvement of ≥10%. Eligible subjects enrolled into this trial had previous inadequate response to topical medication.

A total of 98 subjects received an initial dose of ADBRY 300 mg followed by 150 mg every other week up to Week 16. Subjects who met the clinical response criteria (IGA of 0 or 1 or EASI-75) at Week 16 without the use of rescue medication were re-randomized in a 1:1 ratio to either ADBRY every other week or every 4 weeks up to Week 52, receiving the same dose as during the initial 16-week treatment period. Subjects who did not meet the clinical response criteria at Week 16 or did not maintain the response during the maintenance treatment period, or used rescue medication during the initial treatment period were transferred to open-label treatment with ADBRY 300 mg every other week with optional use of topical corticosteroids. Subjects randomized to placebo in the initial treatment period who achieved a clinical response at Week 16 continued to receive placebo every other week in the maintenance treatment period.

In this trial, the mean subject age was 14.6 years, the mean weight was 61.5 kg, 48% of subjects were female, 57% were White, 25% were Asian, and 11% were Black. At baseline, 53% of subjects had a baseline IGA score of 3 (moderate AD), 47% of subjects had a baseline IGA score of 4 (severe AD), the mean BSA involvement was 51%, and 21% of subjects had received prior systemic immunosuppressants (cyclosporine, methotrexate, azathioprine and mycophenolate). Also, at baseline the mean EASI score was 32, the baseline Adolescent Worst Pruritus NRS score was 8. Overall, 84% of subjects had at least one co-morbid allergic condition; 68% had allergic rhinitis, 51% had asthma, and 57% had food allergies.

The primary endpoints were the proportion of subjects with IGA 0 or 1 at Week 16 ("clear" or "almost clear") and the proportion of patients with EASI-75 (improvement of at least 75% in EASI from baseline) at Week 16. Secondary endpoints included the reduction in itch, as measured by the proportion of subjects with ≥4 point improvement in Adolescent Worst Pruritus NRS from baseline.

The efficacy results at Week 16 for the pediatric subjects 12 to 17 years of age are presented in Table 3.

In ECZTRA 6, a higher proportion of subjects in the ADBRY 150 mg every other week group achieved EASI-90 compared to placebo.

How Supplied

ADBRY (tralokinumab-ldrm) injection is a sterile, clear to opalescent, colorless to pale yellow solution, supplied in single-dose prefilled syringe with a 27-gauge, ½ inch needle and a needle guard.

Each prefilled syringe delivers 150 mg/mL of ADBRY.

ADBRY is available in pack sizes containing 2 or 4 prefilled syringes with needle guard.

Storage and Handling

ADBRY does not contain preservatives. Discard any unused product remaining in the prefilled syringe.

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

If necessary, prefilled syringes may be kept at room temperature up to 30°C (86°F) for a maximum of 14 days in the original carton. Do not store above 30°C (86°F). Do not put the prefilled syringes back in the refrigerator after they have reached room temperature. If the carton needs to be removed permanently from refrigerator, the date of removal may be recorded on the outer carton in the space provided. After removal from the refrigerator, ADBRY must be used within 14 days or discarded.

Do not expose the prefilled syringe to heat or direct sunlight.

Do not freeze. Do not shake.

Administration Instructions

Instruct patients or caregivers:

• to perform the first self-injection under the supervision and guidance of a qualified healthcare provider for proper training in subcutaneous injection technique.
• to inject the full dose of ADBRY.
• to follow sharps disposal recommendations [see Instructions for Use].

Hypersensitivity

Advise patients to discontinue ADBRY and to seek immediate medical attention if they experience any symptoms of systemic hypersensitivity reactions [see Warnings and Precautions (5.1)].

Conjunctivitis and Keratitis

Advise patients to consult their healthcare provider if new onset or worsening eye symptoms develop [see Adverse Reactions (6.1)].

Risk of Infection with Live Vaccines

Advise patients that ADBRY may increase the risk of infection following administration of live vaccines and that vaccination with live vaccines is not recommended during ADBRY treatment. Instruct patients to inform the healthcare provider that they are taking ADBRY prior to a potential vaccination [see Warnings and Precautions (5.4)].

Pregnancy Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADBRY during pregnancy. Encourage participation and advise patients about how they may enroll in the registry [see Use in Specific Populations (8.1)].