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Tildrakizumab-asmn Injection

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Tildrakizumab-asmn is a humanized IgG1/k antibody that specifically binds to the p19 subunit of interleukin-23 (IL-23).

Tildrakizumab-asmn is produced in a recombinant Chinese hamster ovary (CHO) cell line and has an approximate molecular mass of 147 kilodaltons.

Tildrakizumab-asmn injection, for subcutaneous use, is a sterile, clear to slightly opalescent, colorless to slightly yellow solution. Tildrakizumab is supplied in a single-dose prefilled syringe with a glass barrel and 29-gauge fixed, 1/2-inch needle.

The syringe is fitted with a passive needle guard and a needle cover.

Each 1 mL single-dose prefilled syringe contains 100 mg of tildrakizumab-asmn formulated in: L-histidine (0.495 mg), L-histidine hydrochloride monohydrate (1.42 mg), polysorbate 80 (0.5 mg), sucrose (70.0 mg), and Water for Injection, USP with a pH of 5.7-6.3.

2. INDICATIONS AND USAGE

Tildrakizumab is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

3. DOSAGE AND ADMINISTRATION

3.1 Dosage

Tildrakizumab is administered by subcutaneous injection. The recommended dose is 100 mg at Weeks 0, 4, and every twelve weeks thereafter. Each syringe contains 1 mL of 100 mg/mL tildrakizumab-asmn.

3.2 Tuberculosis Assessment Prior to Initiation of Tildrakizumab

Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with tildrakizumab [see Warnings and Precautions (5.3)].

3.3 Important Administration Instructions

Tildrakizumab should only be administered by a healthcare provider. Administer tildrakizumab subcutaneously. Each pre-filled syringe is for single-dose only. Inject the full amount (1 mL), which provides 100 mg of tildrakizumab per syringe. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regularly scheduled interval.

3.4 Preparation and Administration of Tildrakizumab

Before injection, remove tildrakizumab carton from the refrigerator, and let the prefilled syringe (in the tildrakizumab carton with the lid closed) sit at room temperature for 30 minutes.

Follow the instructions on the tildrakizumab carton to remove the prefilled syringe correctly, and remove only when ready to inject. Do not pull off the needle cover until you are ready to inject.

Inspect tildrakizumab visually for particulate matter and discoloration prior to administration. Tildrakizumab is a clear to slightly opalescent, colorless to slightly yellow solution. Do not use if the liquid contains visible particles or the syringe is damaged. Air bubbles may be present; there is no need to remove them.

Choose an injection site with clear skin and easy access (such as abdomen, thighs, or upper arm). Do not administer 2 inches around the navel or where the skin is tender, bruised, erythematous, indurated, or affected by psoriasis. Also do not inject into scars, stretch marks, or blood vessels.

 While holding the body of the syringe, pull the needle cover straight off (do not twist) and discard.

 Inject tildrakizumab subcutaneously as recommended [see Dosage and Administration (3.3)].

 Press down the blue plunger until it can go no further. This activates the safety mechanism that will ensure full retraction of the needle after the injection is given.

 Remove the needle from the skin entirely before letting go of the blue plunger. After the blue plunger is released, the safely lock will draw the needle inside the needle guard.

 Discard of any unused portion. Dispose of used syringe.

4. CONTRAINDICATIONS

Tildrakizumab is contraindicated in patients with a previous serious hypersensitivity reaction to tildrakizumab or to any of the excipients [see Warnings and Precautions (5.1)].

5. WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

Cases of angioedema and urticaria occurred in tildrakizumab treated subjects in clinical trials. If a serious hypersensitivity reaction occurs, discontinue tildrakizumab immediately and initiate appropriate therapy [see Adverse Reactions (6.1)].

5.2 Infections

Tildrakizumab may increase the risk of infection. Although infections were slightly more common in the tildrakizumab group (23%), the difference in frequency of infections between the tildrakizumab group and the placebo group was less than 1% during the placebo-controlled period. However, subjects with active infections or a history of recurrent infections were not included in clinical trials. Upper respiratory infections occurred more frequently in the tildrakizumab group than in the placebo group [see Adverse Reactions (6.1)].

The rates of serious infections for the tildrakizumab group and the placebo group were ≤0.3%. Treatment with tildrakizumab should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.

In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing tildrakizumab. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection or is not responding to standard therapy, monitor the patient closely and consider discontinuation of tildrakizumab until the infection resolves [see Adverse Reactions (6.1)].

5.3 Pretreatment Evaluation for Tuberculosis

Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with tildrakizumab. Initiate treatment of latent TB prior to administering tildrakizumab. In clinical trials, of 55 subjects with latent TB who were concurrently treated with tildrakizumab and appropriate TB prophylaxis, no subjects developed active TB (during the mean follow-up of 56.5 weeks). One other subject developed TB while receiving tildrakizumab. Monitor patients for signs and symptoms of active TB during and after tildrakizumab treatment. Consider anti-TB therapy prior to initiation of tildrakizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Do not administer tildrakizumab to patients with active TB infection.

5.4 Immunizations

Prior to initiating therapy with tildrakizumab, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid the use of live vaccines in patients treated with tildrakizumab. No data are available on the response to live or inactive vaccines.

6. ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

 Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

 Infections [see Warnings and Precautions (5.2)]

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.

In clinical trials, a total of 1994 subjects with plaque psoriasis were treated with tildrakizumab, of which 1083 subjects were treated with tildrakizumab 100 mg. Of these, 672 subjects were exposed for at least 12 months, 587 for 18 months, and 469 for 24 months.

Data from three placebo-controlled trials (Trials 1, 2, and 3) in 705 subjects (mean age 46 years, 71% males, 81% white) were pooled to evaluate the safety of tildrakizumab (100 mg administered subcutaneously at Weeks 0 and 4, followed by every 12 weeks [Q12W]) [see Clinical Studies].

Placebo-Controlled Period (Weeks 0-16 of Trial 1 and Weeks 0-12 of Trials 2 and 3)

In the placebo-controlled period of Trials 1, 2, and 3 in the 100 mg group, adverse events occurred in 48.2% of subjects in the tildrakizumab group compared to 53.8% of subjects in the placebo group. The rates of serious adverse events were 1.4% in the tildrakizumab group and 1.7% in the placebo group.

Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the tildrakizumab group than in the placebo group.

Table 1: Adverse Reactions Occurring in ≥1% of Subjects in the Tildrakizumab Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Trials 1, 2, and 3

* Upper respiratory infections include nasopharyngitis, upper respiratory tract infection, viral upper respiratory tract infection, and pharyngitis.

† Injection site reactions include injection site urticaria, pruritus, pain, reaction, erythema, inflammation, edema, swelling, bruising, hematoma, and hemorrhage.

During the placebo-controlled period of Trials 1, 2, and 3, adverse reactions that occurred at rates less than 1% but greater than 0.1% in the tildrakizumab group and at a higher rate than in the placebo group included dizziness and pain in extremity.

Specific Adverse Reactions

Hypersensitivity Reactions

Cases of angioedema and urticaria occurred in tildrakizumab-treated subjects in clinical trials [see Warnings and Precautions (5.1)].

Infections

Infections were slightly more common in the tildrakizumab group. The difference in frequency of infections between the tildrakizumab group (23%) and the placebo group was less than 1% during the placebo-controlled period. The most common (≥1%) infections were upper respiratory infections. The rates of severe infections for the tildrakizumab group and the placebo group were ≤0.3%.

Safety Through Week 52/64

Through Week 52 (Trials 1 and 3) and Week 64 (Trial 2), no new adverse reactions were identified with tildrakizumab use and the frequency of the adverse reactions was similar to that observed during the placebo-controlled period.

6.2 Immunogenicity

As with all therapeutic proteins there is the potential for immunogenicity. 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 incidence of antibodies to tildrakizumab in the studies described below with the incidences of antibodies in other studies or to other products may be misleading.

Up to Week 64, approximately 6.5% of subjects treated with tildrakizumab 100 mg developed antibodies to tildrakizumab. Of the subjects who developed antibodies to tildrakizumab, approximately 40% (2.5% of all subjects receiving tildrakizumab) had antibodies that were classified as neutralizing. Development of neutralizing antibodies to tildrakizumab was associated with lower serum tildrakizumab concentrations and reduced efficacy.

7. DRUG INTERACTIONS

7.1 Live Vaccinations

Avoid use of live vaccines in patients treated with tildrakizumab [see Warnings and Precautions (5.4)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited available data with tildrakizumab use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Human IgG is known to cross the placental barrier; therefore, tildrakizumab may be transferred from the mother to the fetus. An embryofetal developmental study conducted with tildrakizumab in pregnant monkeys revealed no treatment-related effects to the developing fetus when tildrakizumab was administered subcutaneously during organogenesis to near parturition at doses up to 159 times the maximum recommended human dose (MRHD). When dosing was continued until parturition, a small increase in neonatal death was observed at 59 times the MRHD [see Data]. The clinical significance of this nonclinical finding is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryofetal developmental study, subcutaneous doses up to 300 mg/kg tildrakizumab were administered to pregnant cynomolgus monkeys once every two weeks during organogenesis to gestation day 118 (22 days from parturition). No maternal or embryofetal toxicities were observed at doses up to 300 mg/kg (159 times the MRHD of 100 mg, based on AUC comparison). Tildrakizumab crossed the placenta in monkeys.

In a pre- and postnatal developmental study, subcutaneous doses up to 100 mg/kg tildrakizumab were administered to pregnant cynomolgus monkeys once every two weeks from gestation day 50 to parturition. Neonatal deaths occurred in the offspring of one control monkey, two monkeys at 10 mg/kg dose (6 times the MRHD based on AUC comparison), and four monkeys at 100 mg/kg dose (59 times the MRHD based on AUC comparison). The clinical significance of these nonclinical findings is unknown. No tildrakizumab-related adverse effects were noted in the remaining infants from birth through 6 months of age.

8.2 Lactation

Risk Summary

There are no data on the presence of tildrakizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is known to be present in human milk. Tildrakizumab was detected in the milk of monkeys [see Data].

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tildrakizumab and any potential adverse effects on the breastfed child from tildrakizumab or from the underlying maternal condition.

Data

Animal Data

Very low levels of tildrakizumab were detected in breast milk of monkeys in the pre- and postnatal developmental study described in 8.1. The mean tildrakizumab concentrations in milk were approximately 0.09 – 0.2% of that in serum on postpartum days 28 and 91.

8.4 Pediatric Use

Safety and effectiveness of tildrakizumab in pediatric patients (<18 years of age) have not been established.

8.5 Geriatric Use

A total of 1083 subjects were exposed to tildrakizumab 100 mg during Phase 2 and 3 trials. A total of 92 subjects were 65 years or older, and 17 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects [see Clinical Pharmacology].

9. OVERDOSAGE

In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately.

10. MECHANISM OF ACTION

Tildrakizumab is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines.

11. PHARMACODYNAMICS

No formal pharmacodynamics studies have been conducted with tildrakizumab.

12. PHARMACOKINETICS

Tildrakizumab pharmacokinetics increases proportionally over a dose range from 50 mg to 200 mg (0.5 to 2 times the approved recommended dosage) following subcutaneous administration in subjects with plaque psoriasis. Steady-state concentrations were achieved by Week 16 following subcutaneous administration of tildrakizumab at Weeks 0, 4, and every 12 weeks thereafter. At the 100 mg dose at Week 16, the mean (± SD) steady-state trough concentrations ranged from 1.22 ± 0.94 mcg/mL to 1.47 ± 1.12 mcg/mL. The geometric mean (CV%) steady-state Cmax was 8.1 mcg/mL (34%).

Absorption

The absolute bioavailability of tildrakizumab was estimated to be 73-80% following subcutaneous injection. The peak concentration (Cmax) was reached by approximately 6 days.

Distribution

The geometric mean (CV%) volume of distribution is 10.8 L (24%).

Elimination

The geometric mean (CV%) systemic clearance was 0.32 L/day (38%) and the half-life was approximately 23 days (23%).

Metabolism

The metabolic pathway of tildrakizumab has not been characterized. As a humanized IgG1/k monoclonal antibody, tildrakizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.

Specific Populations

No clinically significant differences in the pharmacokinetics of tildrakizumab were observed based on age (≥18 years). No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of tildrakizumab.

Body Weight

Tildrakizumab concentrations were lower in subjects with higher body weight.

Drug Interaction Studies

Cytochrome P450 Substrates

The AUCinf of dextromethorphan (CYP2D6 substrate) increased by 20% when used concomitantly with tildrakizumab 200 mg (two times the approved recommended dose) administered subcutaneously at Weeks 0 and 4 in subjects with plaque psoriasis. No clinically significant changes in AUCinf of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) were observed.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

ILUMYA (tildrakizumab-asmn) Injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution. ILUMYA is supplied as one single-dose prefilled syringe per carton that delivers 1 mL of a 100 mg/mL solution.

 NDC 0006-4241-00

Each prefilled syringe is equipped with a passive needle guard and a needle cover.

Storage and Handling:

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until the time of use. Do not freeze. Do not shake. ILUMYA can be kept at room temperature at 25°C (77°F) for up to 30 days in the original carton to protect from light. Once stored at room temperature, do not place back in the refrigerator. If not used within 30 days, discard ILUMYA. Do not store ILUMYA above 25°C (77°F).

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Rev 03/18