Ilumya

Each ml contains Tildrakizumab 100 mg.
ILUMYA is a sterile solution for injection.
It is a clear to slightly opalescent and colourless to slightly yellow solution.
Excipients/Inactive Ingredients: L-histidine, L-histidine hydrochloride monohydrate, Polysorbate 80, Sucrose, Water for injection.

Pharmacology: 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.
Pharmacodynamics: No formal pharmacodynamics studies have been conducted with ILUMYA.
Clinical Studies: In two multicenter, randomized, double-blind, placebo-controlled trials (Trial 2 [NCT01722331] and Trial 3 [NCT01729754]), 926 subjects were treated with ILUMYA 100 mg (N=616) or placebo (N=310). Subjects had a Physician Global Assessment (PGA) score of ≥3 (moderate) on a 5-point scale of overall disease severity, Psoriasis Area and Severity Index (PASI) score ≥12, and a minimum body surface area (BSA) involvement of 10%. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded.
In both trials, subjects were randomized to either placebo or ILUMYA (100 mg at Week 0, Week 4, and every twelve weeks thereafter [Q12W]) up to 64 weeks.
Trials 2 and 3 assessed the changes from baseline to Week 12 in the two co-primary endpoints: PASI 75, the proportion of subjects who achieved at least a 75% reduction in the PASI composite score.
PGA of 0 ("cleared") or 1 ("minimal"), the proportion of subjects with a PGA of 0 or 1 and at least a 2-point improvement.
Other evaluated outcomes in Trials 2 and 3 included the proportion of subjects who achieved a reduction from baseline in PASI score of at least 90% (PASI 90) and a reduction of 100% in PASI score (PASI 100) at Week 12 and maintenance of efficacy up to Week 64.
In both trials, subjects in the ILUMYA 100 mg and placebo treatment groups were predominantly men (69%) and White (80%), with a mean age of 46 years. At baseline, these subjects had a median affected BSA of 27%, a median PASI score of 17.8, and approximately 33% had a PGA score of 4 ("marked") or 5 ("severe"). Approximately 34% had received prior phototherapy, 39% had received prior conventional systemic therapy, and 18% had received prior biologic therapy for the treatment of psoriasis. Approximately 16% of subjects had a history of psoriatic arthritis.
Clinical Response at Week 12: The results of Trials 2 and 3 are presented in Table 1. (See Table 1.)

Click on icon to see table/diagram/image

Examination of age, gender, race, and previous treatment with a biologic did not identify differences in response to ILUMYA among these subgroups at Week 12.
Maintenance of Response and Durability of Response: In Trial 2, subjects originally randomized to ILUMYA and who were responders at Week 28 (i.e., PASI 75) were re-randomized to an additional 36 weeks of either maintaining the same dose of ILUMYA Q12W (every twelve weeks) or placebo.
At Week 28, 229 (74%) subjects treated with ILUMYA 100 mg were PASI 75 responders. At Week 64, 84% of subjects who continued on ILUMYA 100 mg Q12W maintained PASI 75 compared to 22% of subjects who were re-randomized to placebo. In addition, for subjects who were re-randomized and also had a PGA score of 0 or 1 at Week 28, 69% of subjects who continued on ILUMYA 100 mg Q12W maintained this response (PGA 0 or 1) at Week 64 compared to 14% of subjects who were rerandomized to placebo.
For PASI 75 responders at Week 28 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to loss of PASI 75 was approximately 20 weeks.
In addition, for subjects who were re-randomized to placebo and also had a PGA score of 0 or 1 at Week 28, the median time to loss of PGA score of 0 or 1 was approximately 16 weeks.
Psoriasis of the Scalp: In a multicenter, randomized, double-blind, placebo-controlled trial (Trial 4 [NCT03897088]) 231 subjects with moderate to severe psoriasis of the scalp were treated with ILUMYA 100 mg (N=117) or placebo (N=114) at Week 0 and 4 and every 12 weeks thereafter. Of the 231 randomized subjects, 217 subjects completed Part 1 (Day 1 to Week 16). For Week 16 to Week 52, subjects randomized to placebo were switched to ILUMYA receiving 100 mg at Weeks 16, 20, 32, and 44.
The primary endpoint was the proportion of subjects with IGA score for the scalp of "clear" and "almost clear" with at least 2-point reduction from Baseline at Week 16.
Other evaluated outcomes included the proportion of subjects achieving a) Psoriasis Scalp Severity Index (PSSI) 90 (≥90% improvement from Baseline in PSSI) at Week 16; b) subjects achieving PSSI 90 at Week 12; and c) IGA for the scalp score of "clear" or "almost clear" with at a least a 2-point reduction from Baseline at Week 12.
Subjects in the ILUMYA and placebo treatment groups were predominantly men (60.2%) and White (78.9%), with a mean age of 44.8 years. At baseline, these subjects had a median affected scalp surface area (SSA) of 50%, a median PASI score of 16.7, and PGA score of 3 ("moderate") or 4 ("severe") in 87.1% and 12.3%, respectively.
Clinical Response at Week 16: The results from Trial 4 are presented in Table 2. (See Table 2.)

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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%).
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.
Elimination: The geometric mean (CV%) systemic clearance was 0.32 L/day (38%) and the half-life was approximately 23 days (23%).
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.
Pediatric: Safety and effectiveness of ILUMYA in pediatric patients (<18 years of age) have not been established.
Geriatric: A total of 1083 subjects were exposed to ILUMYA 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.
Body Weight: Tildrakizumab concentrations were lower in subjects with higher body weight.
Drug Interaction Studies: Cytochrome P450 Substrates: The AUC_inf 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 AUC_inf of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) were observed.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ILUMYA.
No effects on fertility parameters were observed in male or female cynomolgus monkeys that were administered tildrakizumab at subcutaneous or intravenous doses up to 140 mg/kg once every two weeks for 3 months (133 or 155 times the MRHD, respectively, based on AUC comparison). The monkeys were not mated to evaluate fertility.

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

Recommended Dose: The recommended dosage is 100 mg at Weeks 0, 4, and every 12 weeks thereafter. Each syringe contains 1 mL of 100 mg/mL tildrakizumab.
Tuberculosis Assessment Prior to Initiation of ILUMYA: Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with ILUMYA (see Precautions).
Mode of Administration: ILUMYA is administered by subcutaneous injection. Injection sites should be alternated. ILUMYA should not be injected into areas where the skin is affected by plaque psoriasis or is tender, bruised, red, hard, thick, or scaly. The prefilled syringe must not be shaken. Each prefilled syringe is for single use only.
Inject the full amount of tildrakizumab according to the instructions for use provided in the package insert.
After proper training in subcutaneous injection technique, patients may self-inject ILUMYA if a physician determines that it is appropriate. However, the physician should ensure appropriate follow-up of patients. Patients should be instructed to inject the full amount of ILUMYA according to the instructions provided in the package leaflet. Comprehensive instructions for administration are given in the package insert.
Preparation and Administration of ILUMYA: Before injection, remove ILUMYA carton from the refrigerator, and let the prefilled syringe (in the ILUMYA carton with the lid closed) sit at room temperature for 30 minutes.
Follow the instructions on the ILUMYA carton to remove the prefilled syringe correctly, and remove only when ready to inject. Do not pull off the needle cover until ready to inject.
Inspect ILUMYA visually for particulate matter and discoloration prior to administration. ILUMYA 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 ILUMYA subcutaneously as recommended (see as previously mentioned).
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 any unused portion. Dispose of used syringe.

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

ILUMYA is contraindicated in patients with a previous serious hypersensitivity reaction to tildrakizumab or to any of the excipients (see Precautions).

Hypersensitivity: Cases of angioedema and urticaria occurred in ILUMYA treated subjects in clinical trials. If a serious hypersensitivity reaction occurs, discontinue ILUMYA immediately and initiate appropriate therapy (see Adverse Reactions).
Infections: ILUMYA may increase the risk of infection. Although infections were slightly more common in the ILUMYA group (23%), the difference in frequency of infections between the ILUMYA 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 ILUMYA group than in the placebo group (see Adverse Reactions).
The rates of serious infections for the ILUMYA group and the placebo group were ≤0.3%. Treatment with ILUMYA 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 ILUMYA. 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 ILUMYA until the infection resolves (see Adverse Reactions).
Pretreatment Evaluation for Tuberculosis: Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with ILUMYA. Initiate treatment of latent TB prior to administering ILUMYA. In clinical trials, of 55 subjects with latent TB who were concurrently treated with ILUMYA 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 ILUMYA. Monitor patients for signs and symptoms of active TB during and after ILUMYA treatment. Consider anti-TB therapy prior to initiation of ILUMYA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Do not administer ILUMYA to patients with active TB infection.
Immunizations: Prior to initiating therapy with ILUMYA, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid the use of live vaccines in patients treated with ILUMYA. No data are available on the response to live or inactive vaccines.

Pregnancy: Risk Summary: Limited available data with ILUMYA 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, ILUMYA 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. 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.
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.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ILUMYA and any potential adverse effects on the breastfed child from ILUMYA 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. The mean tildrakizumab concentrations in milk were approximately 0.09-0.2% of that in serum on postpartum days 28 and 91.

The following serious adverse reactions are discussed elsewhere in the labeling: Hypersensitivity Reactions (see Precautions).
Infections (see Precautions).
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 ILUMYA, of which 1083 subjects were treated with ILUMYA 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 ILUMYA (100 mg administered subcutaneously at Weeks 0 and 4, followed by every 12 weeks [Q12W]) (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
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 ILUMYA group compared to 53.8% of subjects in the placebo group. The rates of serious adverse events were 1.4% in the ILUMYA group and 1.7% in the placebo group.
Table 3 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the ILUMYA group than in the placebo group. (See Table 3.)

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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 ILUMYA 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 ILUMYA-treated subjects in clinical trials (see Precautions).
Infections: Infections were slightly more common in the ILUMYA group. The difference in frequency of infections between the ILUMYA 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 ILUMYA 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 ILUMYA use and the frequency of the adverse reactions was similar to that observed during the placebo-controlled period.
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 ILUMYA 100 mg developed antibodies to tildrakizumab. Of the subjects who developed antibodies to tildrakizumab, approximately 40% (2.5% of all subjects receiving ILUMYA) had antibodies that were classified as neutralizing. Development of neutralizing antibodies to tildrakizumab was associated with lower serum tildrakizumab concentrations and reduced efficacy.

Live Vaccinations: Avoid use of live vaccines in patients treated with ILUMYA (see Precautions).

Refrigerate 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. Discard if not used within 30 days. Do not store ILUMYA above 25°C (77°F).

Immunosuppressants / Psoriasis, Seborrhea & Ichthyosis Preparations

L04AC17 - tildrakizumab ; Belongs to the class of interleukin inhibitors. Used as immunosuppressants.

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