STELARA

Ustekinumab-aekn, a human IgG1κ monoclonal antibody, is a human interleukin-12 and -23 antagonist.

DNA recombinant technology, ustekinumab-aekn is produced in a murine cell line (Sp2/0).

The manufacturing process contains steps for the clearance of viruses.

Ustekinumab-aekn is comprised of 1326 amino acids and has an estimated molecular mass that ranges from to 149,690 Daltons.

Ustekinumab-aekn injection is a sterile, preservative-free, clear and colorless to slightly yellow solution free of visible particles with pH of 5.7 to 6.3.

Available as 45 mg of ustekinumab-aekn in 0.5 mL and 90 mg of ustekinumab-aekn in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 29-gauge fixed 1/2 inch needle and as 45 mg of ustekinumab-aekn in 0.5 mL in a single-dose borosilicate Type I glass vial with a rubber stopper.

Not made with natural rubber latex.

Each 0.5 mL prefilled syringe or vial delivers 45 mg ustekinumab-aekn, histidine (0.122 mg), L-histidine monohydrochloride monohydrate (0.507 mg), polysorbate 80 (0.02 mg), sucrose (38 mg) and water for injection (q.s).

Each 1 mL prefilled syringe delivers 90 mg ustekinumab-aekn, histidine (0.243 mg), L-histidine monohydrochloride monohydrate (1.013 mg), polysorbate 80 (0.04 mg), sucrose (76 mg) and water for injection (q.s).

Available as 130 mg of ustekinumab-aekn in 26 mL, supplied as a single-dose borosilicate type I glass vial with a rubber stopper.

Each 26 mL vial delivers 130 mg ustekinumab-aekn, edetate disodium (0.47 mg), histidine (20.02 mg), L.

• histidine monohydrochloride monohydrate (27.04 mg), methionine (10.4 mg), polysorbate 80 (10.4 mg), sucrose (2,210 mg), and water for injection (q.s).

Ustekinumab-aekn is a human interleukin-12 and -23 antagonist indicated for the treatment of: Adult patients with: moderate to severe plaque psoriasis (PsO) who are candidates for phototherapy or systemic therapy. active psoriatic arthritis (PsA) . moderately to severely active Crohn’s disease (CD). moderately to severely active ulcerative colitis.

Pediatric patients 6 years and older with: moderate to severe plaque psoriasis (PsO) , who are candidates for phototherapy or systemic therapy. active psoriatic arthritis (PsA) . 1.1 Plaque Psoriasis (PsO) Ustekinumab-aekn is indicated for the treatment of adults and pediatric patients 6 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. 1.2 Psoriatic Arthritis (PsA) Ustekinumab-aekn is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic arthritis. 1.3 Crohn’s Disease (CD) Ustekinumab-aekn is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease. 1.4 Ulcerative Colitis Ustekinumab-aekn is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.

Mechanism of Action Ustekinumab products are human IgG1κ monoclonal antibodies that bind with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines.

IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation.

In in vitro models, ustekinumab products were shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell.

• surface receptor chain, IL-12Rβ1.

The cytokines

IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn’s disease and ulcerative colitis.

In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab products, was shown to be protective. 12.2 Pharmacodynamics Plaque Psoriasis In a small exploratory trial, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post-treatment in subjects with plaque psoriasis.

Ulcerative Colitis In both trial

UC-1 (induction) and trial UC-2 (maintenance), a positive relationship was observed between exposure and rates of clinical remission, clinical response, and endoscopic improvement.

The response rate approached a plateau at the ustekinumab exposures associated with the recommended dosing regimen for maintenance treatment. 12.3 Pharmacokinetics Absorption In adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration (T max ) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg (N=22) and 90 mg (N=24) of ustekinumab.

In healthy subjects (N=30), the median T max value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with plaque psoriasis.

Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28.

The mean (±SD) steady-state trough serum ustekinumab concentrations were 0.69 ± 0.69 mcg/mL for subjects less than or equal to 100 kg receiving a 45 mg dose and 0.74 ± 0.78 mcg/mL for subjects greater than 100 kg receiving a 90 mg dose.

There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.

Following the recommended intravenous induction dose, mean ±SD peak serum ustekinumab concentration was 125.2 ± 33.6 mcg/mL in subjects with Crohn’s disease, and 129.1 ± 27.6 mcg/mL in subjects with ulcerative colitis.

Starting at

Week 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 weeks.

Steady state ustekinumab concentration was achieved by the start of the second maintenance dose.

There was no apparent accumulation in ustekinumab concentration over time when given subcutaneously every 8 weeks.

Mean ±SD steady-state trough concentration was 2.5 ± 2.1 mcg/mL in subjects with Crohn’s disease, and 3.3 ± 2.3 mcg/mL in subjects with ulcerative colitis for 90 mg ustekinumab administered every 8 weeks.

Population pharmacokinetic analyses showed that the volume of distribution of ustekinumab in the central compartment was 2.7 L (95% CI: 2.69, 2.78) in subjects with Crohn’s disease and 3.0 L (95% CI: 2.96, 3.07) in subjects with ulcerative colitis.

The total volume of distribution at steady-state was 4.6 L in subjects with Crohn’s disease and 4.4 L in subjects with ulcerative colitis.

The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all trials in subjects with plaque psoriasis following subcutaneous administration.

Population pharmacokinetic analyses showed that the clearance of ustekinumab was 0.19 L/day (95% CI: 0.185, 0.197) in subjects with Crohn’s disease and 0.19 L/day (95% CI: 0.179, 0.192) in subjects with ulcerative colitis with an estimated median terminal half-life of approximately 19 days for both IBD (Crohn’s disease and ulcerative colitis) populations.

These results indicate the pharmacokinetics of ustekinumab were similar between subjects with Crohn’s disease and ulcerative colitis.

The metabolic pathway of ustekinumab products has not been characterized.

As a human

IgG1κ monoclonal antibody, ustekinumab products are expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

When given the same dose, subjects with plaque psoriasis or psoriatic arthritis weighing more than 100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing 100 kg or less.

The median trough serum concentrations of ustekinumab in subjects of higher weight (greater than 100 kg) in the 90 mg group were comparable to those in subjects of lower weight (100 kg or less) in the 45 mg group.

Geriatric Population A population pharmacokinetic analysis (N=106/1937 subjects with plaque psoriasis greater than or equal to 65 years old) was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab.

There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old.

Pediatric Population Following multiple recommended doses of ustekinumab in pediatric subjects 6 years of age and older with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28.

At Week 28, the mean ±SD steady-state trough serum ustekinumab concentrations were 0.36 ± 0.26 mcg/mL and 0.54 ± 0.43 mcg/mL, respectively, in pediatric subjects to 11 years of age and pediatric subjects 12 years of age and older.

Overall, the observed steady-state ustekinumab trough concentrations in pediatric subjects with plaque psoriasis were within the range of those observed for adult subjects with plaque psoriasis and adult subjects with PsA after administration of ustekinumab.

Drug Interaction Studies The effects of

IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4).

No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with ustekinumab at the approved recommended dosage in subjects with Crohn’s disease.

Population pharmacokinetic analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to a TNF blocker in subjects with psoriatic arthritis.

In subjects with

Crohn’s disease and ulcerative colitis, population pharmacokinetic analyses did not indicate changes in ustekinumab clearance with concomitant use of corticosteroids or immunomodulators (AZA, 6-MP, or MTX); and serum ustekinumab concentrations were not impacted by concomitant use of these medications.

Infections Malignancies Serious Hypersensitivity Reactions Posterior Reversible Encephalopathy Syndrome (PRES) Noninfectious Pneumonia Most common adverse reactions are: Psoriasis and Psoriatic Arthritis (≥3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue.

Crohn’s Disease, induction (≥3%): vomiting.

Crohn’s Disease, maintenance (≥3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis.fda.gov/medwatch. 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.

The safety data reflect exposure to ustekinumab in 3117 adult subjects with plaque psoriasis, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years.

Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the ustekinumab groups during the placebo-controlled period of Ps STUDY and Ps STUDY 2.

Table 5: Adverse Reactions, Reported by ≥1% of Subjects with Plaque Psoriasis and at Higher Rates in the ustekinumab groups through Week in Ps STUDY and Ps STUDY 2 Ustekinumab Placebo 45 mg 90 mg Subjects treated 665 664 666 Nasopharyngitis 51 (8%) 56 (8%) 49 (7%) Upper respiratory tract infection 30 (5%) 36 (5%) 28 (4%) Headache 23 (3%) 33 (5%) 32 (5%) Fatigue 14 (2%) 18 (3%) 17 (3%) Back pain 8 (1%) 9 (1%) 14 (2%) Dizziness 8 (1%) 8 (1%) 14 (2%) Pharyngolaryngeal pain 7 (1%) 9 (1%) 12 (2%) Pruritus 9 (1%) 10 (2%) 9 (1%) Injection site erythema 3 (<1%) 6 (1%) 13 (2%) Myalgia 4 (1%) 7 (1%) 8 (1%) Depression 3 (<1%) 8 (1%) 4 (1%) Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis, and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation).

One case of

PRES occurred during clinical trials in adult subjects with plaque psoriasis.

Infections In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow-up of 12.6 weeks for subjects receiving placebo and 13.4 weeks for ustekinumab-treated subjects), 27% of ustekinumab-treated subjects reported infections (1.39 per patient-years of follow-up) compared with 24% of subjects receiving placebo (1.21 per patient-years of follow-up).

Serious infections occurred in 0.3% of ustekinumab-treated subjects (0.01 per patient-years of follow-up) and in 0.4% of subjects receiving placebo (0.02 per patient-years of follow-up) .

In the controlled and non-controlled portions of clinical trials in subjects with plaque psoriasis (median follow-up of 3.2 years), representing 8998 patient-years of exposure, 72.3% of ustekinumab-treated subjects reported infections (0.87 per patient-years of follow-up).

Serious infections were reported in 2.8% of subjects (0.01 per patient-years of follow-up).

In the controlled and non-controlled portions of clinical trials in subjects with plaque psoriasis (median follow-up of 3.2 years, representing 8998 patient-years of exposure), 1.7% of ustekinumab-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred patient-years of follow-up).

Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated subjects (0.52 per hundred patient-years of follow-up) .

The most frequently observed malignancies other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast.

Malignancies other than non-melanoma skin cancer in ustekinumab-treated subjects during the controlled and uncontrolled portions of trials were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).

The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis.

Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects to 17 years old.

Ps STUDY 4 evaluated safety for up to 56 weeks in 44 pediatric subjects to 11 years old.

The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque psoriasis.

The safety of ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo-controlled trials in adults with active psoriatic arthritis (PsA).

The overall safety profile of ustekinumab in subjects with PsA was consistent with the safety profile seen in clinical trials in adult subjects with plaque psoriasis.

A higher incidence of arthralgia, nausea, and dental infections was observed in ustekinumab-treated subjects when compared with placebo-treated subjects (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials.

Crohn’s Disease The safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] greater than or equal to and less than or equal to 450) in three randomized, double-blind, placebo-controlled, parallel-group, multicenter trials.

These 1407 subjects included 40 subjects who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses.

In trials

CD-1 and CD-2 there were 470 subjects who received ustekinumab 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo.

Subjects who were responders in either trial CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or placebo for 44 weeks in trial CD-3.

Subjects in these 3 trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX)], oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn’s disease.

The overall safety profile of ustekinumab was consistent with the safety profile seen in the clinical trials in adult subjects with plaque psoriasis and psoriatic arthritis.

Common adverse reactions in trials

CD-1 and CD-2 and in trial CD-3 are listed in Tables and 7, respectively.

Table 6: Common Adverse Reactions Through Week in Trials CD-1 and CD-2 occurring in ≥3% of Ustekinumab–Treated Subjects and Higher Than Subjects Receiving Placebo Placebo Ustekinumab 6 mg/kg single intravenous induction dose N=466 N=470 Vomiting 3% 4% Other less common adverse reactions reported in subjects in trials CD-1 and CD-2 included asthenia (1% vs 0.4%), acne (1% vs 0.4%), and pruritus (2% vs 0.4%).

Table 7: Common Adverse Reactions Through Week in Trial CD-3 occurring in ≥3% of Ustekinumab-Treated Subjects and Higher Than Subjects Receiving Placebo Placebo Ustekinumab 90 mg subcutaneous maintenance dose every 8 weeks N=133 N=131 Nasopharyngitis 8% 11% Injection site erythema 0 5% Vulvovaginal candidiasis/mycotic infection 1% 5% Bronchitis 3% 5% Pruritus 2% 4% Urinary tract infection 2% 4% Sinusitis 2% 3%.

Infections In subjects with Crohn’s disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and pneumonia.

In addition, listeria meningitis and ophthalmic herpes zoster were reported in one subject each.

Malignancies With up to one year of treatment in the Crohn’s disease clinical trials, 0.2% of ustekinumab.

• treated subjects (0.36 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient - years) developed non-melanoma skin cancer.

Malignancies other than non-melanoma skin cancers occurred in 0.2% of ustekinumab-treated subjects (0.27 events per hundred patient-years) and in none of the placebo-treated subjects.

Hypersensitivity Reactions Including Anaphylaxis In

CD trials, two subjects reported hypersensitivity reactions following ustekinumab administration.

One subject experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing) after a single subcutaneous administration (0.1% of subjects receiving subcutaneous ustekinumab).

In addition, one subject experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous ustekinumab dose (0.08% of subjects receiving intravenous ustekinumab).

These subjects were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour.

The safety of ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely active ulcerative colitis.

The overall safety profile of ustekinumab in subjects with ulcerative colitis was consistent with the safety profile seen across all approved indications.

Adverse reactions reported in at least 3% of ustekinumab-treated subjects and at a higher rate than placebo were: Induction (UC-1): nasopharyngitis (7% vs 4%).

Maintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%).

Infections In subjects with ulcerative colitis, serious or other clinically significant infections included gastroenteritis and pneumonia.

In addition, listeriosis and ophthalmic herpes zoster were reported in one subject each.

With up to one year of treatment in the ulcerative colitis clinical trials, 0.4% of ustekinumab-treated subjects (0.48 events per hundred patient-years) and 0.0% of subjects receiving placebo (0.00 events per hundred patient-years) developed non-melanoma skin cancer.

Malignancies other than non-melanoma skin cancers occurred in 0.5% of ustekinumab-treated subjects (0.64 events per hundred patient-years) and 0.2% of subjects receiving placebo (0.40 events per hundred patient-years). 6.2 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those ustekinumab.

Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity.

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

Consider contacting the Poison

Help line or a medical toxicologist for additional overdose management recommendations.

Ustekinumab-aekn is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of the excipients in Ustekinumab-aekn.

Clinically significant hypersensitivity to ustekinumab products or to any of the excipients in Ustekinumab-aekn.

Adult Patients with Plaque Psoriasis Subcutaneous Recommended Dosage: Weight Range (kilograms) Dosage less than or equal to 100 kg 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks greater than 100 kg 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks Pediatric Patients 6 Years of Age and Older with Plaque Psoriasis Subcutaneous Recommended Dosage: Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter.

Range (kilograms) Dose less than 60 kg 0.75 mg/kg 60 kg to 100 kg 45 mg greater than 100 kg 90 mg Psoriatic Arthritis Adult Subcutaneous Recommended Dosage: The recommended dosage is 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks.

For patients with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks.

Pediatric 6 years of Age and Older Subcutaneous Recommended Dosage: Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter.

Range (kilograms) Dose less than 60 kg 0.75 mg/kg 60 kg or more 45 mg greater than 100 kg with co.

• existent moderate-to-severe plaque psoriasis 90 mg Crohn’s Disease and Ulcerative Colitis Initial Adult Intravenous Recommended Dosage: A single intravenous infusion using weight-based dosing: Weight Range (kilograms) Recommended Dose up to 55 kg 260 mg (2 vials) greater than 55 kg to 85 kg 390 mg (3 vials) greater than 85 kg 520 mg (4 vials) Crohn’s Disease and Ulcerative Colitis Maintenance Adult Subcutaneous Recommended Dose: A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. 2.1 Recommended Dosage in Plaque Psoriasis Subcutaneous Adult Dosage Regimen For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.

For patients weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.

In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious.

However, 90 mg resulted in greater efficacy in these subjects.

Subcutaneous Pediatric Dosage Regimen Administer

Ustekinumab-aekn subcutaneously at Weeks and 4, then every 12 weeks thereafter.

The recommended dose of

Ustekinumab-aekn for pediatric patients 6 years of age and older with plaque psoriasis based on body weight is shown below (Table 1).

Table 1: Recommended Dose of Ustekinumab-aekn for Subcutaneous Injection in Pediatric Patients 6 Years of Age and Older With Plaque Psoriasis Body Weight of Patient at the Time of Dosing Recommended Dose less than 60 kg 0.75 mg/kg 60 kg to 100 kg 45 mg more than 100 kg 90 mg For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the vial.

Table 2: Injection volumes of Ustekinumab-aekn 45 mg/0.5 mL Vials for Pediatric Patients 6 Years of Age and Older With Plaque Psoriasis and Pediatric Patients 6 Years of Age and Older With Psoriatic Arthritis Weighing Less Than 60 kg Body Weight (kg) at the time of dosing Dose (mg) Volume of injection (mL) 15 11.3 0.12 16 12 0.13 17 12.8 0.14 18 13.5 0.15 19 14.3 0.16 20 15 0.17 21 15.8 0.17 22 16.5 0.18 23 17.3 0.19 24 18 0.20 25 18.8 0.21 26 19.5 0.22 27 20.3 0.22 28 21 0.23 29 21.8 0.24 30 22.5 0.25 31 23.3 0.26 32 24 0.27 33 24.8 0.27 34 25.5 0.28 35 26.3 0.29 36 27 0.3 37 27.8 0.31 38 28.5 0.32 39 29.3 0.32 40 30 0.33 41 30.8 0.34 42 31.5 0.35 43 32.3 0.36 44 33 0.37 45 33.8 0.37 46 34.5 0.38 47 35.3 0.39 48 36 0.4 49 36.8 0.41 50 37.5 0.42 51 38.3 0.42 52 39 0.43 53 39.8 0.44 54 40.5 0.45 55 41.3 0.46 56 42 0.46 57 42.8 0.47 58 43.5 0.48 59 44.3 0.49 Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen. 2.2 Recommended Dosage in Psoriatic Arthritis Subcutaneous Adult Dosage Regimen The recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.

For patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.

Ustekinumab-aekn for pediatric patients 6 years of age and older with psoriatic arthritis, based on body weight, is shown below (Table 3).

Table 3: Recommended Dose of Ustekinumab-aekn for Subcutaneous Injection in Pediatric Patients 6 Years of Age and Older With Psoriatic Arthritis Body Weight of Patient at the Time of Dosing Recommended Dose less than 60 kg 0.75 mg/kg 60 kg or more 45 mg greater than 100 kg with co-existent moderate-to-severe plaque psoriasis 90 mg For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the vial. 2.3 Recommended Dosage in Crohn’s Disease and Ulcerative Colitis I ntravenous Induction Adult Dosage Regimen A single intravenous infusion dose of Ustekinumab-aekn using the weight-based dosage regimen specified in Table 4.

Table 4: Initial Intravenous Dosage of Ustekinumab-aekn Body Weight of Patient at the time of dosing Dose Number of 130 mg/26 mL (5 mg/mL) Ustekinumab-aekn vials 55 kg or less 260 mg 2 more than 55 kg to 85 kg 390 mg 3 more than 85 kg 520 mg 4 Subcutaneous Maintenance Adult Dosage Regimen The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. 2.4 General Considerations for Administration Ustekinumab-aekn is intended for use under the guidance and supervision of a healthcare provider.

Ustekinumab-aekn should only be administered to patients who will be closely monitored and have regular follow-up visits with a healthcare provider.

The appropriate dose should be determined by a healthcare provider using the patient’s current weight at the time of dosing.

In pediatric patients, it is recommended that Ustekinumab-aekn be administered by a healthcare provider.

If a healthcare provider determines that it is appropriate, a patient may self-inject or a caregiver may inject Ustekinumab-aekn after proper training in subcutaneous injection technique.

Instruct patients to follow the directions provided in the Instructions for Use.

Not made with natural rubber latex.

It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, or indurated.

When using the vial, a 1 mL syringe with a 27-gauge, 1/2 inch needle is recommended.

Prior to administration, visually inspect Ustekinumab-aekn for particulate matter and discoloration.

Ustekinumab-aekn is a clear and colorless to slightly yellow solution and free of visible particles.

Do not use

Ustekinumab-aekn if it is discolored or cloudy, or if other particulate matter is present.

Ustekinumab-aekn does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe. 2.5 Preparation and Administration of Ustekinumab-aekn 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and Ulcerative Colitis) Ustekinumab-aekn solution for intravenous infusion must be diluted, prepared and infused by a healthcare professional using aseptic technique.

Calculate the dose and the number of Ustekinumab-aekn vials needed based on patient weight (Table 4).

Each 26 mL vial of Ustekinumab-aekn contains 130 mg of ustekinumab-aekn.

Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection from the 250 mL infusion bag equal to the volume of Ustekinumab-aekn to be added (discard 26 mL sodium chloride for each vial of Ustekinumab-aekn needed, for 2 vials - discard 52 mL, for 3 vials - discard 78 mL, 4 vials - discard 104 mL).

Withdraw 26 mL of Ustekinumab-aekn from each vial needed and add it to the 250 mL infusion bag.

The final volume in the infusion bag should be 250 mL.

Gently mix.

Visually inspect the diluted solution before infusion.

Do not use if visibly opaque particles, discoloration or foreign particles are observed.

Infuse the diluted solution over a period of at least one hour.

Once diluted, the infusion should be completely administered within four hours of the dilution in the infusion bag.

Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer).

Do not infuse

Ustekinumab-aekn concomitantly in the same intravenous line with other agents.

Ustekinumab-aekn does not contain preservatives.

Each vial is for one-time use in only one patient.

Discard any remaining solution.

Dispose any unused medicinal product in accordance with local requirements.

If necessary, the diluted infusion solution may be kept at room temperature up to 25°C (77°F) for up to 4 hours.

Protect the diluted solution from light.

Storage time at room temperature begins once the diluted solution has been prepared.

The infusion should be completed within 4 hours after the dilution in the infusion bag (cumulative time after preparation including the storage and the infusion period).

Do not freeze.

Discard any unused portion of the infusion solution.

Ustekinumab-aekn injection, is a sterile, preservative-free, clear and colorless to slightly yellow solution and free of visible particles for subcutaneous use.

It is supplied as individually packaged, single-dose prefilled syringes or single-dose vials.

Syringes 45 mg/0.5 mL NDC 51759.

• 413 -32 90 mg/mL NDC 51759.

• 414 -32 Each prefilled syringe is equipped with a 29-gauge fixed 1/2 inch needle equipped with a passive safety device and a needle cover.

Not made with natural rubber latex.

Vial 45 mg/0.5 mL NDC 51759.

• 413 -13 For Intravenous Infusion Single-dose Vial 130 mg/26 mL (5 mg/mL) NDC 51759.

• 415 -13 Storage and Stability Store Ustekinumab-aekn vials and prefilled syringes refrigerated between 36°F to 46°F (2°C to 8°C).

Ustekinumab-aekn vials upright.

Keep the product in the original carton to protect from light until the time of use.

Do not freeze.

Do not shake.

If needed, individual prefilled syringes may be stored at room temperature up to 86°F (30°C) for a maximum single period of up to 30 days in the original carton to protect from light.

Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided.

Once a syringe has been stored at room temperature, do not return to the refrigerator.

Discard the syringe if not used within 30 days at room temperature storage.

Do not use

Ustekinumab-aekn after the expiration date on the carton or on the prefilled syringe.

If needed, Ustekinumab-aekn 130 mg vials may be stored at room temperature up to 86°F (30°C) for a maximum single period of up to 7 days, in the original carton to protect from light.

Once a vial has been stored at room temperature, do not return to the refrigerator.

Discard the vial if not used within 7 days at room temperature storage.

Ustekinumab-aekn after the expiration date on the carton or on the vial.

Risk Summary Available data from the Organization of Teratology Information Specialists (OTIS)/Mother To Baby Pregnancy Registry, published literature and pharmacovigilance in pregnant women have not identified an ustekinumab-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

There are risks to the mother and the fetus associated with inflammatory bowel disease (IBD) in pregnancy.

In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the maximum recommended human dose (MRHD).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-associated Maternal and

Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with IBD is associated with increased disease activity.

Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Fetal/Neonatal Adverse Reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester.

Therefore, ustekinumab products may be present in infants exposed in utero.

The potential clinical impact of ustekinumab products exposure in infants exposed in utero should be considered.

An observational pregnancy registry conducted by (OTIS)/Mother To Baby in the U.S. and Canada (enrollment between and 2019) assessed the risk of major birth defects, pattern of major and minor anomalies in live-born infants, miscarriage, and adverse infant outcomes in women with ustekinumab exposure.

In the registry study, there were 101 participants and 107 pregnancies with exposure to ustekinumab (88 prospective; 19 retrospective).

Most participants had a primary indication of CD (65.4%) or psoriasis (30.8%).

The pregnancy registry did not identify a ustekinumab-associated risk of major birth defects, pattern of major or minor anomalies, increased risk of miscarriage or adverse infant outcomes.

Methodological limitations of the registry include small sample size, lack of an internal comparison group, a mix of prospective and retrospective reports, and unmeasured confounders.

The conclusions from the pregnancy registry were consistent with the published literature and pharmacovigilance.

Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys.

No teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period of organogenesis.

Serum concentrations of ustekinumab in pregnant monkeys were greater than 100 times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab weekly for 4 weeks.

In a combined embryo-fetal development and pre.

• and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures greater than 100 times the MRHD from the beginning of organogenesis to Day 33 after delivery.

Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related-effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age.

Plaque Psoriasis The safety and effectiveness of Ustekinumab-aekn have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 years of age and older who are candidates for phototherapy or systemic therapy.

Use of

Ustekinumab-aekn in pediatric patients to less than 17 years of age is supported by evidence from a multicenter, randomized, 60 week trial (Ps STUDY 3) of ustekinumab that included a 12 week, double-blind, placebo-controlled, parallel group portion, in 110 pediatric subjects 12 years of age and older.

Ustekinumab-aekn in pediatric patients to 11 years of age is supported by evidence from an open-label, single-arm, efficacy, safety, and pharmacokinetics trial (Ps STUDY 4) of ustekinumab in 44 subjects.

The safety and effectiveness of

Ustekinumab-aekn have not been established in pediatric patients less than 6 years of age with plaque psoriasis.

Psoriatic Arthritis The safety and effectiveness of Ustekinumab-aekn have been established for treatment of psoriatic arthritis in pediatric patients 6 years of age and older.

Ustekinumab-aekn in these age groups is supported by evidence from adequate and well controlled trials of ustekinumab in adult subjects with psoriasis and PsA, pharmacokinetic data from adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and safety data of ustekinumab from two clinical trials in 44 pediatric subjects to 11 years old with psoriasis and 110 pediatric subjects 12 years of age and older with psoriasis.

The observed pre-dose (trough) concentrations are generally comparable between adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric subjects with PsA.

Ustekinumab-aekn have not been established in pediatric patients less than 6 years old with psoriatic arthritis.

Crohn’s Disease and Ulcerative Colitis The safety and effectiveness of Ustekinumab-aekn have not been established in pediatric patients with Crohn’s disease or ulcerative colitis.

Of the 6709 subjects exposed to ustekinumab, a total of were 65 years of age or older (183 subjects with plaque psoriasis, 65 subjects with psoriatic arthritis, 58 subjects with Crohn’s disease, and 34 subjects with ulcerative colitis), and 40 subjects were 75 years of age or older.

Clinical trials of ustekinumab did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.