STELARA

Ustekinumab is a human immunoglobulin (Ig) G1 kappa monoclonal antibody directed against interleukin(IL)-12 and IL-23, which are cytokines that are involved in immune and inflammatory responses.

It was generated via recombinant human

IL-12 immunization of human Ig (hu-Ig) transgenic mice.

It is a targeted biologic disease-modifying anti-rheumatic drug (bDMARDs) that is used in the management of various inflammatory conditions that involve the activation of IL-12 and IL-23 signalling pathways.

The therapeutic use of the drug started in Canada, the US, and Europe since 2009 when it was first approved for the treatment of adult patients with moderate to severe plaque psoriasis and active psoriatic arthritis, alone or in combination with methotrexate.

In September 2016, ustekinumab was additionally approved for the management of moderate to severe Crohn's disease in selected adult patients.

In October 2019, it was also approved by the FDA for use to manage moderately to severely active ulcerative colitis in adults.

Ustekinumab is currently the first and only approved biologic therapy for ulcerative colitis that targets the interleukin (IL)-12 and IL-23 cytokines.

The dosing regimen for ustekinumab is based on the patient's weight and there are intravenous and subcutaneous formulations of the drug based on the dosing schedule and condition being treated.

Ustekinumab is commonly marketed under the trade name STELARA.

Ustekinumab biosimilars are available in some markets, including Wezlana 11, Yesintek 16, Selarsdi 17, Otulfi and Pyzchiva in the US, Jamteki (AVT04) 12, Steqeyma and Wezlana in Canada., Uzpruvo in the EU 14.

Ustekinumab is indicated for the management of moderate to severe plaque psoriasis in patients 6 years of age and older who are candidates for phototherapy or systemic therapy.

In adult patients, it is also indicated for the management of active psoriatic arthritis (PsA) alone or in combination with methotrexate, moderately to severely active Crohn's disease (CD) and moderately to severely active ulcerative colitis.

Ustekinumab is a targeted antibody therapy that suppresses immune responses.

It acts by reducing the signaling pathways of pro-inflammatory cytokines IL-12 and IL-23, which play a role in various inflammatory conditions.

It downregulates the gene expression of inflammatory cytokines and chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8.

The formation of cytochrome

P-450 enzymes may be altered by elevated levels of certain cytokines during chronic inflammation.

Research shows that there is an inverse relationship between plasma levels of inflammatory cytokines and CYP450 enzyme formation and activity.

While ustekinumab may potentially normalize the formation of CYP enzymes and enhance the CYP-mediated metabolism of drugs, 5 there were no clinically significant effects on human CYP enzyme activities.

The steady-state was achieved by 28 weeks after multiple subcutaneous dose administration in adult patients with psoriasis.

The median

Tmax following a single subcutaneous dose administration of 45 mg and 90 mg in adults with psoriasis was 13.5 days and 7 days, respectively.

Cmax in the same group of patients was 2.4 μg/mL and 5.3 μg/mL at doses of 45 mg and 90 mg, respectively.

AUC was 84.9 μg-day/mL and 226.9 μg-day/mL, respectively.

Following an intravenous induction dose administration, the mean ± SD Cmax was 125.2 ± 33.6 mcg/mL in patients with Crohn's disease and 129.1 ± 27.6 mcg/mL in patients with ulcerative colitis.

The systemic exposure of ustekinumab (Cmax and AUC) increases in a linear or dose-proportional manner following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis.

The estimated absolute bioavailability (F) of ustekinumab following a single subcutaneous dose administration in patients with psoriasis is 57.2%.

The total volume of distribution at steady-state was 4.62 L in patients with Crohn's disease and 4.4 L in patients with ulcerative colitis.

The median apparent volume of distribution during the terminal phase (Vz/F) ranged from 76-161 mL/kg in patients with psoriasis receiving a single subcutaneous dose.

The metabolic pathway of ustekinumab has not been fully characterized; it is expected to undergo nonspecific protein degradation via catabolic pathways in the same manner as endogenous IgG.

There is limited information on the main route of elimination of ustekinumab; it is expected to undergo renal excretion following degradation.

Following administration of a single subcutaneous dose of 45 mg or 90 mg in patients with psoriasis, the median half-life was 19.8 days and 21.2, respectively.

The estimated median terminal half-life of approximately 19 days in patients with Crohn's disease or ulcerative colitis.

The median apparent clearance (CL/F) following a single subcutaneous administration to patients with psoriasis ranged from 2.7-5.3 mL/day/kg.

In patients with

Crohn's disease, the clearance was 0.19 L/day in patients with Crohn's disease or ulcerative colitis.

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Signs of dose-limiting toxicity were not observed with intravenous administration of single doses up to 6 mg/kg in clinical trials.

Information on overdose of ustekinumab is limited: in the event of overdose, patients should be monitored for any signs and symptoms of drug-related adverse events and appropriate symptomatic treatment should be initiated.

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.