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Dosage & administration

DOSAGE AND ADMINISTRATION

Adult Patients with Plaque Psoriasis Subcutaneous Recommended Dosage (2.1 ) :

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 (2.1 ) : Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter.

Weight 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 (2.2 ):

  • 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.

Psoriatic Arthritis Pediatric 6 years of Age and Older Subcutaneous Recommended Dosage (2.2 ): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter.

Weight 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 Dose (2.3 ) :

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 Dosage (2.3 ) :

A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter.

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 [see Clinical Studies (14) ] .

Subcutaneous Pediatric Dosage Regimen

Administer STELARA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.

The recommended dose of STELARA 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 STELARA 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 STELARA 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 Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen. 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

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.

Subcutaneous Pediatric Dosage Regimen

Administer STELARA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.

The recommended dose of STELARA 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 STELARA 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 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. 0.75 mg/kg
60 kg or more 45 mg
greater than 100 kg with co-existent moderate-to-severe plaque psoriasis 90 mg

Recommended Dosage in Crohn's Disease and Ulcerative Colitis

Intravenous Induction Adult Dosage Regimen

A single intravenous infusion dose of STELARA using the weight-based dosage regimen specified in Table 4 [see Instructions for dilution of STELARA 130 mg vial for intravenous infusion (2.5) ] .

Table 4: Initial Intravenous Dosage of STELARA
Body Weight of Patient at the time of dosing Dose Number of 130 mg/26 mL (5 mg/mL) STELARA 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.

General Considerations for Administration

  • STELARA is intended for use under the guidance and supervision of a healthcare provider . STELARA 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 STELARA 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 STELARA after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Instructions for Use [see Instructions for Use] .
  • The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex). The needle cover should not be handled by persons sensitive to 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, ½ inch needle is recommended.
  • Prior to administration, visually inspect STELARA for particulate matter and discoloration. STELARA is a colorless to light yellow solution and may contain a few small translucent or white particles. Do not use STELARA if it is discolored or cloudy, or if other particulate matter is present. STELARA does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe.

Preparation and Administration of STELARA 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohn's Disease and Ulcerative Colitis)

STELARA solution for intravenous infusion must be diluted, prepared, and infused by a healthcare professional using aseptic technique.

  1. Calculate the dose and the number of STELARA vials needed based on patient weight (Table 4). Each 26 mL vial of STELARA contains 130 mg of ustekinumab.
  2. Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume of STELARA to be added (discard 26 mL sodium chloride for each vial of STELARA needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used.
  3. Withdraw 26 mL of STELARA 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.
  4. Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
  5. Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should be completely administered within eight hours of the dilution in the infusion bag.
  6. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer).
  7. Do not infuse STELARA concomitantly in the same intravenous line with other agents.
  8. STELARA does not contain preservatives. Each vial is for a one-time use in only one patient. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements.

Storage

If necessary, the diluted infusion solution may be kept at room temperature up to 25 °C (77 °F) for up to 7 hours. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 8 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.

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Stelara prescribing information

Recent Major Changes
Warnings and Precautions
Serious Hypersensitivity Reactions (5.5 ) 		11/2025
Indications & Usage

INDICATIONS AND USAGE

STELARA 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. (1.1 )
  • active psoriatic arthritis (PsA) . (1.2 )
  • moderately to severely active Crohn's disease (CD) . (1.3 )
  • moderately to severely active ulcerative colitis. (1.4 )

Pediatric patients 6 years and older with:

  • moderate to severe plaque psoriasis (PsO) , who are candidates for phototherapy or systemic therapy. (1.1 )
  • active psoriatic arthritis (PsA) . (1.2 )

Plaque Psoriasis (PsO)

STELARA 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.

Psoriatic Arthritis (PsA)

STELARA is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic arthritis.

Crohn's Disease (CD)

STELARA is indicated for the treatment of adult patients with moderately to severely active Crohn's disease.

Ulcerative Colitis

STELARA is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.

Dosage & Administration

DOSAGE AND ADMINISTRATION

Adult Patients with Plaque Psoriasis Subcutaneous Recommended Dosage (2.1 ) :

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 (2.1 ) : Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter.

Weight 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 (2.2 ):

  • 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.

Psoriatic Arthritis Pediatric 6 years of Age and Older Subcutaneous Recommended Dosage (2.2 ): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter.

Weight 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 Dose (2.3 ) :

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 Dosage (2.3 ) :

A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter.

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 [see Clinical Studies (14) ] .

Subcutaneous Pediatric Dosage Regimen

Administer STELARA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.

The recommended dose of STELARA 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 STELARA 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 STELARA 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 Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen. 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

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.

Subcutaneous Pediatric Dosage Regimen

Administer STELARA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.

The recommended dose of STELARA 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 STELARA 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 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. 0.75 mg/kg
60 kg or more 45 mg
greater than 100 kg with co-existent moderate-to-severe plaque psoriasis 90 mg

Recommended Dosage in Crohn's Disease and Ulcerative Colitis

Intravenous Induction Adult Dosage Regimen

A single intravenous infusion dose of STELARA using the weight-based dosage regimen specified in Table 4 [see Instructions for dilution of STELARA 130 mg vial for intravenous infusion (2.5) ] .

Table 4: Initial Intravenous Dosage of STELARA
Body Weight of Patient at the time of dosing Dose Number of 130 mg/26 mL (5 mg/mL) STELARA 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.

General Considerations for Administration

  • STELARA is intended for use under the guidance and supervision of a healthcare provider . STELARA 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 STELARA 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 STELARA after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Instructions for Use [see Instructions for Use] .
  • The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex). The needle cover should not be handled by persons sensitive to 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, ½ inch needle is recommended.
  • Prior to administration, visually inspect STELARA for particulate matter and discoloration. STELARA is a colorless to light yellow solution and may contain a few small translucent or white particles. Do not use STELARA if it is discolored or cloudy, or if other particulate matter is present. STELARA does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe.

Preparation and Administration of STELARA 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohn's Disease and Ulcerative Colitis)

STELARA solution for intravenous infusion must be diluted, prepared, and infused by a healthcare professional using aseptic technique.

  1. Calculate the dose and the number of STELARA vials needed based on patient weight (Table 4). Each 26 mL vial of STELARA contains 130 mg of ustekinumab.
  2. Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume of STELARA to be added (discard 26 mL sodium chloride for each vial of STELARA needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used.
  3. Withdraw 26 mL of STELARA 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.
  4. Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
  5. Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should be completely administered within eight hours of the dilution in the infusion bag.
  6. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer).
  7. Do not infuse STELARA concomitantly in the same intravenous line with other agents.
  8. STELARA does not contain preservatives. Each vial is for a one-time use in only one patient. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements.

Storage

If necessary, the diluted infusion solution may be kept at room temperature up to 25 °C (77 °F) for up to 7 hours. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 8 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.

Dosage Forms & Strengths

DOSAGE FORMS AND STRENGTHS

STELARA (ustekinumab) is a colorless to light yellow solution and may contain a few small translucent or white particles.

Subcutaneous Injection

  • Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe
  • Injection: 45 mg/0.5 mL solution in a single-dose vial

Intravenous Infusion

  • Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
Pregnancy & Lactation

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Available data from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby STELARA Pregnancy Registry, published literature and pharmacovigilance in pregnant women have not identified a STELARA-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data ) . 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.

Data

Human Data

An observational pregnancy registry conducted by (OTIS)/MotherToBaby in the U.S. and Canada (enrollment between 2013 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 STELARA exposure. In the registry study, there were 101 participants and 107 pregnancies with exposure to STELARA (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 STELARA -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.

Animal Data

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.

Lactation

Risk Summary

Limited data from published literature suggests that ustekinumab is present in human breast milk. There are no available data on the effects of ustekinumab on milk production. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab are unknown. No adverse effects on the breastfed infant causally related to ustekinumab have been identified in the published literature or postmarketing experience.

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

Pediatric Use

Plaque Psoriasis

The safety and effectiveness of STELARA 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 STELARA in pediatric patients 12 to less than 17 years of age is supported by evidence from a multicenter, randomized, 60 week trial (Ps STUDY 3) that included a 12 week, double-blind, placebo-controlled, parallel group portion, in 110 pediatric subjects 12 years of age and older [see Adverse Reactions (6.1) , Clinical Studies (14.2) ] .

Use of STELARA in pediatric patients 6 to 11 years of age is supported by evidence from an open-label, single-arm, efficacy, safety, and pharmacokinetics trial (Ps STUDY 4) in 44 subjects [see Adverse Reactions (6.1) , Pharmacokinetics (12.3) ] .

The safety and effectiveness of STELARA have not been established in pediatric patients less than 6 years of age with plaque psoriasis.

Psoriatic Arthritis

The safety and effectiveness of STELARA have been established for treatment of psoriatic arthritis in pediatric patients 6 years of age and older.

Use of STELARA in these age groups is supported by evidence from adequate and well controlled trials of STELARA 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 from two clinical trials in 44 pediatric subjects 6 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 [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1 , 14.2 , 14.3) ].

The safety and effectiveness of STELARA 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 STELARA have not been established in pediatric patients with Crohn's disease or ulcerative colitis.

Geriatric Use

Of the 6709 subjects exposed to STELARA, a total of 340 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 STELARA did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

Contraindications

CONTRAINDICATIONS

STELARA is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or to any of the excipients in STELARA [see Warnings and Precautions (5.5) ].

Warnings & Precautions

WARNINGS AND PRECAUTIONS

  • Infections : Serious infections have occurred. Avoid starting STELARA during any clinically important active infection. If a serious infection or clinically significant infection develops, discontinue STELARA until the infection resolves. (5.1 )
  • Theoretical Risk for Particular Infections : Serious infections from mycobacteria, salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL-12/IL-23. Consider diagnostic tests for these infections as dictated by clinical circumstances. (5.2 )
  • Tuberculosis (TB) : Evaluate patients for TB prior to initiating treatment with STELARA. Initiate treatment of latent TB before administering STELARA. (5.3 )
  • Malignancies : STELARA may increase risk of malignancy. The safety of STELARA in patients with a history of or a known malignancy has not been evaluated. (5.4 )
  • Serious Hypersensitivity Reactions : If a severe or other clinically significant hypersensitivity reaction occurs, discontinue STELARA immediately and initiate appropriate medical treatment. (5.5 )
  • Posterior Reversible Encephalopathy Syndrome (PRES) : If PRES is suspected, treat promptly, and discontinue STELARA. (5.6 )
  • Immunizations: Avoid use of live vaccines in patients during treatment with STELARA . (5.7 )
  • Noninfectious Pneumonia : Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA. If diagnosis is confirmed, discontinue STELARA and institute appropriate treatment. (5.8 )

Infections

STELARA may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving STELARA [see Adverse Reactions (6.1 , 6.3) ] .

Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical trials included the following:

  • Plaque Psoriasis : diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis, and urinary tract infections.
  • Psoriatic arthritis : cholecystitis.
  • Crohn's disease : anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis.
  • Ulcerative colitis : gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis.

Avoid initiating treatment with STELARA in patients with any clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of STELARA in patients with a chronic infection or a history of recurrent infection.

Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with STELARA and discontinue STELARA for serious or clinically significant infections until the infection resolves or is adequately treated.

Theoretical Risk for Vulnerability to Particular Infections

Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients.

It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA may be susceptible to these types of infections. Consider appropriate diagnostic testing, (e.g., tissue culture, stool culture, as dictated by clinical circumstances).

Pre-treatment Evaluation for Tuberculosis

Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA.

Avoid administering STELARA to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering STELARA. Consider anti-tuberculosis therapy prior to initiation of STELARA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving STELARA for signs and symptoms of active tuberculosis during and after treatment.

Malignancies

STELARA is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA in clinical trials [see Adverse Reactions (6.1) ] . In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology (13) ] .

The safety of STELARA has not been evaluated in patients who have a history of malignancy or who have a known malignancy.

There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving STELARA who had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all patients receiving STELARA for the appearance of non-melanoma skin cancer. Closely follow patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment [see Adverse Reactions (6.1) ] .

Serious Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with STELARA in clinical trials and postmarketing. Some serious hypersensitivity reactions have occurred during the first intravenous dose of STELARA [see Adverse Reactions (6.1 , 6.3) ].

If a severe or clinically significant hypersensitivity reaction occurs, discontinue STELARA immediately and initiate appropriate medical treatment [see Contraindications (4) ].

Posterior Reversible Encephalopathy Syndrome (PRES)

Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis, and Crohn's disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab.

Monitor all patients treated with STELARA for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue STELARA.

Immunizations

Prior to initiating therapy with STELARA, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with STELARA should avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with STELARA or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA because of the potential risk for shedding from the household contact and transmission to patient.

Non-live vaccinations received during a course of STELARA may not elicit an immune response sufficient to prevent disease.

Noninfectious Pneumonia

Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue STELARA and institute appropriate treatment [see Postmarketing Experience (6.3) ] .

Adverse Reactions

ADVERSE REACTIONS

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

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.

Adult Subjects with Plaque Psoriasis

The safety data reflect exposure to STELARA 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 STELARA groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies (14) ] .

Table 5: Adverse Reactions, Reported by ≥1% of Subjects with Plaque Psoriasis and at Higher Rates in the STELARA groups through Week 12 in Ps STUDY 1 and Ps STUDY 2
STELARA
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 1 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 [see Warnings and Precautions (5.6) ] .

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 STELARA-treated subjects), 27% of STELARA-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 STELARA-treated subjects (0.01 per patient-years of follow-up) and in 0.4% of subjects receiving placebo (0.02 per patient-year of follow-up) [see Warnings and Precautions (5.1) ] .

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 STELARA-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).

Malignancies

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 STELARA-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 STELARA-treated subjects (0.52 per hundred patient-years of follow-up) [see Warnings and Precautions (5.4) ] . 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 STELARA-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). 1

Pediatric Subjects with Plaque Psoriasis

The safety of STELARA 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 12 to 17 years old. Ps STUDY 4 evaluated safety for up to 56 weeks in 44 pediatric subjects 6 to 11 years old. The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque psoriasis.

Psoriatic Arthritis

The safety of STELARA 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 STELARA 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 STELARA-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 STELARA was assessed in 1407 subjects with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] greater than or equal to 220 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 STELARA 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo [see Dosage and Administration (2.3) ] . Subjects who were responders in either trial CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA 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 [see Clinical Studies (14.4) ] .

The overall safety profile of STELARA 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 6 and 7, respectively.

Table 6: Common Adverse Reactions Through Week 8 in Trials CD-1 and CD-2 occurring in ≥3% of STELARA-Treated Subjects and Higher Than Subjects Receiving Placebo
Placebo STELARA
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 44 in Trial CD-3 occurring in ≥3% of STELARA-Treated Subjects and Higher Than Subjects Receiving Placebo
Placebo STELARA
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 [see Warnings and Precautions (5.1) ] .

Malignancies

With up to one year of treatment in the Crohn's disease clinical trials, 0.2% of STELARA-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 STELARA-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 STELARA 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 STELARA). 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 STELARA dose (0.08% of subjects receiving intravenous STELARA). These subjects were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour [see Warnings and Precautions (5.5) ] .

Ulcerative Colitis

The safety of STELARA 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 [see Clinical Studies (14.5) ] . The overall safety profile of STELARA in subjects with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of STELARA-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 [see Warnings and Precautions (5.1) ] .

Malignancies

With up to one year of treatment in the ulcerative colitis clinical trials, 0.4% of STELARA-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 STELARA-treated subjects (0.64 events per hundred patient-years) and 0.2% of subjects receiving placebo (0.40 events per hundred patient-years).

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 studies of other ustekinumab products.

Approximately 6 to 12.4% of subjects treated with STELARA in clinical trials in subjects with plaque psoriasis and psoriatic arthritis developed antibodies to ustekinumab, which were generally low-titer. In clinical trials in subjects with plaque psoriasis, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In trials in subjects with plaque psoriasis, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing antibodies.

In clinical trials in subjects with Crohn’s disease and ulcerative colitis, 2.9% and 4.6% of subjects, respectively, developed antibodies to ustekinumab when treated with STELARA for approximately one year. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of STELARA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to STELARA exposure.

Immune system disorders: Hypersensitivity reactions (e.g., anaphylaxis, angioedema, dyspnea, rash, urticaria), including a fatal case that presented with chest tightness and dyspnea during infusion of the first dose .

Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis).

Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES) .

Respiratory, thoracic, and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia.

Skin reactions : Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.

Drug Interactions

DRUG INTERACTIONS

Concomitant Therapies

In trials in subjects with plaque psoriasis the safety of STELARA in combination with immunosuppressive agents or phototherapy has not been evaluated . In trials in subjects with psoriatic arthritis, concomitant MTX use did not appear to influence the safety or efficacy of STELARA. In trials in subjects with Crohn's disease (CD-1 and CD-2) and ulcerative colitis (UC-1), immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately 30% of subjects and corticosteroids were used concomitantly in approximately 40% and 50% of Crohn's disease and ulcerative colitis subjects, respectively. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of STELARA.

CYP450 Substrates

The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL-1, IL-6, TNFα, IFN) during chronic inflammation. Thus, use of STELARA, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of STELARA in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and adjust the individual dosage of the CYP substrate as needed. See the prescribing information of specific CYP substrates.

A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical Pharmacology (12.3) ] .

Allergen Immunotherapy

STELARA has not been evaluated in patients who have undergone allergy immunotherapy. STELARA may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis.

Description

DESCRIPTION

Ustekinumab, a human IgG1κ monoclonal antibody, is a human interleukin-12 and -23 antagonist. Using DNA recombinant technology, ustekinumab is produced in a murine cell line (Sp2/0). The manufacturing process contains steps for the clearance of viruses. Ustekinumab is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons.

STELARA ® (ustekinumab) injection is a sterile, preservative-free, colorless to light yellow solution and may contain a few small translucent or white particles with pH of 5.7– 6.3.

STELARA for Subcutaneous Use

Available as 45 mg of ustekinumab in 0.5 mL and 90 mg of ustekinumab in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 27 gauge fixed ½ inch needle and as 45 mg of ustekinumab in 0.5 mL in a single-dose Type I glass vial with a coated stopper. The syringe is fitted with a passive needle guard and a needle cover that contains dry natural rubber (a derivative of latex).

Each 0.5 mL prefilled syringe or vial delivers 45 mg ustekinumab, L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg).

Each 1 mL prefilled syringe delivers 90 mg ustekinumab, L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg).

STELARA for Intravenous Infusion

Available as 130 mg of ustekinumab in 26 mL, supplied as a single-dose Type I glass vial with a coated stopper.

Each 26 mL vial delivers 130 mg ustekinumab, EDTA disodium salt dihydrate (0.52 mg), L-histidine (20 mg), L-histidine hydrochloride monohydrate (27 mg), L-methionine (10.4 mg), Polysorbate 80 (10.4 mg), and sucrose (2210 mg).

Pharmacology

CLINICAL PHARMACOLOGY

Mechanism of Action

Ustekinumab is a human IgG1қ monoclonal antibody that binds 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 was 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, was shown to be protective.

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 [see Clinical Studies (14.5) ] .

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 STELARA 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.

Distribution

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.

Elimination

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.

Metabolism

The metabolic pathway of ustekinumab has not been characterized. As a human IgG1κ monoclonal antibody, ustekinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

Specific Populations

Weight

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.

Age: 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.

Age: Pediatric Population

Following multiple recommended doses of STELARA 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 6 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 STELARA.

Nonclinical Toxicology

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of STELARA. Published literature showed that administration of murine IL-12 caused an anti-tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV-induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown.

No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated females.

No effects on fertility were observed in female mice that were administered an analogous IL-12/IL-23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy.

Animal Toxicology and/or Pharmacology

In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection.

Clinical Studies

CLINICAL STUDIES

Adult Subjects with Plaque Psoriasis

Two multicenter, randomized, double-blind, placebo-controlled trials (Ps STUDY 1 and Ps STUDY 2) enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the trials.

Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The trials had the same design through Week 28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of STELARA. Subjects randomized to STELARA received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4 crossed over to receive STELARA (either 45 mg or 90 mg) at Weeks 12 and 16.

In both trials, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2. Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and 43% receiving prior biologic therapy. A total of 28% of subjects had a history of psoriatic arthritis.

In both trials, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physician's Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician's overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling.

Clinical Response

The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 8 below.

Table 8: Clinical Outcomes at Week 12 in Adult Subjects with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2
Ps STUDY 1 Ps STUDY 2
STELARA STELARA
Placebo 45 mg 90 mg Placebo 45 mg 90 mg
Subjects randomized 255 255 256 410 409 411
PASI 75 response 8 (3%) 171 (67%) 170 (66%) 15 (4%) 273 (67%) 311 (76%)
PGA of Cleared or Minimal 10 (4%) 151 (59%) 156 (61%) 18 (4%) 277 (68%) 300 (73%)

Examination of age, gender, and race subgroups did not identify differences in response to STELARA among these subgroups.

In subjects who weighed 100 kg or less, response rates were comparable with both the 45 mg and 90 mg doses; however, in subjects who weighed greater than 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing (Table 9 below).

Table 9: Clinical Outcomes by Weight at Week 12 in Adult Subjects with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2
Ps STUDY 1 Ps STUDY 2
STELARA STELARA
Placebo 45 mg 90 mg Placebo 45 mg 90 mg
Subjects randomized 255 255 256 410 409 411
PASI 75 response Subjects were dosed with trial medication at Weeks 0 and 4.
≤100 kg 4% 74% 65% 4% 73% 78%
6/166 124/168 107/164 12/290 218/297 225/289
>100 kg 2% 54% 68% 3% 49% 71%
2/89 47/87 63/92 3/120 55/112 86/121
PGA of Cleared or Minimal
≤100 kg 4% 64% 63% 5% 74% 75%
7/166 108/168 103/164 14/290 220/297 216/289
>100 kg 3% 49% 58% 3% 51% 69%
3/89 43/87 53/92 4/120 57/112 84/121

Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at Week 40 to either continued dosing of STELARA (STELARA at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomized to STELARA treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks.

Pediatric Subjects with Plaque Psoriasis

A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric subjects 12 years of age and older with a minimum BSA involvement of 10%, a PASI score greater than or equal to 12, and a PGA score greater than or equal to 3, who were candidates for phototherapy or systemic therapy and whose disease was inadequately controlled by topical therapy.

Subjects were randomized to receive placebo (n = 37), the recommended dose of STELARA (n = 36), or one-half the recommended dose of STELARA (n = 37) by subcutaneous injection at Weeks 0 and 4 followed by dosing every 12 weeks (q12w). The recommended dose of STELARA was 0.75 mg/kg for subjects weighing less than 60 kg, 45 mg for subjects weighing 60 kg to 100 kg, and 90 mg for subjects weighing greater than 100 kg. At Week 12, subjects who received placebo were crossed over to receive STELARA at the recommended dose or one-half the recommended dose.

Of the pediatric subjects, approximately 63% had prior exposure to phototherapy or conventional systemic therapy and approximately 11% had prior exposure to biologics.

The endpoints were the proportion of subjects who achieved a PGA score of cleared (0) or minimal (1), PASI 75, and PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first administration of trial agent.

Clinical Response

The efficacy results at Week 12 for Ps STUDY 3 are presented in Table 10.

Table 10: Efficacy Results at Week 12 in Pediatric Subjects 12 Years of Age and Older with Plaque Psoriasis in Ps STUDY 3
Ps STUDY 3
Placebo
n (%) 		STELARA Using the weight-based dosage regimen specified in Table 1 and Table 2.
n (%)
N 37 36
PGA
PGA of cleared (0) or minimal (1) 2 (5.4%) 25 (69.4%)
PASI
PASI 75 responders 4 (10.8%) 29 (80.6%)
PASI 90 responders 2 (5.4%) 22 (61.1%)

Psoriatic Arthritis

The safety and efficacy of STELARA was assessed in 927 subjects (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled trials in adult subjects 18 years of age and older with active PsA (≥5 swollen joints and ≥5 tender joints) despite nonsteroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Subjects in these trials had a diagnosis of PsA for at least 6 months. Subjects with each subtype of PsA were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the patients, respectively, had enthesitis and dactylitis at baseline.

Subjects were randomized to receive treatment with STELARA 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% of subjects continued on stable doses of MTX (≤25 mg/week). The primary endpoint was the percentage of subjects achieving ACR 20 response at Week 24.

In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the subjects, respectively, had been previously treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed. In PsA STUDY 2, 58% (n=180) of the subjects had been previously treated with TNF blocker, of whom over 70% had discontinued their TNF blocker treatment for lack of efficacy or intolerance at any time.

Clinical Response

In both trials, a greater proportion of subjects achieved ACR 20, ACR 50 and PASI 75 response in the STELARA 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 11 ). ACR 70 responses were also higher in the STELARA 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in STUDY 2. Responses were consistent in subjects treated with STELARA alone or in combination with methotrexate. Responses were similar in subjects regardless of prior TNFα exposure.

Table 11: ACR 20, ACR 50, ACR 70 and PASI 75 Responses In PsA STUDY 1 And PsA STUDY 2 At Week 24
PsA STUDY 1 PsA STUDY 2
STELARA STELARA
Placebo 45 mg 90 mg Placebo 45 mg 90 mg
Number of subjects randomized 206 205 204 104 103 105
ACR 20 response, N (%) 47 (23%) 87 (42%) 101 (50%) 21 (20%) 45 (44%) 46 (44%)
ACR 50 response, N (%) 18 (9%) 51 (25%) 57 (28%) 7 (7%) 18 (17%) 24 (23%)
ACR 70 response, N (%) 5 (2%) 25 (12%) 29 (14%) 3 (3%) 7 (7%) 9 (9%)
Number of subjects with ≥ 3% BSA Number of subjects with ≥ 3% BSA psoriasis skin involvement at baseline 146 145 149 80 80 81
PASI 75 response, N (%) 16 (11%) 83 (57%) 93 (62%) 4 (5%) 41 (51%) 45 (56%)

The percent of subjects achieving ACR 20 responses by visit is shown in Figure 1.

Figure 1: Percent of subjects achieving ACR 20 response through Week 24
PsA STUDY 1
Referenced Image

The results of the components of the ACR response criteria are shown in Table 12.

Table 12: Mean Change From Baseline In ACR Components At Week 24
PsA STUDY 1
STELARA
Placebo
(N = 206) 		45 mg
(N = 205) 		90 mg
(N = 204)
Number of swollen joints Number of swollen joints counted (0–66)
Baseline 15 12 13
Mean Change at Week 24 -3 -5 -6
Number of tender joints Number of tender joints counted (0–68)
Baseline 25 22 23
Mean Change at Week 24 -4 -8 -9
Subject's assessment of pain Visual analogue scale; 0= best, 10=worst.
Baseline 6.1 6.2 6.6
Mean Change at Week 24 -0.5 -2.0 -2.6
Subject global assessment
Baseline 6.1 6.3 6.4
Mean Change at Week 24 -0.5 -2.0 -2.5
Physician global assessment
Baseline 5.8 5.7 6.1
Mean Change at Week 24 -1.4 -2.6 -3.1
Disability index (HAQ) Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient's ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.
Baseline 1.2 1.2 1.2
Mean Change at Week 24 -0.1 -0.3 -0.4
CRP (mg/dL) CRP: (Normal Range 0.0–1.0 mg/dL)
Baseline 1.6 1.7 1.8
Mean Change at Week 24 0.01 -0.5 -0.8

An improvement in enthesitis and dactylitis scores was observed in each STELARA group compared with placebo at Week 24.

Physical Function

STELARA-treated subjects showed improvement in physical function compared to subjects receiving placebo as assessed by HAQ-DI at Week 24. In both trials, the proportion of HAQ-DI responders (≥0.3 improvement in HAQ-DI score) was greater in the STELARA 45 mg and 90 mg groups compared to placebo at Week 24.

Crohn's Disease

STELARA was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult subjects with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220 to 450). There were two 8-week intravenous induction trials(CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal maintenance trial (CD-3) representing 52 weeks of therapy. Subjects in CD-1 had failed or were intolerant to treatment with one or more TNF blockers, while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a TNF blocker.

Trial CD-3

The maintenance trial (CD-3), evaluated 388 subjects who achieved clinical response (≥100 point reduction in CDAI score) at Week 8 with either induction dose of STELARA in trials CD-1 or CD-2. Subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA every 8 weeks or placebo for 44 weeks (see Table 14 ).

Table 14: Clinical Response and Remission In CD-3 (Week 44; 52 Weeks From Initiation Of Induction Dose)
Placebo The placebo group consisted of subjects who were in response to STELARA and were randomized to receive placebo at the start of maintenance therapy. 90 mg STELARA every 8 weeks Treatment difference and 95% CI
N = 131 Subjects who achieved clinical response to STELARA at the end of the induction trial. N = 128
Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at least 100 points or being in clinical remission
Clinical Remission 47 (36%) 68 (53%) p < 0.01 17% (5%, 29%)
Clinical Response 58 (44%) 76 (59%) 0.01≤ p < 0.05 15% (3%, 27%)
Clinical Remission in patients in remission at the start of maintenance therapy Subjects in remission at the end of maintenance therapy who were in remission at the start of maintenance therapy. This does not account for any other time point during maintenance therapy. 36/79 (46%) 52/78 (67%) 21% (6%, 36%)

At Week 44, 47% of subjects who received STELARA were corticosteroid-free and in clinical remission, compared to 30% of subjects in the placebo group.

At Week 0 of trial CD-3, 34/56 (61%) STELARA-treated subjects who previously failed or were intolerant to TNF blocker therapies were in clinical remission and 23/56 (41%) of these subjects were in clinical remission at Week 44. In the placebo arm, 27/61 (44%) subjects were in clinical remission at Week 0 while 16/61 (26%) of these subjects were in remission at Week 44.

At Week 0 of trial CD-3, 46/72 (64%) STELARA-treated subjects who had previously failed immunomodulator therapy or corticosteroids (but not TNF blockers) were in clinical remission and 45/72 (63%) of these subjects were in clinical remission at Week 44. In the placebo arm, 50/70 (71%) of these subjects were in clinical remission at Week 0 while 31/70 (44%) were in remission at Week 44. In the subset of these subjects who were also naïve to TNF blockers, 34/52 (65%) of STELARA-treated subjects were in clinical remission at Week 44 as compared to 25/51 (49%) in the placebo arm.

Subjects who were not in clinical response 8 weeks after STELARA induction were not included in the primary efficacy analyses for trial CD-3; however, these subjects were eligible to receive a 90 mg subcutaneous injection of STELARA upon entry into trial CD-3. Of these subjects, 102/219 (47%) achieved clinical response eight weeks later and were followed for the duration of the trial.

Ulcerative Colitis

STELARA was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1 and UC-2 (NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response to or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab), corticosteroids, and/or 6-MP or AZA therapy. The 8-week intravenous induction trial (UC-1) was followed by the 44-week subcutaneous randomized withdrawal maintenance trial (UC-2) for a total of 52 weeks of therapy.

Disease assessment was based on the Mayo score, which ranged from 0 to 12 and has four subscores that were each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on centrally-reviewed endoscopy, and physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (Week 0) as Mayo score of 6 to 12, including a Mayo endoscopy subscore ≥2. An endoscopy score of 2 was defined by marked erythema, absent vascular pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration. At baseline, subjects had a median Mayo score of 9, with 84% of subjects having moderate disease (Mayo score 6–10) and 15% having severe disease (Mayo score 11–12).

Subjects in these trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone).

Trial UC-1

In UC-1, 961 subjects were randomized at Week 0 to a single intravenous administration of STELARA of approximately 6 mg/kg, 130 mg (a lower dose than recommended), or placebo. Subjects enrolled in UC-1 had to have failed therapy with corticosteroids, immunomodulators or at least one biologic. A total of 51% had failed at least one biologic and 17% had failed both a TNF blocker and an integrin receptor blocker. Of the total population, 46% had failed corticosteroids or immunomodulators but were biologic-naïve and an additional 3% had previously received but had not failed a biologic. At induction baseline and throughout the trial, approximately 52% subjects were receiving oral corticosteroids, 28% subjects were receiving immunomodulators (AZA, 6-MP, or MTX) and 69% subjects were receiving aminosalicylates.

The primary endpoint was clinical remission at Week 8. Clinical remission with a definition of: Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0 (no rectal bleeding), and Mayo endoscopy subscore of 0 or 1 (Mayo endoscopy subscore of 0 defined as normal or inactive disease and Mayo subscore of 1 defined as presence of erythema, decreased vascular pattern and no friability) is provided in Table 15.

The secondary endpoints were clinical response, endoscopic improvement, and histologic-endoscopic mucosal improvement. Clinical response with a definition of (≥ 2 points and ≥ 30% decrease in modified Mayo score, defined as 3-component Mayo score without the Physician's Global Assessment, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1), endoscopic improvement with a definition of Mayo endoscopy subscore of 0 or 1, and histologic-endoscopic mucosal improvement with a definition of combined endoscopic improvement and histologic improvement of the colon tissue [neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue] are provided in Table 15.

In UC-1, a significantly greater proportion of subjects treated with STELARA (at the recommended dose of approximately 6 mg/kg dose) were in clinical remission and response and achieved endoscopic improvement and histologic-endoscopic mucosal improvement compared to placebo (see Table 15 ).

Table 15: Proportion of Subjects Meeting Efficacy Endpoints at Week 8 in UC-1

Endpoint 		Placebo
N = 319 		STELARA Infusion dose of STELARA using the weight-based dosage regimen specified in Table 4.
N = 322 		Treatment difference and 97.5% CI Adjusted treatment difference (97.5% CI)
N % N %
Clinical Remission Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). 22 7% 62 19% 12%
(7%, 18%) p < 0.001
Bio-naïve An additional 7 subjects on placebo and 9 subjects on STELARA (6 mg/kg) had been exposed to, but had not failed, biologics. 14/151 9% 36/147 24%
Prior biologic failure 7/161 4% 24/166 14%
Endoscopic Improvement Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). 40 13% 80 25% 12%
(6%, 19%)
Bio-naïve 28/151 19% 43/147 29%
Prior biologic failure 11/161 7% 34/166 20%
Clinical Response Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. 99 31% 186 58% 27%
(18%, 35%)
Bio-naïve 55/151 36% 94/147 64%
Prior biologic failure 42/161 26% 86/166 52%
Histologic-Endoscopic Mucosal Improvement Histologic-endoscopic mucosal improvement was defined as combined endoscopic improvement (Mayo endoscopy subscore of 0 or 1) and histologic improvement of the colon tissue (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue). 26 8% 54 17% 9%
(3%, 14%)
Bio-naïve 19/151 13% 30/147 20%
Prior biologic failure 6/161 4% 21/166 13%

The relationship of histologic-endoscopic mucosal improvement, as defined in UC-1, at Week 8 to disease progression and long-term outcomes was not evaluated during UC-1.

Rectal Bleeding and Stool Frequency Subscores

Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in STELARA-treated subjects.

Trial UC-2

The maintenance trial (UC-2) evaluated 523 subjects who achieved clinical response 8 weeks following the intravenous administration of either induction dose of STELARA in UC-1. These subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA every 8 weeks, or every 12 weeks (a lower dose than recommended), or placebo for 44 weeks.

The primary endpoint was the proportion of subjects in clinical remission at Week 44. The secondary endpoints included the proportion of subjects maintaining clinical response at Week 44, the proportion of subjects with endoscopic improvement at Week 44, the proportion of subjects with corticosteroid-free clinical remission at Week 44, and the proportion of subjects maintaining clinical remission at Week 44 among subjects who achieved clinical remission 8 weeks after induction.

Results of the primary and secondary endpoints at Week 44 in subjects treated with STELARA at the recommended dosage (90 mg every 8 weeks) compared to the placebo are shown in Table 16.

Table 16: Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction Dose)
Endpoint Placebo The placebo group consisted of subjects who were in response to STELARA and were randomized to receive placebo at the start of maintenance therapy.
N = 175 Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. 		90 mg STELARA every 8 weeks
N = 176 		Treatment difference and 95% CI
N % N %
Clinical Remission Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). 46 26% 79 45% 19%
(9%, 28%) p =<0.001
Bio-naïve An additional 3 subjects on placebo and 6 subjects on STELARA had been exposed to, but had not failed, biologics. 30/84 36% 39/79 49%
Prior biologic failure 16/88 18% 37/91 41%
Maintenance of Clinical Response at Week 44 84 48% 130 74% 26%
(16%, 36%)
Bio-naïve 49/84 58% 62/79 78%
Prior biologic failure 35/88 40% 64/91 70%
Endoscopic Improvement Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). 47 27% 83 47% 20%
(11%, 30%)
Bio-naïve 29/84 35% 42/79 53%
Prior biologic failure 18/88 20% 38/91 42%
Corticosteroid-free Clinical Remission Corticosteroid-free clinical remission was defined as subjects in clinical remission and not receiving corticosteroids at Week 44. 45 26% 76 43% 17%
(8%, 27%)
Bio-naïve 30/84 36% 38/79 48%
Prior biologic failure 15/88 17% 35/91 38%
Maintenance of Clinical Remission at Week 44 in subjects who achieved clinical remission 8 weeks after induction 18/50 36% 27/41 66% 31%
(12%, 50%) p=0.004
Bio-naïve 12/27 44% 14/20 70%
Prior biologic failure 6/23 26% 12/18 67%

Other Endpoints

Week 16 Responders to Ustekinumab Induction

Subjects who were not in clinical response 8 weeks after induction with STELARA in UC-1 were not included in the primary efficacy analyses for trial UC-2; however, these subjects were eligible to receive a 90 mg subcutaneous injection of STELARA at Week 8. Of these subjects, 55/101 (54%) achieved clinical response eight weeks later (Week 16) and received STELARA 90 mg subcutaneously every 8 weeks during the UC-2 trial. At Week 44, there were 97/157 (62%) subjects who maintained clinical response and there were 51/157 (32%) who achieved clinical remission.

Histologic-Endoscopic Mucosal Improvement at Week 44

The proportion of subjects achieving histologic-endoscopic mucosal improvement during maintenance treatment in UC-2 was 75/172 (44%) among subjects on STELARA and 40/172 (23%) in subjects on placebo at Week 44. The relationship of histologic-endoscopic mucosal improvement, as defined in UC-2, at Week 44 to progression of disease or long-term outcomes was not evaluated in UC-2.

Endoscopic Normalization

Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0. At Week 8 in UC-1, endoscopic normalization was achieved in 25/322 (8%) of subjects treated with STELARA and 12/319 (4%) of subjects in the placebo group. At Week 44 of UC-2, endoscopic normalization was achieved in 51/176 (29%) of subjects treated with STELARA and in 32/175 (18%) of subjects in placebo group.

How Supplied/Storage & Handling

HOW SUPPLIED/STORAGE AND HANDLING

STELARA ® (ustekinumab) injection is a sterile, preservative-free, colorless to light yellow solution and may contain a few small translucent or white particles. It is supplied as individually packaged, single-dose prefilled syringes or single-dose vials.

For Subcutaneous Use

Prefilled Syringes

  • 45 mg/0.5 mL (NDC 57894-060-03)
  • 90 mg/mL (NDC 57894-061-03)

Each prefilled syringe is equipped with a 27 -gauge fixed ½ inch needle, a needle safety guard, and a needle cover that contains dry natural rubber.

Single-dose Vial

  • 45 mg/0.5 mL (NDC 57894-060-02)

For Intravenous Infusion

Single-dose Vial

  • 130 mg/26 mL (5 mg/mL) (NDC 57894-054-27)

Storage and Stability

Store STELARA vials and prefilled syringes refrigerated between 2 °C to 8 °C (36 °F to 46 °F). Store STELARA 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 30 °C (86 °F) 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 STELARA after the expiration date on the carton or on the prefilled syringe.

Instructions for Use
Mechanism of Action

Mechanism of Action

Ustekinumab is a human IgG1қ monoclonal antibody that binds 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 was 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, was shown to be protective.

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