1.1 Plaque Psoriasis (PsO)

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

1.2 Psoriatic Arthritis (PsA)

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

1.3 Crohn's Disease (CD)

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

1.4 Ulcerative Colitis

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

2.1 Recommended Dosage in Plaque Psoriasis

2.2 Recommended Dosage in Psoriatic Arthritis

2.3 Recommended Dosage in Crohn's Disease and Ulcerative Colitis

2.4 General Considerations for Administration

• Ustekinumab is intended for use under the guidance and supervision of a healthcare provider. Ustekinumab 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 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 after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Medication Guide [see Medication Guide] .
• 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 single-dose vial, a 1 mL syringe with a 27 gauge, ½ inch needle is recommended.
• Prior to administration, visually inspect Ustekinumab for particulate matter and discoloration. Ustekinumab is a colorless to light yellow solution and may contain a few small translucent or white particles. Do not use Ustekinumab if it is discolored or cloudy, or if other particulate matter is present. Ustekinumab does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe.

2.5 Instructions for Administration of Ustekinumab Prefilled Syringes Equipped with Needle Safety Guard

Refer to the diagram below for the provided instructions.

To prevent premature activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use.

• Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER or PLUNGER HEAD while removing the NEEDLE COVER or the PLUNGER may move. Do not use the prefilled syringe if it is dropped without the NEEDLE COVER in place.
• Inject Ustekinumab subcutaneously as recommended [see Dosage and Administration (2.1, 2.2, 2.3)] .
• Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is completely between the needle guard wings. Injection of the entire prefilled syringe contents is necessary to activate the needle guard.
  

  

• After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the skin. Slowly take your thumb off the PLUNGER HEAD to allow the empty syringe to move up until the entire needle is covered by the needle guard, as shown by the illustration below:
  

  

• Used syringes should be placed in a puncture-resistant container.

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

Ustekinumab 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 Ustekinumab vials needed based on patient weight (Table 4). Each 26 mL vial of Ustekinumab 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 Ustekinumab to be added (discard 26 mL sodium chloride for each vial of Ustekinumab 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 Ustekinumab 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 Ustekinumab concomitantly in the same intravenous line with other agents.
8. Ustekinumab 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.

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

5.1 Infections

Ustekinumab may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving Ustekinumab [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 Ustekinumab 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 Ustekinumab 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 Ustekinumab and discontinue Ustekinumab for serious or clinically significant infections until the infection resolves or is adequately treated.

5.2 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 Ustekinumab may be susceptible to these types of infections. Consider appropriate diagnostic testing, (e.g., tissue culture, stool culture, as dictated by clinical circumstances).

5.3 Pre-treatment Evaluation for Tuberculosis

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

Avoid administering Ustekinumab to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering Ustekinumab. Consider anti-tuberculosis therapy prior to initiation of Ustekinumab 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 Ustekinumab for signs and symptoms of active tuberculosis during and after treatment.

5.4 Malignancies

Ustekinumab is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received Ustekinumab 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 Ustekinumab 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 Ustekinumab who had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all patients receiving Ustekinumab 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)] .

5.5 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with Ustekinumab [see Adverse Reactions (6.1, 6.3)] . If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue Ustekinumab.

5.6 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 Ustekinumab for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue Ustekinumab.

5.7 Immunizations

Prior to initiating therapy with Ustekinumab, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with Ustekinumab should avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with Ustekinumab 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 Ustekinumab because of the potential risk for shedding from the household contact and transmission to patient.

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

5.8 Noninfectious Pneumonia

Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of Ustekinumab. 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 Ustekinumab and institute appropriate treatment [see Postmarketing Experience (6.3)] .

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab in the trials described below with the incidence of antibodies to other products may be misleading.

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

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

6.3 Postmarketing Experience

The following adverse reactions have been reported during post-approval use of Ustekinumab. 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 Ustekinumab exposure.

Immune system disorders:Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria) .

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.

7.1 Concomitant Therapies

In plaque psoriasis trials the safety of Ustekinumab in combination with immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis trials, concomitant MTX use did not appear to influence the safety or efficacy of Ustekinumab. In Crohn's disease and ulcerative colitis induction trials, 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 Ustekinumab.

7.2 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 Ustekinumab, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of Ustekinumab 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)] .

7.3 Allergen Immunotherapy

Ustekinumab has not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab 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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

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

Ustekinumab 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 2 mL 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).

Ustekinumab for Intravenous Infusion

Available as 130 mg of ustekinumab in 26 mL, supplied as a single-dose 30 mL 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).

12.1 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 vitromodels, 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of Ustekinumab. 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.

13.2 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.

14.1 Adult 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 Ustekinumab. Subjects randomized to Ustekinumab 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 Ustekinumab (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.

14.2 Pediatric Plaque Psoriasis

A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric subjects 12 to 17 years of age 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 Ustekinumab (n = 36), or one-half the recommended dose of Ustekinumab (n = 37) by subcutaneous injection at Weeks 0 and 4 followed by dosing every 12 weeks (q12w). The recommended dose of Ustekinumab 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 Ustekinumab 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.

14.3 Psoriatic Arthritis

The safety and efficacy of Ustekinumab 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 Ustekinumab 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 Ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 11). ACR 70 responses were also higher in the Ustekinumab 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in STUDY 2. Responses were consistent in subjects treated with Ustekinumab 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
		Ustekinumab			Ustekinumab
	Placebo	45 mg	90 mg	Placebo	45 mg	90 mg
* Number of subjects with ≥ 3% BSA psoriasis skin involvement at baseline
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 *	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

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
		Ustekinumab
	Placebo (N = 206)	45 mg (N = 205)	90 mg (N = 204)
* Number of swollen joints counted (0–66) † Number of tender joints counted (0–68) ‡ Visual analogue scale; 0= best, 10=worst. § 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. ¶ CRP: (Normal Range 0.0–1.0 mg/dL)
Number of swollen joints *
Baseline	15	12	13
Mean Change at Week 24	-3	-5	-6
Number of tender joints †
Baseline	25	22	23
Mean Change at Week 24	-4	-8	-9
Subject's assessment of pain ‡
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) §
Baseline	1.2	1.2	1.2
Mean Change at Week 24	-0.1	-0.3	-0.4
CRP (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 Ustekinumab group compared with placebo at Week 24.

14.4 Crohn's Disease

Ustekinumab 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.

14.5 Ulcerative Colitis

Ustekinumab 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).

For Subcutaneous Use

Prefilled Syringes

• 45 mg/0.5 mL (NDC 57894-440-01)
• 90 mg/mL (NDC 57894-441-01)

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 57894-440-03)

For Intravenous Infusion

Single-dose Vial

• 130 mg/26 mL (5 mg/mL) (NDC 57894-444-01)

Storage and Stability

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

Infections

Inform patients that Ustekinumab may lower the ability of their immune system to fight infections and to contact their healthcare provider immediately if they develop any signs or symptoms of infection [see Warnings and Precautions (5.1)] .

Malignancies

Inform patients of the risk of developing malignancies while receiving Ustekinumab [see Warnings and Precautions (5.4)] .

Hypersensitivity Reactions

• Advise patients to seek immediate medical attention if they experience any signs or symptoms of serious hypersensitivity reactions and discontinue Ustekinumab [see Warnings and Precautions (5.5)].
• Inform patients the needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex [see Dosage and Administration (2.4)]

Posterior Reversible Encephalopathy Syndrome (PRES)

Inform patients to immediately contact their healthcare provider if they experience signs and symptoms of PRES (which may include headache, seizures, confusion, or visual disturbances) [see Warnings and Precautions (5.6)] .

Immunizations

Inform patients that Ustekinumab can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.7)] .

Administration

Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use.